Gold(I)-Catalyzed 1,3-O-Transposition Reactions: Ynesulfonamides to Ynamides

Article abstract of DOI:10.1002/ejoc.201500604

The gold-catalyzed 1,3-O-transposition reaction of ynesulfonamides provides a practical synthetic protocol for the synthesis of ynamides under mild conditions. This is the first 1,3-O-transposition example of ynesulfonamides in which a heteroatom is attached to the alkynyl terminal. A plausible mechanism is been proposed on the basis of ¹⁸O-labeling and control experiments as well as DFT calculation. By simple treatment, the obtained ynamides can easily be transformed into useful products. The gold-catalyzed 1,3-O-transposition reaction of ynesulfonamides provides a practical synthetic protocol for the synthesis of ynamides under mild conditions. This is the first 1,3-O-transposition example of ynesulfonamides in which a heteroatom is attached to the alkynyl terminal.

Full text of DOI:10.1002/ejoc.201500604

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500604
Gold(I)-Catalyzed 1,3-O-Transposition Reactions:
Ynesulfonamides to Ynamides
De-Yao Li,[a] Yin Wei,*[a] and Min Shi*[a]
Keywords: Synthetic methods / Gold catalysis / Alkynes / Sulfonamides / Ynamides
The gold-catalyzed 1,3-O-transposition reaction of ynesulf-
onamides provides a practical synthetic protocol for the syn-
thesis of ynamides under mild conditions. This is the first 1,3-
mechanism is been proposed on the basis of 18O-labeling and
control experiments as well as DFT calculation. By simple
treatment, the obtained ynamides can easily be transformed
O-transposition example of ynesulfonamides in which a het- into useful products.
eroatom is attached to the alkynyl terminal. A plausible
Intramolecular transposition reactions are atom econom-
ical processes which have been widely reported in recent
years.[1] Among them, 1,3-shift of allylic alcohols is well-
studied and employed to synthesize biologically active com-
pounds and natural products such as (–)-Galanthamine,
(–)-Amphidinolide B1 and Laulimalide.[2] Moreover, transi-
tion-metal-catalyzed transposition reactions are recently at-
tracting much more research interests especially as for these
involved with a carbenoid intermediate.[3] 1,3-Transposition
reactions are common reaction modes, proceeding through
an unsaturated and delocalized system (such as allylic or
propargylic system) under metal catalysis [Scheme 1, Equa-
tion (1)].[4] Propargylic metal carbenes can also undergo a
1,3-transposition known as a metallotropic shift [Scheme 1,
Equation (2)].[5] In 2014, gold-catalyzed 1,3-transposition
of ynones and diynones have been disclosed by Gevorgyan
and co-workers [Scheme 1, Equation (3)].[6a] To the best of
Scheme 1. Transition-metal-catalyzed 1,3-transposition.
our knowledge, gold(I)-catalyzed 1,3-transposition reac-
tions of propyne having a heteroatom at the alkynyl ter-
minal have been rarely reported.[6] Herein, we report a novel
gold-catalyzed 1,3-transposition of readily available yne-
sulfonamides to ynamides [Scheme 1, Equation (4)].[7] This
new reaction has the advantages of mild conditions and a
wide range of substrate scope. Besides, the products can
further undergo an easy detosylation process to deliver use-
ful compounds.
der gold catalysis. This reaction proceeded efficiently in the
presence of gold catalyst, affording the desired ynamide in
good yield within 10 min (Scheme 2). Due to the similar
polarity of both substrate and product, the transformation
was difficult to be monitored by TLC (silica gel: SiO2)
checking and the reaction proceeding should be traced on
1
the basis of the crude reaction mixture’s H-NMR spectro-
During our exploration of novel reaction pathways of
electron-deficient alkynes under gold catalysis, we found an
entire transformation of ynesulfonamides to ynamides un-
scopic analysis. After mixing the starting materials 1a with
gold(I) catalyst which is generated in situ from IPrAuCl
(5 mol-%) with AgNTf2 (5 mol-%), the crude reaction mix-
ture was tracked by 1H-NMR spectra. Initially, a new signal
at δ = +1.67 ppm (Me of ynamide 2a) appeared within 30 s.
After 3.0 min, the intensity of this signal increased and the
intensity of the signal at δ = +2.33 ppm (Me of ynesulfon-
amide 1a) decreased. Within 10 min, the signal at δ =
+2.33 ppm almost disappeared and the intensity of signal
at δ = +1.67 ppm reached to its maximal value (Scheme 2).
[a] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Ling-Ling Lu, Shanghai 200032, P. R. China
E-mail: weiyin@mail.sioc.ac.cn
mshi@mail.sioc.ac.cn
http://www.sioc.ac.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500604.
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Gold(I)-Catalyzed 1,3-O-Transposition Reactions
The structure of 2a has been unambiguously assigned by found that the yield of 2a increased to 91% NMR yield
X-ray diffraction. The ORTEP drawing of 2a is shown in along with 90% isolated yield (Table 1, entry 9). After iden-
Supporting Information and its CIF data are also presented tification of the better gold catalyst, the screening of sol-
in Supporting Information.
vents affirmed that DCM (dichloromethane) was the better
solvent because carrying out the reaction in DCE (1,2-
dichloroethane), toluene and MeCN all afforded 2a in
lower yields (Table 1, entries 10–12). The reaction can be
also performed in a 2.0 gram scale under the optimal condi-
tions, giving 2a in 88% isolated yield (Table 1, entry 13).
Thus, we identified that IPrAuNTf2 (5 mol-%) as gold cata-
lyst and the reaction should be carried out in DCM. This
gold-catalytic system is quite efficient for the 1,3-O-trans-
position of ynesulfonamides to ynamides.
Having the optimal reaction conditions in hand, we next
investigated the scope of the reaction with respect to dif-
ferent ynesulfonamides. As shown in Table 2, the 1,3-O-
transpositions proceeded smoothly to afford the desired
products in moderate to excellent yields (75–93%). In gene-
ral, this transformation proceeded more efficiently for elec-
tron-donating group substituted ynesulfonamides (R1 = Ts,
Mes), leading to the corresponding products in high yields,
and as for electron-withdrawing group substituted yne-
sulfonamide (R1 = Bs, 2b), the yield of the desired product
was slightly lower. Moreover, we also attempted to synthe-
size Ns-substituted ynesulfonamide (Ns = 4-nitrophenyl-
sulfonamide), however, the substrate decomposed very
rapidly probably due to that the electron deficiency caused
instability during gold catalysis. Different alkyl-substituted
benzene derivatives had no influences on this transforma-
Scheme 2. Gold-catalyzed 1,3-O-transposition reaction.
Upon reaction condition screening, we first utilized
IPrAuCl (5 mol-%) as the gold catalyst to seek out the best
gold catalytic system (Table 1). After our examination of
different silver salts, NTf2– was identified as the best coordi-
nation anion, affording 2a in 75% NMR yield within
10 min (Table 1, entries 1–4). Then, gold catalysts with dif-
ferent phosphine ligands were employed (Table 1, entries 5–
8). Using tBuXPhosAuSbF6 as the catalyst produced 2a in
82% yield within 10 min (Table 1, entry 6). Ligands nBu3P
and Ph3P gave 2a in lower yields presumably due to the
steric factor. Considering that Ag species (AgCl) generated
in situ may affect the reaction outcome,[8] IPrAuNTf2 was
used directly to rule out the silver salt’s effects, and it was
Table 2. Reaction scope of ynesulfonamides 1 to ynamide products
2 with substituent at alkynyl N site.
Table 1. Condition screening for the synthesis of 2a.
Entry[a] Au cat.
Ag salts
Solvent
Yields [%][b]
1
2
3
4
5
6
7
8
IPrAuCl
IPrAuCl
IPrAuCl
IPrAuCl
JohnPhosAuCl
tBuXPhosAuSbF6
nBu3PAuSbF6
PPh3AuSbF6
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
IPrAuNTf2
AgOTf
AgNTf2
AgSbF6
NaBArF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
75
35
60
70
57
82
66
73
AgNTf2
–
–
–
–
–
–
–
–
9
91 (90)[c]
85
10
11
12
13
toluene
MeCN
DCM
84
19
(88)[d]
[a] Reactions were run as 0.1 m in solvents. [b] HPLC yields with
4-bromoanisole as an internal standard. [c] Isolated yields. [d] 2.0
gram scale, isolated yield.
[a] Isolated yields. [b] Reaction time is 0.5 h.
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D.-Y. Li, Y. Wei, M. Shi
SHORT COMMUNICATION
tion, all giving the desired products in good yields (2d, 2g Table 3. Reaction scope of ynesulfonamides 1 to ynamides 2 with
substituent at carbonyl C site.
and 2h). Sterically bulky 2,6-dimethyl-substituted yne-
sulfonamide afforded the corresponding product in the
highest yield (2f, 93%). When different halogen atoms such
as F, Cl or Br were presented at the benzene ring, no obvi-
ous erosion of yields was observed (2e, 2i and 2j). Even if
the starting material having two halogen-atom substituents
on the benzene ring, the reaction also proceeded very well,
giving the desired products in good yields (for 2k and 2m).
The substrate having phenyl substituent on the benzene ring
was also tolerated, affording the desired product 2l in 89%
yield. Naphthylamine containing substrate gave the ex-
pected product 2n in 75% yield.
We next synthesized substrates with different substituents
at the carbonyl carbon terminal to examine the reaction
outcome. The results are summarized in Table 3. The de-
sired products were obtained in good yields in most cases.
Alkyl-substituted products (2o, 2p and 2q) were obtained in
good to excellent yields. No obvious alternation on yield
was observed when cyclohexyl group was introduced at the
carbonyl carbon terminal (2r). In the cases of aryl-substi-
tuted substrates, yields of the corresponding ynamides had
a little decrease probably due to the electronic property (2s
and 2t). Alkenyl group substituted substrates such as 1- or
2-propenyl substituent did not affect the reaction outcome,
affording the desired products 2u and 2v in good to excel-
[a] Isolated yields. [b] After detosylation, two steps’ yield.
lent yields. Using 1w as substrate, the corresponding pro-
Scheme 3. Control experiments for investigation on mechanism.
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Eur. J. Org. Chem. 2015, 4108–4113

Gold(I)-Catalyzed 1,3-O-Transposition Reactions
duct 2w was only obtained in 42% yield since the reaction 1,3-O-transposition process is outlined in Scheme 4. As for
mixture became complex quickly within 10 min. Product 2x substrate 1a, the coordination of gold(I) catalyst with alk-
was unstable during purification with silica gel column yne gives intermediate A, which can initiate an intramolecu-
chromatography, but it could be readily transformed to lar O attack to the alkyne moiety to deliver a gold stabilized
product 3x through a one-pot detosylation process, which is carbocationic intermediate C via transition state B. Subse-
a useful compound for photochemical study (see Scheme 6). quent C–O bond cleavage in the intermediate C and dissoci-
Product 2y is also a useful precursor of drug candidate and ation of the gold catalyst generate product 2a.
the detailed transformation can be seen in Scheme 6.
Two 18O labeling experiments were conducted to clarify
the O-atom-transfer process of the carbonyl group
(Scheme 3). 18O containing compound 6 could be readily
prepared through bromination of compound 5 with NBS,
which is derived from the hydrolysis of ketal 4 with H218O
in the presence of HCO2H. The target compound 18O-1a
was then obtained via cooper catalyzed coupling reaction.
The content of 18O was only 10% presumably due to that
the water in situ generated from decomposition of formic
acid upon heating is unavoidable. However, 10% of 18O
content of 1a is good enough as compared to 0.2% of 18O
content in nature. The cross-over experiment was conducted
with 18O-1a and 1s as the substrates. After the one-pot gold
catalysis, no cross-over products were observed on the basis
of Mass spectroscopic analysis of the reaction mixture, sug-
gesting an intramolecular atom transferring manner
(Scheme 3). Moreover, adding H218O into the reaction sys-
Scheme 4. A proposed mechanism.
tem of 1a did not give 18O containing product under the
standard conditions and the desired product 2a was given
In order to understand the detailed mechanism for the
in 92% yield, indicating that the ambient water did not af- formation of product 2, we have also theoretically investi-
fect the reaction proceeding. These results firmly demon- gated the reaction pathway (for details, see Supporting In-
strated that the O atom transferring process takes place formation). All calculations have been performed at the
through an intramolecular manner.
B3LYP/6-311+G(d,p)/SDD//B3LYP/6-31+G(d)/SDD level
Based on the previous literature[6a,8] and our control ex- of theory with Gaussian 09 program. The relative energies
periments, a plausible mechanism for this gold-catalyzed of all intermediates and transitional states along the reac-
Scheme 5. Reaction energy profile.
Eur. J. Org. Chem. 2015, 4108–4113
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D.-Y. Li, Y. Wei, M. Shi
SHORT COMMUNICATION
20672127, 21421091, 21372250, 21121062, 21302203 and
20732008).
tion pathways are shown in Scheme 5. Initially, the coordi-
nation of ynesulfonamide 1a with AuI catalyst generates
gold complex Int 1. The gold complex Int 1 is transferred
to the more stable carbocationic intermediate Int 2 without [1] a) P. A. Wender, B. L. Miller, Nature 2009, 460, 197; b) P. A.
Wender, F. C. Bi, G. G. Gamber, F. Gosselin, R. D. Hubbard,
M. J. C. Scanio, R. Sun, T. J. Williams, L. Zhang, Pure Appl.
Chem. 2002, 74, 25; c) B. M. Trost, Acc. Chem. Res. 2002, 35,
an energy barrier. Passing through transition state TS 1
with an energy barrier of 26.7 kcal/mol, the O attacks the
electrophilic carbon to give another stable carbocationic in-
695.
termediate Int 3. Then the intermediate Int 3 undergoes C–
O bond cleavage via transition state TS 2 with an energy
barrier of 26.2 kcal/mol, generating the product complex
Int 4. The product complex Int 4 is finally cleaved to yield
separate product 2a with AuI catalyst. Moreover, the DFT
calculations show that the product 2a is more stable than
the reactant 1a by 4.5 kcal/mol, indicating that the forma-
tion of product 2 is an exothermic process.
Due to product 2x’s instability in silica gel column
chromatography, it was transformed into stable and separa-
ble product 3x via a one-pot detosylation process in the
presence of a magnesium scraps with methanol (Scheme 6).
The product 2y could be easily transformed into detosyl-
ated derivative 3y in good yield (Scheme 6). The compound
3x is a useful material since it has excellent UV block activi-
ties,[9] and compound 3y could be used as a model com-
pound for treating tumors, cancer and hyper proliferative
diseases.[10]
[2] For a reviews, see: a) I. Volchkov, D. Lee, Chem. Soc. Rev. 2014,
43, 4381; for natural products syntheses, see: b) B. M. Trost,
F. D. Toste, J. Am. Chem. Soc. 2000, 122, 11262; c) B. M. Trost,
W. Tang, F. D. Toste, J. Am. Chem. Soc. 2005, 127, 14785; d)
A. K. Mandal, J. S. Schneekloth, K. Kuramochi, C. M. Crews,
Org. Lett. 2006, 8, 427; e) B. M. Trost, D. Amans, W. M. Segan-
ish, C. K. Chung, Chem. Eur. J. 2012, 18, 2961. For several
typical examples, see: f) S. Matsubara, K. Takai, H. Nozaki,
Tetrahedron Lett. 1983, 24, 3741; g) T. Hosogai, Y. Fujita, Y.
Ninagawa, T. Nishida, Chem. Lett. 1982, 357; h) J. Belgacem,
J. Kress, J. A. Osborn, J. Am. Chem. Soc. 1992, 114, 1501; i) J.
Jacob, J. H. Espenson, J. H. Jensen, M. S. Gordon, Organome-
tallics 1998, 17, 1835; j) G. Wang, A. Jimtaisong, R. L. Luck,
Organometallics 2004, 23, 4522; k) S. Bellemin-Laponnaz, H.
Gisie, J. P. Le Ny, J. A. Osborn, Angew. Chem. Int. Ed. Engl.
1997, 36, 976; Angew. Chem. 1997, 109, 1011.
[3] For a review, see: a) D. Lee, M. Kim, Org. Biomol. Chem. 2007,
5, 3418; For Au- and Pt-involved 1,3-transposition, see: b) K.
Miki, K. Ohe, S. Uemura, J. Org. Chem. 2003, 68, 8505; c) S.
López, E. Herrero-Gomez, P. Perez-Galan, C. Nieto-Ober-
huber, A. M. Echavarren, Angew. Chem. Int. Ed. 2006, 45,
6029; Angew. Chem. 2006, 118, 6175; d) C. Nieto-Oberhuber,
S. Lopez, M. P. Munoz, E. Jimenez-Nunez, E. Bunuel, D. J.
Cardenas, A. M. Echavarren, Chem. Eur. J. 2006, 12, 1694; e)
B. Martin-Matute, C. Nevado, D. J. Cardenas, A. M. Echav-
arren, J. Am. Chem. Soc. 2003, 125, 5757; f) E. J. Cho, M. Kim,
D. Lee, Org. Lett. 2006, 8, 5413; g) K. Ohe, M. Fujita, H.
Matsumoto, Y. Tai, K. Miki, J. Am. Chem. Soc. 2006, 128,
9270; h) D. J. Gorin, P. Dube, F. D. Toste, J. Am. Chem. Soc.
2006, 128, 14480. For other metal involved 1,3-transposition,
see:; i) M. Kim, R. L. Miller, D. Lee, J. Am. Chem. Soc. 2005,
127, 12818; j) T. Takeda, S. Kuroi, M. Ozaki, A. Tsubouchi,
Org. Lett. 2004, 6, 3207; k) J. Barluenga, P. García-García, D.
de Sáa, M. A. Fernández-Rodríguez, R. B. de la Rúa, A. Ball-
esteros, E. Aguilar, M. Tomás, Angew. Chem. Int. Ed. 2007, 46,
2610; Angew. Chem. 2007, 119, 2664; l) D. B. Kimball, T. J. R.
Weakley, R. Herges, M. M. Haley, J. Am. Chem. Soc. 2002,
124, 13463; m) D. B. Kimball, R. Herges, M. M. Haley, J. Am.
Chem. Soc. 2002, 124, 1572.
Scheme 6. Further transformation of products 2x and 2y.
In summary, we have explored a novel and efficient
gold(I)-catalyzed intramolecular 1,3-O-transposition reac-
tion under mild conditions. Through further transforma-
tions, two useful compounds can be easily obtained after
simple treatment. This new strategy demonstrates a practi-
cal protocol for synthesis of ynamides starting from yne
sulfonamides, which have a nitrogen atom tethered at alk-
ynyl terminal. The control experiments and DFT calcula-
tion results give experimental and theoretical explanations
for the proposed intramolecular 1,3-O atom transfer
mechanism, and also show that the formation of product 2
is an exothermic process.
[4] a) C. Morrill, R. H. Grubbs, J. Am. Chem. Soc. 2005, 127,
2842; b) C. Morrill, G. L. Beutner, R. H. Grubbs, J. Org. Chem.
2006, 71, 7813; c) J. Belgacem, J. Kress, J. A. Osborn, J. Am.
Chem. Soc. 1992, 114, 1501; d) J. Belgacem, J. Kress, J. A. Os-
born, J. Mol. Catal. 1994, 86, 267; e) P. Chabardes, E. Kuntz,
J. Varagnat, Tetrahedron 1977, 33, 1775.
[5] a) M. Franck-Neumann, P. Geoffroy, J. J. Lohmann, Tetrahe-
dron Lett. 1983, 24, 1775; b) M. Franck-Neumann, P. Geoffroy,
Tetrahedron Lett. 1983, 24, 1779; c) R. A. Seburg, E. V. Pat-
terson, J. F. Stanton, R. J. McMahon, J. Am. Chem. Soc. 1997,
119, 5847.
[6] For both ends attached to carbon atoms, see: a) R. K. Shi-
roodi, M. Soltani, V. Gevorgyan, J. Am. Chem. Soc. 2014, 136,
9882; b) T. Takeda, S. Kuroi, M. Ozaki, A. Tsubouchi, Org.
Lett. 2004, 6, 3207; c) T. Takeda, M. Ozaki, S. Kuroi, A. Tsu-
bouchi, J. Org. Chem. 2005, 70, 4233.
[7] For review on ynamides, see: a) K. A. DeKorver, H. Li, A. G.
Lohse, R. Hayashi, Z. Lu, Y. Zhang, R. P. Hsung, Chem. Rev.
2010, 110, 5064. For gold-catalyzed of ynamide, see:; b) C. Li,
L. Zhang, Org. Lett. 2011, 13, 1738; c) S. N. Karad, R.-S. Liu,
Angew. Chem. Int. Ed. 2014, 53, 9072; Angew. Chem. 2014, 126,
9218; d) S. N. Karad, S. Bhunia, R.-S. Liu, Angew. Chem. Int.
Ed. 2012, 51, 8722; Angew. Chem. 2014, 124, 8852.
Acknowledgments
The authors are grateful for the financial support from the
National Basic Research Program of China [grant number (973)-
2015CB856603] and the National Natural Science Foundation of
China (NSFC) (grant numbers 20472096, 21372241, 21361140350,
4112
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Gold(I)-Catalyzed 1,3-O-Transposition Reactions
[8] D. Wang, R. Cai, S. Sharma, J. Jirak, S. K. Thummanapelli,
N. G. Akhmedov, H. Zhang, X. Liu, J. L. Petersen, X. Shi, J.
Am. Chem. Soc. 2012, 134, 9012.
[9] a) Y. G. Han, I. J. Byun, B. R. Jeon, H. J. Lee, S. H. Kim, Pro-
piolamide-based compound with excellent UV blocking properties
utilized in various devices such as display device, propiolamide-
based polymer, and manufacturing method of the compound,
patent KR 2014099388 A 20140812; b) Y. G. Han, I. J. Byun,
B. R. Jeon, H. J. Lee, S. H. Kim, Ultraviolet blocking film used
in e.g. display devices, comprising ultraviolet blocking compound
(e.g. propiolamide compounds or acrylamide-based compounds),
and a polymer binder, patent KR 2014092973 A 20140725.
[10] D. J. Austin, V. A. Nguyen, D. Pupowicz, A. Deisseroth, T.
Wang, E. Lerma, Compounds and methods for treating tumors,
cancer, and hyperproliferative diseases, United States patent US
7304092 B1.
Received: May 13, 2015
Published Online: June 2, 2015
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