A facile access to N-sulfonylimidates and their synthetic utility for the transformation to amidines and amides

Article abstract of DOI:10.1021/ol060056j

It is shown that N-sulfonylimidates can be efficiently prepared by a three-component coupling of terminal alkynes, sulfonyl azides, and alcohols with use of a copper catalyst and an amine base. The reaction is characterized by mild conditions, high select

Full text of DOI:10.1021/ol060056j

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1347-1350
A Facile Access to N-Sulfonylimidates
and Their Synthetic Utility for the
Transformation to Amidines and Amides
Eun Jeong Yoo, Imhyuck Bae, Seung Hwan Cho, Hoon Han, and Sukbok Chang*
Center for Molecular Design and Synthesis (CMDS), Department of Chemistry and
School of Molecular Science (BK21), Korea AdVanced Institute of Science and
Technology (KAIST), Daejon 305-701, Republic of Korea
sbchang@kaist.ac.kr
Received January 10, 2006
ABSTRACT
It is shown that N-sulfonylimidates can be efficiently prepared by a three-component coupling of terminal alkynes, sulfonyl azides, and alcohols
with use of a copper catalyst and an amine base. The reaction is characterized by mild conditions, high selectivity, and tolerance with various
functional groups. Facile transformation of imidates to amidines was also achieved by sodium cyanide. Additionally, a protocol for the extremely
efficient Pd-catalyzed [3,3]-sigmatropic rearrangement of allylic sulfonimidates to N-allylic sulfonamides has been developed.
Inspired by nature, synthetic chemists endeavor to develop
useful organic transformations with high efficiency and
selectivity, wide substrate scope, easy product isolation, and
modular approaches under mild conditions.1 Catalytic mul-
ticomponent reactions (MCR) have served as a rapid and
effective synthetic approach because they frequently offer
complex molecules in a single operation with satisfaction
of the criteria mentioned above.2 Recently, we have disclosed
novel reactivity of sulfonyl azides in Cu-catalyzed coupling
reactions with a wide range of terminal alkynes and amines
or water to give N-sulfonyl amido compounds such as
amidines and amides, respectively, under mild condi-
tions.3
Imidates, also known as imidoates, imidic acid esters, or
imido esters, are known to be important pharmacophores and
useful synthetic building blocks.4 Whereas most of the
present synthetic approaches take advantage of Pinner-type
reactions,5 some difficulties are often encountered such as
low yields and rather limited substrate scope. As a result,
new synthetic methods, especially for the production of
functionalized imidates, have been investigated.6 Since our
MCR protocol for the synthesis of amidines and amides has
demonstrated that both single and double carbon-heteroatom
(4) (a) Neilson, D. G. In The Chemistry of Amdines and Imidates; Patai,
S., Ed.; John Wiley & Sons: London, UK, 1975; Chapter 8. (b) Kantlehner,
W. Synthesis of Iminium Salts, Orthoesters and Related Compounds. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 2, pp 485-599. (c) Baindur, N.;
Neumeyer, J. L.; Niznik, H. B.; Bozowej, N. H.; Jarvie, K. R.; Seeman, P.;
Garlick, R. K.; Miller, J. J., Jr. J. Med. Chem. 1988, 31, 2069-2071.
(5) (a) Pinner, A.; Klein, F. Chem. Ber. 1877, 10, 1889-1897. (b) Gavin,
D. J.; Mojica, C. A. Org. Process Res. DeV. 2001, 5, 659-664. (c) For a
review, see: Roger, R.; Neilson, D. G. Chem. ReV. 1961, 61, 179-211.
(6) (a) Saluste, C. G.; Whitby, R. J.; Furber, M. Tetrahedron Lett. 2001,
42, 619-6194. (b) Nakajima, N.; Saito, M.; Kudo, M.; Ubukata, M.
Tetrahedron 2002, 58, 3579-3588. (c) Kishore, K.; Tetala, R.; Whitby, R.
J.; Light, M. E.; Hurtshouse, M. B. Tetrahedron Lett. 2004, 45, 6991-
6994. (d) Yadav, V. K.; Babu, K. G. Eur. J. Org. Chem. 2005, 452-456.
(1) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004-2021. (b) Trost, B. M. Science 1991, 254, 1471-
1477. (c) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
(d) Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233-1246. (e) Wangelin,
A. J.; Neumann, H.; Gordes, D.; Klaus, S.; Strubing, D.; Beller, M. Chem.
Eur. J. 2003, 9, 4286-4294.
(2) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (b) Do¨mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210.
(3) (a) Bae, I.; Han, H.; Chang, S. J. Am. Soc. Chem. 2005, 127, 2038-
2039. (b) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc.
2005, 127, 16046-16047.
10.1021/ol060056j CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/07/2006

bonds are simultaneously generated with high efficiency, we
envisioned that imidates could also be readily prepared with
the use of alcohols as one part of the reacting components.7
We report herein the facile synthesis of N-sulfonylimidates
and their synthetic utility in the conversion to amidines. A
new protocol for the extremely efficient Pd-catalyzed rear-
rangement of allylic sulfonimidates to N-allylic sulfonamides
also will be described (eq 1).
Table 1. Cu-Catalyzed Three-Component Coupling for the
Formation of Imidatesa
entry
R1
Ph (1a)
R2
R3
yield [%]b
4a 87
4-BrC6H4CH2 4bc 91
1
2
3
4
5
6
7
8
9
4-MeC6H4 (2a) PhCH2 (3a)
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
Me
Me
i-Pr
Ph
4c
4d 73
4e
93
61
65
31
4-MeOC6H4 4f
t-Bu
4g
MeO2CCH2
Br(CH2)3
4h 62
4i
92
68
10 1a
11 1a
CH3C≡CCH2 4j
HO(CH2)3
4k 86d
12 1a
3a
4l
84
13 1a
14 1a
15 1a
TMS-CH2CH2 3a
CH3(CH2)3 3a
4-NO2C6H5CH2 3a
4m 84
4n 77
At the outset of our studies on the optimization for imidate
synthesis, we tried a copper-catalyzed three-component
reaction of phenylacetylene, p-toluenesulfonyl azide, and
benzyl alcohol under similar conditions as those applied in
the amidine synthesis.3a In contrast to the amidine case, no
coupled product was generated in the absence of additional
amine bases. Among those examined, a slight excess of
triethylamine (1.2 equiv) in CHCl3 solvent turned out to be
most efficient for the formation of imidates. While no
conversion was observed without a Cu catalyst, CuI was
superior to other copper sources examined.8
The generality of the imidate synthesis was next investi-
gated with a range of terminal alkynes, sulfonyl azides, and
alcohols under the optimized reaction conditions (Table 1).
Primary and secondary alcohols readily participated in the
reaction leading to the corresponding imidates in high yields
(entries 1-4). Phenol derivatives also work well in this
coupling (entries 5 and 6). However, the use of a tertiary
alcohol resulted in a sluggish reaction rate and gave a rather
low yield, probably due to steric reasons (entry 7). Alcohols
bearing various functional groups such as ester, halo, or
propargyl internal triple bond moieties were compatible under
the reaction conditions (entries 8-10). When a diol was
allowed to react, the corresponding bisimidate product could
be obtained in a high yield (entry 11).
4o
37
16 4-CF3C6H4
17 4-MeC6H4
18 4-MeOC6H4
19 3-thienyl
20 CH3(CH2)3
21 t-Bu
22 Cl(CH2)3
23 MeOCH2
24 1-cyclohexenyl 2a
25 H2CdCHCH2C- 2a
(CO2Et)2CH2
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
4p 88
4q
4r
4s
4t
89
70
72
86
4u 93
4v 78
4w 82
4x
4y
79
80
26 TMS
2a
3a
4z
71e
a Alkyne (0.5 mmol), sulfonyl azide (1.2 equiv), alcohol (1.2 equiv),
Et3N (1.2 equiv), and CuI (0.1 equiv) in CHCl3 (1 mL). b Isolated yield.
c Z-configuration of CdN double bond based on the X-ray crystal analysis
(see the Supporting Information). d Yield of 1,3-bisimidate. e Yield of the
desilylated imidate product.
for the formation of acetimidate with concomitant desilyla-
tion under the reaction conditions (entry 26). Additionally,
it should be mentioned that the reaction is readily scaled up
with lower amounts of copper catalyst, and pure imidate
product can be obtained by simple crystallization, thus
making this process highly practical.8
Since ketenimine species are known to react with alcohols
leading to imidates,9 it may be reasonable to postulate a
ketenimine intermediacy in the present case although a more
conclusive description needs further detailed studies. Initial
attack of a putative copper acetylide species, generated by
the action of 1-alkyne with copper salts, onto a sulfonyl azide
may be envisioned to take place leading to a highly reactive
ketenimine intermediate or its copper complex (A) upon
release of N2 (Scheme 1, pathway a). Alternatively, formation
of the ketenimine species may be postulated to take place
stepwise (pathway b) via a copper triazole species, which
probably forms by the 1,3-dipolar cycloaddition between
On the other hand, not only arylsulfonyl azides but also
alkyl or benzyl variants were equally competent in the
coupling reactions (entries 12-15). The efficiency of this
process was not significantly affected by the electronic
variations of aromatic alkynes (entries 16-18). Note that a
broad range of functional groups on alkyne substrates such
as heteroaromatic, halo, ether, alkenyl, or ester were tolerated
in this transformation (entries 19 and 22-25). It is intriguing
that trimethylsilylacetylene can serve as a two-carbon source
(7) For seminal reports on the Cu-catalyzed cycloaddition between
1-alkynes and alkyl(aryl) azides, see: (a) Rostovtsev, V. V.; Green, L. G.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596-
2599. (b) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057-3064.
(9) Sauers, R. R.; Van Arnum, S. D. Phosphorus, Sulfur, Silicon, Relat.
Elem. 2003, 178, 2169-2181.
(8) See the Supporting Information for details.
1348
Org. Lett., Vol. 8, No. 7, 2006

found that methyl imidates were readily transformed to the
corresponding amidines upon the reaction with amines in
the presence of catalytic amounts of NaCN (Scheme 3).13
Scheme 1. Postulated Pathways for the Formation of Imidates
Scheme 3. Conversion of Imidates to Amidines and
N-Desulfonylation
copper acetylide and sulfonyl azide in analogy with the
explanation by Fokin and Sharpless et al.10 In this route, the
rearrangement may be attributed to be responsible for the
ring opening of 1,2,3-triazole (B), giving rise to the keten-
imine species (A) upon release of a N2 molecule. During
the course of the rearrangemnent, it also can be possible to
have an ynamide intermediate species (C).11
It was highly interesting to observe that when 2,6-lutidine
was employed as an amine base instead of triethylamine, a
1,4-substituted 1,2,3-triazole (5a) was also seen to be
produced along with imidates (Scheme 2).12 This observation
Subsequent N-desulfonylation of amidines was success-
fully achieved with sodium naphthalide. Since the MCR
protocol developed by us for the synthesis of amidines often
affords rather low yields with some cyclic amine component,
this indirect route would be a facile complementary pathway
for specific types of amidines.14
We also briefly surveyed a catalytic [3,3]-sigmatropic
rearrangement of allylic sulfonimidates to N-allylic sulfon-
amides15 as this type of conversion has been frequently
applied as a key step in total synthesis.16 Since we succeeded
in setting up an effective MCR for a series of allylic imidates
using allyl alcohols, the subsequent rearrangement was
investigated using a range of transition metal catalysts.8 We
were pleased to find that [PdCl2(PhCN)2] readily catalyzes
the transformation under very mild conditions to furnish the
corresponding allylic amides in excellent yields (Scheme 4).
Scheme 2
Scheme 4. Pd-Catalyzed Rearrangement of Allylic Imidates to
N-Allylic Amides
may imply that the suggested key intermediate of ketenimine
(A in Scheme 1) is likely generated via the triazole adduct
(B) according to path b. However, the possibility that both
pathways a and b are in action competitively at the same
time cannot be completely ruled out at present.
The synthetic utility of imidates was next investigated in
the conversion to amidine derivatives. It was immediately
(10) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210-216.
(b) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int. Ed.
2005, 44, 2210-2215.
(11) We thank one referee for this suggestion. A similar transforamtion
of 5-lithiated triazoles into the corresponding ynamides has been reported:
(a) Raap, R. Can. J. Chem. 1971, 49, 1792-1798. (b) Gilchrist, T. L. AdV.
Heterocycl. Chem. 1987, 41, 41-74.
(12) When Et3N was used as a base, the formation of triazole species
was not observed. The difference in the acidity of conjugated ammonium
ions between triethylamine and 2,6-lutidine may be attributed to these
outcomes. The more acidic 2,6-lutidinium ion [pKa(THF): 7.2] relative to
triethylammonium salt [pKa(THF): 12.5], formed presumably during the
course of generation of copper acetylides, is believed to transfer its proton
more readily to the postulated copper triazole species (B in Scheme 1)
leading to the triazole species 5. For a reference on the indicated acidity
values, see: Rodima, T.; Kaljurand, I.; Pihl, A.; Ma¨emets, V.; Leito, I.;
Koppel, I. J. Org. Chem. 2002, 67, 1873-1881.
The scope of the rearrangement turned out to be wide enough
to cover a range of substituted allylic imidates (8b-d). When
an internal allylic sulfonimidate (e.g., 8d) was subjected to
(13) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc. 2004, 126, 15652-
15653.
Org. Lett., Vol. 8, No. 7, 2006
1349

the conditions, an N-allylic sulfonamide bearing a substituent
at the R-position (9d) was isolated in almost quantitative
yield. To the best of our knowledge, this represents the first
example in which N-allylic sulfonamides can be obtained
by a catalytic rearrangement with such an extremely high
efficiency.
In summary, it is shown that N-sulfonylimidates can be
prepared highly efficiently by a three-component coupling
of terminal alkynes, sulfonyl azides, and alcohols by the
action of a copper catalyst in the presence of an amine base.
The process appears to provide high efficiency and selectiv-
ity, very mild conditions, a wide substrate scope, and high
tolerance with diverse functional groups. Facile transforma-
tion of imidates to amidines was readily achieved with the
help of NaCN as a catalyst. Additionally, a protocol for the
extremely efficient Pd-catalyzed [3,3]-sigmatropic rearrange-
ment of allylic sulfonimidates to N-allylic sulfonamides has
been developed.
(14) For example, a reaction of phenylacetylene, p-toluenesulfonyl azide,
and morpholine provided the corresponding amidine 6c in a poor 19% yield
under the previously described conditions (ref 3a).
(15) For the rearrangement of allylic acyl(aryl)imidates, see: (a) Over-
man, L. E. J. Am. Chem. Soc. 1978, 98, 2901-2910. (b) Overman, L. E.
Acc. Chem. Res. 1980, 13, 218-224. (c) Hollis, T. K.; Overman, L. E. J.
Organomet. Chem. 1999, 576, 290-299. For a recent report on the
rearrangement of allylic phosphorimidates, see: (d) Chen, B.; Mapp, A.
K. J. Am. Chem. Soc. 2004, 126, 5364-5365.
(16) For selected examples, see: (a) Danishefsky, S.; Lee, J. Y. J. Am.
Chem. Soc. 1989, 111, 4829-4837. (b) Nishikawa, T.; Asai, M.; Ohyabu,
N.; Yamamoto, N.; Fukuda, Y.; Isobe, M. Tetrahedron 2001, 57, 3875-
3883. (c) Kim, S.; Lee, T.; Lee, E.; Lee, J.; Fan, G.-j.; Lee, S. K.; Kim, D.
J. Org. Chem. 2004, 67, 3144-3149.
Acknowledgment. This research was supported by Korea
Research Foundation Grant (KRF-2005-015-C00248) and by
the CMDS at KAIST.
Supporting Information Available: Experimental details
plus 1H and 13C NMR spectra of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060056J
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Org. Lett., Vol. 8, No. 7, 2006