Formation of N-sulfonylamidines by copper-catalyzed coupling of sulfonyl azides, terminal alkynes, and trialkylamines

Article abstract of DOI:10.1016/j.tetlet.2010.11.135

A copper-catalyzed synthesis of N-sulfonylamidines via three-component coupling of sulfonyl azides, terminal alkynes, and trialkylamines is reported.

Full text of DOI:10.1016/j.tetlet.2010.11.135

Tetrahedron Letters 52 (2011) 668–670
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formation of N-sulfonylamidines by copper-catalyzed coupling of sulfonyl
azides, terminal alkynes, and trialkylamines
⇑
Issa Yavari , Salome Ahmadian, Majid Ghazanfarpur-Darjani, Yazdan Solgi
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed synthesis of N-sulfonylamidines via three-component coupling of sulfonyl azides, ter-
minal alkynes, and trialkylamines is reported.
Received 24 August 2010
Revised 14 November 2010
Accepted 26 November 2010
Available online 2 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Terminal alkyne
Trialkylamine
Sulfonyl azide
Copper catalyst
N-Sulfonylamidine
Amidines have fascinating chemical properties by virtue of their
structures, and they have been widely applied in medicinal and
synthetic chemistry.1 Substituted amidines are useful intermedi-
ates for the synthesis of heterocyclic compounds and metal com-
plexes.2,3 Traditional methods for the preparation of amidine
derivatives are based on functional group transformation of pre-
cursors such as thioamides,4 isocyanides,5 and aldoximes.6
Tandem reactions of sulfonyl azides, terminal alkynes, and sec-
ondary amines have been reported and the structures of the result-
ing amidines were confirmed unambiguously by an X-ray
crystallographic analysis, which disclosed the E-form of the C@N
double bond.7 In this Letter, we report a one-pot synthesis of N-
sulfonylamidines via the Cu-catalyzed three-component coupling
of trialkylamines, sulfonyl azides, and terminal alkynes. Trialkyl-
amines are frequently applied as bases, but rarely used as the
nucleophile in these reactions.8–10
The formation of ketenimine intermediates from terminal al-
kynes, sulfonyl azides, and triethylamine, as the base, in the pres-
ence of copper catalysts,11,12 has encouraged us to trap these
intermediates using trialkylamines. It should be mentioned that
the ketenimine intermediate can be generated using activated
azides such as sulfonyl, carbonyl, and phosphoryl azides.13,14 Thus,
the reaction of phenylacetylene (1a), p-toluenesulfonyl azide (2a),
and triethylamine (3a) gave N1,N1-diethyl-2-phenyl-N2-tosylace-
tamidine (4a) in 83% yield (Scheme 1). This result prompted us
to optimize the reaction conditions for the synthesis of other sulf-
onylamidine derivatives15 (Table 1).
While only a trace of product was obtained at ambient temper-
ature, heating at 60 °C was found to be effective for complete con-
version. Also, an increased loading of the tertiary amine gave better
yields. Several catalysts such as CuI, CuBr, CuCl, Cu2O, and copper
powder were tested with CuI and CuBr giving the best results.
Among several solvents screened, THF was the best; nonpolar sol-
vents such as toluene and hexane were not suitable for the forma-
tion of sulfonylamidine derivatives. Thus, the optimized reaction
conditions used were 10 mol % of CuI relative to the alkyne and
3 equiv of the trialkylamine in THF at 60 °C.
Phenylacetylene readily participates in the coupling to furnish
the corresponding amidine in good yields (Table 1, entries 1–3).
Aliphatic acetylenes served as low-yielding substrates compared
to phenylacetylene (Table 1, entries 4–8). Aromatic sulfonyl azides
reacted efficiently with 1a and the corresponding products were
obtained in good yields. Several types of aliphatic acyclic trialkyl-
amines were utilized successfully.
Ph
CuI (0.1 equiv)
Ph
TsN3
+
+
NTs
Et3N
THF, 60 °C, 12 h
Et
N
Et
4a
1a
2a
3a
⇑
Corresponding author. Tel.:+98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
Scheme 1. Copper-catalyzed three-component coupling of phenyacetylene, p-
toluenesulfonyl azide, and triethylamine.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.135

I. Yavari et al. / Tetrahedron Letters 52 (2011) 668–670
669
Table 1
Copper-catalyzed three-component coupling
Entry
1
Alkyne
Sulfonyl azide
Amine
Et3N
Amidine
NTs
Yield (%)
Ph
O
O
4a
S
Ph
Et
83
N
p-Tolyl
N3
1a
Et
2a
NTs
Ph
iPr
(iPr)2NEt
(iPr)2NEt
86
73
4b
4c
2
3
1a
2a
N
iPr
O
NSO2Ph
O
iPr
N
S
Ph
1a
Ph
N3
iPr
2b
n-Pr
O
NTs
O
4d
S
n-Pr
Et
4
Et3N
31
p-Tolyl
2a
N
Et
N3
1b
2a
NTs
4e
4f
n-Pr
n-Bu
n-Bu
iPr
Et
5
6
7
8
1b
(iPr)2NEt
Et3N
34
51
45
42
N
iPr
n-Bu
NTs
1c
2a
N
Et
NTs
iPr
4g
1c
1c
2a
(iPr)2NEt
(iPr)NMe2
N
iPr
NTs
Me
n-Bu
21a
4h
N
iPr
7,18 which is attacked by the trialkylamine to afford the zwitterion
8. This intermediate is converted into salt 9, presumably by mois-
ture. Dealkylation of intermediate 9 by the trialkylamine would
produce the desired product 4.
Ph
+
CuI
Ph
Cu
+
Ts-N
3
In conclusion, ketenimine intermediates generated by the addi-
tion of copper acetylides to tosyl azides are trapped by trialkyl-
amines to yield N-sulfonylamidine derivatives. The present
method may be considered a practical route for the synthesis of
functionalized N-sulfonylamidines.
5
1
2
Ph
Cu
Cu
Ph
_
N2
R3N
+
C
C
NTs
C
NTs
NTs
N
N
Supplementary data
Ts
Ph
R3N
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.135.
7
6
8
Ph
Ph
References and notes
R N
+
_
3
moisture
C
R
C
NTs
1. Sienkiewich, P.; Bielawski, K.; Bielawska, A.; Palka, J. Environ. Toxicol.
Pharmacol. 2005, 20, 118.
2. Boyd, G. V. In The Chemistry of Amidines and Imidates; Patai, S., Rappoport, Z.,
Eds.; Wiley: New York, 1991; Vol. 2,. Chapter 8.
3. Barker, J.; Kilner, M. Coord. Chem. Rev. 1994, 133, 219.
4. Kumagai, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2004, 43, 478.
5. Lange, U. E. W.; Schafer, B.; Baucke, D.; Buschmann, E.; Mack, H. Tetrahedron
Lett. 1999, 40, 7067.
R4N
R
N
R3N
9
4
Scheme 2. A plausible mechanism for the reaction.
6. Takuwa, T.; Minowa, T.; Onishi, J. Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2004,
77, 1717.
7. Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.
8. Xu, X.; Li, X. Org. Lett. 2009, 11, 1027.
A plausible rationalization for the formation of compounds 4 is
given in Scheme 2. The yellow copper acetylide 5, formed from 1
and CuI,7 undergoes a 1,3-dipolar cycloaddition reaction with sul-
fonyl azide 2 to generate the triazole derivative 6.16,17 This inter-
mediate can then be converted into the ketenimine derivative
9. Xu, X.; Li, X.; Ma, L.; Ye, N.; Weng, B. J. Am. Chem. Soc. 2008, 130, 14048.
10. Liu, N.; Tang, B.; Chen, Y.; He, L. Eur. J. Org. Chem. 2009, 2059.
11. Chang, S.; Yoo, E.; Bae, I.; Cho, S.; Han, H. Org. Lett. 2006, 8, 1347.
12. Chang, S.; Yoo, E.; Bae, I.; Cho, S.; Han, H. J. Am. Chem. Soc. 2005, 127,
16046.

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I. Yavari et al. / Tetrahedron Letters 52 (2011) 668–670
13. Fokin, V.; Cassidy, M.; Raushel, J. Angew. Chem., Int. Ed. 2006, 45, 3154.
14. Chang, S.; Kim, S.; Jung, D. J. Org. Chem. 2007, 72, 9769.
(500.1 MHz, CDCl3): dH = 0.92 (3H, t, 3J = 7.2 Hz, Me), 1.10 (3H, t, 3J = 7.0 Hz,
Me), 1.23 (3H, t, 3J = 7.0 Hz, Me), 1.40–1.46 (2H, m, CH2), 1.58–1.63 (2H, m,
CH2), 2.39 (3H, s, Me), 2.83–2.86 (2H, m, CH2), 3.45 (2H, q, 3J = 7.0 Hz, CH2N),
3.49 (2H, q, 3J = 7.0 Hz, CH2N), 7.23 (2H, d, 3J = 8.1 Hz, Ar), 7.81 (2H, d,
3J = 8.1 Hz, Ar). 13C NMR (125.7 MHz, CDCl3): dC = 12.1 (Me), 13.6 (Me), 14.2
(Me), 21.0 (Me), 21.3 (CH2), 26.3 (CH2), 29.3 (CH2), 43.1 (CH2), 43.2 (CH2), 126.0
(2CH), 129.3 (2CH), 137.1 (C), 139.2 (C), 167.6 (C@N).
15. General procedure. To a mixture of azide 2 (1.2 mmol), alkyne 1 (1 mmol), and
CuI (0.1 mmol) in THF (2 mL) was slowly added the tertiary amine (3 mmol).
The mixture was stirred at 60 °C. After completion of the reaction [about 12 h;
TLC (AcOEt/hexane 1:4) monitoring], the mixture was diluted with CH2Cl2
(2 mL) and aqueous NH4Cl solution (3 mL), stirred for 30 min, and the layers
were separated. The aqueous layer was extracted with CH2Cl2 (3 mL Â 3) and
the combined organic fractions were dried (NaSO4) and concentrated under
reduced pressure. The residue was purified by flash column chromatography
[silica gel (230–400 mesh; Merck), hexane/AcOEt 5:1] to give the product. N-
sulfonylamidines 4b and 4g are known.7
N1-Isopropyl-N1-methyl-N2-tosylhexanamidine (4h). Colorless solid, mp 110–
112 °C, 0.13 g, yield: 42%. IR (KBr) (m
max, cmÀ1): 2973, 1545, 1313, 1256, 1128,
1063, 841, 753, 558. Anal. Calcd for C17H28N2O2S (324.5): C, 62.93; H, 8.70; N,
8.63%. Found: C, 62.95; H, 8.73; N, 8.61%. MS (EI, 70 eV): m/z (%): 325.5 (M+1,
2), 218 (3), 170 (5), 156 (4), 155 (3), 91 (100), 72 (81), 58 (49). 1H NMR
(500.1 MHz, CDCl3): dH = 0.85 (3H, t, 3J = 7.1 Hz, Me), 1.09 (6H, d, 3J = 6.8 Hz,
CMe2), 1.23 (6H, d, 3J = 6.8 Hz, CMe2), 1.28–1.37 (4H, m, 2CH2), 1.49–1.60 (2H,
m, CH2), 2.39 (3H, s, Me), 2.83 (3H, s, Me), 2.91 (3H, s, Me), 2.93 (2H, m, CH2),
3.65 (1H, m, CH), 4.11 (1H, m, CH), 7.24 (2H, d, 3J = 7.9 Hz, Ar), 7.85 (2H, d,
3J = 7.9 Hz, Ar). 13C NMR (125.7 MHz, CDCl3): dC = 13.8 (Me), 18.9 (CMe2), 20.5
(CMe2), 22.2 (Me), 26.2 (CH2), 27.0 (CH2), 29.7 (CH2), 31.2 (CH2), 31.8 (MeN),
47.2 (CHN), 48.7 (CHN), 126.1 (2CH), 129.0 (2CH), 141.3 (C), 143.5 (C), 172.0
(C@N).
N1,N1-Diethyl-2-phenyl-N2-tosylacetamidine (4a). Colorless solid, mp 136–
139 °C, 0.28 g, yield: 83%. IR (KBr) (m
max, cmÀ1): 2977, 1549, 1455, 1360,
1272, 1142, 1090, 761, 589. Anal. Calcd for C19H24N2O2S (344.47): C, 66.25; H,
7.02; N, 8.13%. Found: C, 66.23; H, 6.99; N, 8.11%. MS (EI, 70 eV): m/z (%): 345.5
(M+1, 3), 238 (7), 190 (9), 162 (2), 155 (33), 91 (100), 72 (59), 44 (63). 1H NMR
(500.1 MHz, CDCl3): dH = 0.95 (3H, t, 3J = 7.0 Hz, Me), 1.15 (3H, t, 3J = 7.0 Hz,
Me), 2.36 (3H, s, Me), 3.20 (2H, q, 3J = 7.0 Hz, CH2N), 3.50 (2H, q, 3J = 7.0 Hz,
CH2N), 4.38 (2H, s, CH2), 7.11 (2H, d, 3J = 7.9 Hz, Ar), 7.16–7.26 (5H, m, Ph), 7.77
(2H, d, 3J = 7.9 Hz, Ar). 13C NMR (125.7 MHz, CDCl3): dC = 13.8 (Me), 13.9 (Me),
21.9 (Me), 22.4 (CH2), 36.5 (CH2N), 41.8 (CH2N), 126.2 (CH), 126.8 (2CH), 128.7
(2CH), 129.4 (2CH), 131.7 (2CH), 139.4 (C), 141.6 (C), 143.6 (C), 164.5 (C@N).
N1,N1-Diethyl-N2-tosylpentanamidine (4d). Colorless solid, mp 107–108 °C,
16. Meldal, M.; Tornøe, Ch. Chem. Rev. 2008, 108, 2952.
17. Recently, Sharpless and co-workers [Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae, I.;
Fokin, V. V.; Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730]
established anhydrous conditions with CuI in CHCl3/2,6-lutidine at 0 °C to
prevent intermediate 6 from decomposing and provide selective formation of
the desired 1-sulfonyltriazoles.
0.09 g, yield: 31%. IR (KBr) (m
max, cmÀ1): 2928, 1567, 1432, 1317, 1287, 1129,
1074, 755, 541. Anal. Calcd for C16H26N2O2S (310.45): C, 61.90; H, 8.44; N,
9.02%. Found: C, 61.89; H, 8.43; N, 9.01%. MS (EI, 70 eV): m/z (%): 311.5 (M+1,
2), 204 (5), 156 (10), 155 (63), 128 (43), 91 (100), 72 (81), 44 (51). 1H NMR
18. Although a 1,3-dipole or a carbene (without migration of the Cu) would fit the
data, we prefer the mechanism shown in Scheme 2.