Efficient ring-closure approach via copper-catalyzed reactions of sulfonyl azide, terminal alkynes and alcohols/amines

Article abstract of DOI:10.1055/s-2007-973883

We have developed a general and efficient method for synthesis of medium- and large-sized heterocycles via copper-catalyzed reactions of sulfonyl azide, terminal alkynes (or bisalkyne) and alcohols/amines (diamines) at room temperature, and the highly practical method provides an entry toward diverse medium- and large-sized heterocycles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-973883

LETTER
901
Efficient Ring-Closure Approach via Copper-Catalyzed Reactions of Sulfonyl
Azide, Terminal Alkynes and Alcohols/Amines
C
opper-Catalyzed
i
Reactio
n
ns of Sulfon
g
yl
A
zide
,
T
ermina
J
A
lkynes
i
a
ndAlncohols/Amin a
,
e
s
Hua Fu,*a Yingwu Yin,a Yuyang Jiang,a,b Yufen Zhaoa
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
b
Key Laboratory of Chemical Biology, Guangdong Province, College of Shenzhen, Tsinghua University, Shenzhen 518057,
P. R. of China
Received 22 November 2006
of medium- and large-sized ring compounds applying
copper-catalyzed three-component reactions of sulfonyl
azide, terminal alkynes and alcohols or amines.
Abstract: We have developed a general and efficient method for
synthesis of medium- and large-sized heterocycles via copper-cata-
lyzed reactions of sulfonyl azide, terminal alkynes (or bisalkyne)
and alcohols/amines (diamines) at room temperature, and the highly
practical method provides an entry toward diverse medium- and
large-sized heterocycles.
Compound 3 was prepared through reaction of phthalide
with propargylamine in ClCH2CH2Cl in the presence of
AlCl3 and triethylamine9 (Scheme 1). We first used 3 and
p-toluenesulfonyl azide (N3Ts) as the model substrates to
optimize the copper-catalyzed cyclization conditions, in-
cluding optimization of the copper catalysts, bases, and
solvents. Several copper salts (10 mol% relative to 3),
CuSO4, CuBr, CuCl, CuI, were tested in the condensation
using chloroform as the solvent, triethylamine as the base,
and the results showed that CuI was the best catalyst. Af-
ter the optimization process of solvents, bases and the
amount of CuI, we decided that the following coupling re-
actions were carried out in the standard conditions, 10
mol% CuI as the catalyst, 1.2 equivalents of triethylamine
as the base relative to 3, chloroform as the solvent at room
temperature. Compound 4 was obtained in 87% isolated
yield after a 10 hours reaction under our standard condi-
tions.
Key words: heterocycle, ring closure, copper-catalyzed, sulfonyl
azide, synthetic method
Medium- and large-sized ring compounds find wide-
spread use in many fields as biologically active natural
products,1 drug candidates2 and materials.3 Direct cycliza-
tion methods are often ineffective because of enthalpic
(increasing strain in the transition state) and entropic in-
fluences (probability of the chain-ends meeting) unless
certain conformational restraints are present in the acyclic
precursor, so the generation of medium- and large-sized
ring compounds possessing defined constitutions and
configurations is still a challenge in organic synthesis.1a
Of the various available methods, such as cycloaddition
reactions, ring transformations and cyclization reactions,
have been developed, the cyclization reactions are proba-
bly the most commonly used because of a number of pos-
sible initiators and terminators. For example, Staudinger
ligation reaction, independently developed by the re-
search groups of Bertozzi4 and Raines,5 might also serve
as a powerful method for the facilitation of difficult lac-
tamization reactions. The 1,3-dipolar cycloaddition of
alkynes with azides, an application of the Huisgen reac-
tion in the field of ‘click chemistry’, was used to construct
large ring compounds.6 Domino copper-catalyzed inter-
molecular N-arylation of a-lactam followed by ring ex-
pansion has been developed for the synthesis of medium-
sized nitrogen heterocycles by Buchwald and co-work-
ers.7 Recently, both the Chang and Fokin groups have de-
veloped copper-catalyzed coupling reactions of sulfonyl
azide with various terminal alkynes and amines or water
or alcohols to give N-sulfonyl imino compounds, respec-
tively, under mild conditions.8 In this communication, we
report a general and efficient method for the preparation
O
AlCl3, Et3N
O
+
H2N H2CC CH
ClCH2CH2Cl, 0 °C to r.t.
2
1
O
O
H
N3 Ts
N
H
CuI, Et3N, r.t.
N
O
CH2OH
3
NTs
4
Scheme 1 Synthesis of a nine-membered ring compound via cop-
per-catalyzed reaction of sulfonyl azide, terminal alkyne and alcohol
Encouraged by the excellent result above, we attempted to
make some large-sized ring compounds as shown in
Scheme 2. Reaction of phthalic anhydride with propar-
gylamine in CH2Cl2 at room temperature produced 6, the
carboxyl of 6 was activated by ethyl chloroformate in the
presence of N-methylmorpholine at 0 °C to provide 7, and
the treatment of the active molecule 7 with different ami-
no alcohol (2-aminoethanol, 3-amino-1-propanol, 4-ami-
no-1-butanol or 5-amino-1-pentanol) yielded the
corresponding coupling product 9. Under our standard
SYNLETT 2007, No. 6, pp 0901–0904
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973883; Art ID: W23606ST
© Georg Thieme Verlag Stuttgart · New York

902
Y. Jin et al.
LETTER
O
O
O
C
O
O
O
Cl
OEt
H2N CH2C CH
CH2Cl2, r.t.
(2)
N
H
NMM, 0 °C
OH
6
5
O
O
O
O
H
N
N
H
NH2(CH2)nOH (8)
N
H
O
O
NMM, r.t.
Et
(CH2)n OH
O
9
7
O
O
H
CuI, Et3N, r.t.
N3 Ts
N
N
H
NTs
O
(CH2)n
(n = 2–5)
10
Scheme 2 Synthesis of large-sized ring compounds via copper-catalyzed reaction of sulfonyl azide, terminal alkynes and alcohols
conditions, cyclization of 9 with N3Ts gave 12- to 15- procedures above also provide efficient approaches to di-
membered cyclic compounds (10) in 76–83% yields (see verse molecules.
Table 1).
The cyclization mechanism was suggested as shown in
We also attempted cyclization of sulfonyl azide, terminal Scheme 4 according to our results and the reaction proce-
alkynes and amines. As shown in Scheme 3, reaction of dures proposed by Chang et al.8c Reaction of alkyne with
compound 7 with different Boc-monoprotected diamine CuI unexceptionally formed copper(I) acetylide,10 fol-
(1,2-ethanediamine, 1,3-propanediamine, 1,4-butanedi- lowed with treatment of N3Ts yielded a highly reactive
amine or 1,5-pentanediamine) produced the correspond- ketenimine intermediate or its copper complex B releas-
ing coupling product 12, the deprotection of 12 and the ing an N2.8,11 The other possible route could also occur,
following cyclization under our standard conditions gave i.e. the 1,3-dipolar cycloaddition of terminal alkyne with
12- to 14-, and 16-membered cyclic compounds (14) in sulfonyl azide yielded a triazole12 or its copper complex
73–79% yields (see Table 1).
C, the triazole species released N2 to give ynamides D
whose rearrangement provided B.13 Intramolecular addi-
tion of hydroxyl or amino group in B provided the target
cyclic compound E (Scheme 4).
Reactions of terminal bisalkyne 15, diamines and sulfonyl
azide yielded large-sized ring compounds 17 under the
optimized conditions (see Table 2). Cyclization of the di-
amines did not need the base (Et3N) in the reaction sys- In conclusion, we have developed a general and efficient
tem, and 1,4-butanediamine and 1,6-diaminohexane gave method for the synthesis of medium- and large-sized het-
18- and 20-membered macrocycles in 77% and 63% erocycles via copper-catalyzed reactions of sulfonyl
yields, respectively. The method provides a facile access azide, terminal alkynes (or bisalkyne) and alcohols/
to various cyclic compounds through one-step copper-cat- amines (or diamines) at room temperature,14 and the high-
alyzed multicomponent reaction (MCR), so it is of highly ly practical method provides an entry toward diverse me-
practical applications.
dium- and large-sized heterocycles and a new strategy for
the construction of diverse and complex molecules in
combinatorial chemistry and medicinal chemistry. Fur-
ther applications of the multicomponent cyclization meth-
od are now under investigation.
All the cyclic compounds prepared above contain N-p-tol-
uenesulfonyl group, in fact desulfonylation can be suc-
cessfully achieved with sodium naphthalide,10 so the
O
O
H
N
H
O
NH2(CH2)nNHBoc (11)
N
N
H
O
NMM
H
N
Et
Boc
(CH2)n
CH2Cl2, r.t.
O
O
O
12
7
O
O
H
H
N3 Ts
CuI, Et3N, r.t.
N
N
H
TFA
N
N
H
NTs
NH
(CH2)n
(CH2)n NH2⋅TFA
O
O
(n = 2–4,6)
13
14
Scheme 3 Synthesis of large-sized ring compounds via copper-catalyzed reactions of sulfonyl azide, terminal alkynes and amines
Synlett 2007, No. 6, 901–904 © Thieme Stuttgart · New York

LETTER
Copper-Catalyzed Reactions of Sulfonyl Azide, Terminal Alkynes and Alcohols/Amines
903
Table 1 Copper-Catalyzed Synthesis of Large-Sized Ring Com-
pounds via Reactions of Sulfonyl Azide, Terminal Alkynes and Alco-
hols or Aminesa
Table 1 Copper-Catalyzed Synthesis of Large-Sized Ring Com-
pounds via Reactions of Sulfonyl Azide, Terminal Alkynes and Alco-
hols or Aminesa (continued)
O
O
O
O
O
H
N
N
H
H
N
N
H
H
N
N
H
H
N
N
H
N3 Ts
N3 Ts
NTs
NTs
CuI, Et3N, r.t.
CuI, Et3N, r.t.
X
X
(CH2)n XH
(CH2)n
(CH2)n XH
(CH2)n
O
O
O
Yield (%)b
Entry X (n)
Time (h) Compound
Yield (%)b
Entry X (n)
Time (h) Compound
a Reaction conditions: p-methylbenzensulfonyl azide (1.2 mmol), 9 or
13 (1 mmol), CuI (0.1 mmol) and Et3N (1.2 mmol for 9, 2.4 mmol for
13) in CHCl3 (3 mL).
O
H
N
N
H
NTs
1
2
3
4
O (2)
O (3)
O (4)
O (5)
9
76
b Isolated yield.
O
O
Table 2 Copper-Catalyzed Synthesis of Macrocycles via Reaction
10a
of Sulfonyl Azide, Terminal Bisalkyne and Diaminesa
O
NTs
O
H
O
O
H
N
N
H
H
N
N
H
10
83
78
76
H2N H2CC CH
N
O
O
NMM
Et
O
CH2Cl2, r.t.
7
O
O
O
15
10b
O
NTs
H
TsN
TsN
O
H
N
N
H
O
NH
(CH2)n
N3 Ts, CuI, r.t.
H2N(CH2)nNH2 (16)
10
N
N
17
NH
O
H
O
10c
TsN
O
Entry
n
4
Time
(h)
Compound
Yield
H
(%)b
O
N
N
H
8
O
H
NTs
H
H
O
N
N
N
1
5
7
77
10d
N
O
H
O
H
N
N
H
NTs
NTs
17a
5
6
7
8
NH (2)
NH (3)
NH (4)
NH (6)
12
79
73
77
74
NH
TsN
TsN
O
H
NH
O
N
N
2
6
63
14a
N
H
O
NTs
NH
H
O
H
N
N
17b
10
a Reaction conditions: p-methylbenzenesulfonyl azide (2.4 mmol), 17
(1 mmol), CuI (0.2 mmol) in CHCl3 (3 mL).
b Isolated yield.
H
O
14b
NTs
NH
O
H
Acknowledgment
N
N
9
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20472042 and 20672065), the Excellent
Dissertation Foundation of the Chinese Ministry of Education (No.
200222), Programs for New Century Excellent Talents in Universi-
ty (NCET) and Changjiang Scholars and innovative Research Team
in University (PCSIRT) (No. IRT0404) in China, the Excellent
Young Teacher Program of MOE, P. R. of China, and the Key Sub-
ject Foundation from Beijing Department of Education
(XK100030514).
H
O
14c
TsN
O
H
NH
N
N
11
H
O
14d
Synlett 2007, No. 6, 901–904 © Thieme Stuttgart · New York

904
Y. Jin et al.
LETTER
Z
.
N
Ts
N
Ts
XH
X
B
CuI, base
N3 Ts
E
XH
X = NH, O
Z
N
N
N
A
N2
N
Ts
XH
XH
Ts
Z
D
X = NH, O Z = Cu or H
C
Scheme 4 Possible copper-catalyzed cyclization mechanism
Compound 10a: eluent: CH2Cl2–MeOH (15:1); white solid,
yield 76%. 1H NMR (300 MHz, DMSO-d6): d = 7.93 (br s, 2
H), 7.29–7.71 (m, 8 H), 3.97 (t, 2 H, J = 2.40 Hz), 3.50 (d, 2
H, J = 2.73 Hz), 3.39 (d, 2 H, J = 2.40 Hz), 2.83 (t, 2 H,
J = 2.73 Hz), 2.27 (s, 3 H). 13C NMR (75 MHz, DMSO-d6):
d = 175.1, 169.2, 168.9, 143.6, 139.6, 136.9, 136.5, 130.1,
130.0, 129.8, 127.8, 127.2, 126.7, 67.7, 37.2, 36.9, 34.4,
21.5. HRMS: m/z calcd for C20H22N3O5S [M + H]+:
416.1280; found: 416.1287.
References and Notes
(1) Reviews: (a) Nubbemeyer, U. Top. Curr. Chem. 2001, 216,
125. (b) Maier, M. E. Angew. Chem. Int. Ed. 2000, 39, 2073.
(c) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran,
P. Angew. Chem. Int. Ed. 2000, 39, 44.
(2) Taunton, J.; Collins, J. L.; Schreiber, S. L. J. Am. Chem. Soc.
1996, 118, 10412.
(3) (a) Sanchez-Quesada, J.; Ghadiri, M. R.; Bayley, H.; Braha,
O. J. Am. Chem. Soc. 2000, 122, 11757. (b) Bong, D. T.;
Clark, T. D.; Granja, J. R.; Ghadiri, M. R. Angew. Chem. Int.
Ed. 2001, 40, 988.
(4) (a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007.
(b) Saxon, E.; Luchansky, S. J.; Hang, H. C.; Yu, C.; Lee, S.
C.; Bertozzi, C. R. J. Am. Chem. Soc. 2002, 124, 14893.
(5) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett.
2000, 2, 1939.
Preparation of Compounds 14a–d
Et3N (2.4 mmol) was slowly added to a stirred mixture of p-
methylbenzenesulfonyl azide (1.2 mmol), 13 (1 mmol) and
CuI (0.1 mmol) in CHCl3 (3 mL) at r.t. under an N2
atmosphere. Later (9–12 h), the solvent was removed in
vacuo, and the crude residue was purified by flash column
chromatography on silica gel with an appropriate eluting
solvent system (CH2Cl2–MeOH, 15:1 to 20:1) to give the
target product 14.
(6) (a) Billing, J. F.; Nilsson, U. J. J. Org. Chem. 2005, 70,
4847. (b) Angell, Y.; Burgess, K. J. Org. Chem. 2005, 70,
9595.
(7) Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J.
Am. Chem. Soc. 2004, 126, 3529.
Compound 14b: eluent: CH2Cl2–MeOH (20:1); white solid,
yield 73%, 1H NMR (300 MHz, DMSO-d6): d = 8.40 (br s, 2
H), 8.22 (br s, 1 H), 7.28–7.68 (m, 8 H), 3.52 (m, 2 H), 3.27
(m, 4 H), 2.82 (m, 2 H), 2.32 (s, 3 H), 1.67 (m, 2 H). 13
C
(8) (a) Bae, I.; Han, H.; Chang, S. J. Am. Soc. Chem. 2005, 127,
2038. (b) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am.
Chem. Soc. 2005, 127, 16046. (c) Yoo, E. J.; Bae, I.; Cho, S.
H.; Han, H.; Chang, S. Org. Lett. 2006, 8, 1347.
(d) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem.
Int. Ed. 2006, 45, 3154.
(9) Bigg, D. C. H.; Lesimple, P. Synthesis 1992, 227.
(10) Ito, H.; Arimoto, K.; Sensui, H.; Hosomi, A. Tetrahedron
Lett. 1997, 38, 3977.
(11) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar,
C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
(12) Gerard, B.; Ryan, J.; Beeler, A. B.; Porco, J. A. Jr.
Tetrahedron 2006, 62, 64055.
NMR (75 MHz, DMSO-d6): d = 168.9, 168.7, 166.6, 142.1,
136.6, 135.6, 130.5, 130.2, 129.8, 128.4, 128.0, 126.2, 42.5,
36.6, 34.9, 27.7, 21.4. HRMS: m/z calcd for C21H25N4O4S
[M + H]+: 429.1597; found: 429.1605.
Preparation of Compounds 17a,b
A solution of diamine (1.2 mmol) in CHCl3 (1 mL) was
slowly added to a stirred mixture of p-methylbenzene-
sulfonyl azide (2.4 mmol), 15 (1 mmol) and CuI (0.2 mmol)
in CHCl3 (3 mL) at r.t. under an N2 atmosphere. After a 5–7
h stirring, the solvent was concentrated in vacuo. The crude
residue was purified by flash column chromatography on
silica gel with an appropriate eluting solvent system to give
17.
(13) Raap, R. Can. J. Chem. 1971, 49, 1792.
(14) Preparation of Compounds 4 and 10a–d
Et3N (1.2 mmol) was slowly added to a stirred mixture of p-
methylbenzenesulfonyl azide (1.2 mmol), 3 or 9 (1 mmol)
and CuI (0.1 mmol) in CHCl3 (3 mL) at r.t. under an N2
atmosphere. Later (8–10 h), the solvent was removed in
vacuo, and the crude residue was purified by flash column
chromatography on silica gel with an appropriate eluting
solvent system (CH2Cl2–MeOH 15:1 to 20:1) to give the
target product 4 or 10.
Compound 17a: eluent: CH2Cl2–MeOH (20:1); white solid,
yield 77%. 1H NMR (300 MHz, DMSO-d6): d = 8.78 (br t, 2
H), 8.62, (br t, 2 H), 7.32–7.70 (m, 12 H), 3.58 (m, 4 H), 3.07
(m, 4 H), 2.90 (m, 4 H), 2.34 (s, 6 H), 1.38 (m, 4 H). 13
C
NMR (75 MHz, DMSO-d6): d = 169.2, 167.2, 142.2, 142.0,
136.1, 130.2, 129.7, 128.2, 126.1, 41.5, 37.5, 34.1, 26.0,
21.4. HRMS: m/z calcd for C32H39N6O6S2 [M + H]+:
667.2372; found: 667.2376.
Synlett 2007, No. 6, 901–904 © Thieme Stuttgart · New York

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