Gold-catalyzed addition of N-hydroxy heterocycles to alkynes and subsequent 3,3-sigmatropic rearrangement

Article abstract of DOI:10.1021/ol4000789

Gold-catalyzed intermolecular addition of hydroxybenzotriazole derivatives to alkynes at room temperature, gives vinyl ethers 3 in high yields and with excellent regioselectivity. Unlike many other vinyl ethers, 3 can easily be purified by regular silica-gel chromatography. On heating, 3,3-sigmatropic rearrangement of 3 gives access to highly functionalized benzotriazoles. This two-step sequence represents an efficient oxygen transfer protocol which incorporates a nucleophilic oxygen atom into an alkyne group. Reaction of 3 with an electrophilic fluorinating reagent (Selectfluor) gives a fluorinated ketone regioselectively and in high yield.

Full text of DOI:10.1021/ol4000789

ORGANIC
LETTERS
2013
Vol. 15, No. 4
724–727
Gold-Catalyzed Addition of N‑Hydroxy
Heterocycles to Alkynes and Subsequent
3,3-Sigmatropic Rearrangement
Manish Kumar,† Martin Scobie,‡ Mark S. Mashuta,† Gerald B. Hammond,*,† and Bo Xu*,†
Department of Chemistry, University of Louisville, Louisville, Kentucky 40292,
United States, and Science for Life Laboratory, Division of Translational Medicine and
Chemical Biology, Department of Medical Biochemistry and Biophysics,
Karolinska Institutet, Stockholm, Sweden
gb.hammond@louisville.edu; bo.xu@louisville.edu
Received August 10, 2012
ABSTRACT
Gold-catalyzed intermolecular addition of hydroxybenzotriazole derivatives to alkynes at room temperature, gives vinyl ethers 3 in high yields
and with excellent regioselectivity. Unlike many other vinyl ethers, 3 can easily be purified by regular silica-gel chromatography. On heating,
3,3-sigmatropic rearrangement of 3 gives access to highly functionalized benzotriazoles. This two-step sequence represents an efficient oxygen
transfer protocol which incorporates a nucleophilic oxygen atom into an alkyne group. Reaction of 3 with an electrophilic fluorinating reagent
(Selectfluor) gives a fluorinated ketone regioselectively and in high yield.
Gold catalysis is regarded as one of the landmark
additions to the field of organic synthesis.1 In particular,
gold catalyzed addition of O-nucleophiles to alkynes will
first give synthetically important vinyl ether products,2
but they are usually not stable enough to be isolated by
standard silica gel chromatography.2 Here we report gold
catalyzed addition of N-hydroxy heterocycles to alkynes
to give an easy isolable vinyl ether product 3. The sub-
sequent 3,3-sigmatropic rearrangement of 3 (Scheme 1a)
gives access to pharmaceutically important functionalized
N-heterocycles.3 Furthermore, reaction of 3 with electro-
philes, such as the electrophilic fluorinating reagent Select-
fluor, gives functionilized R-fluoroketones.
The two-step sequence (nucleophilic addition/sigmatropic
rearrangement) represents an efficient protocol for transfer of
† University of Louisville.
‡ Karolinska Institutet.
(1) (a) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232–5241.
(b) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994–2009. (c) Hashmi,
A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766–1775. (d) Gorin,
D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351–3378.
(e) Widenhoefer, R. A. Chem.;Eur. J. 2008, 14, 5382–5391.
(2) Muzart, J. Tetrahedron 2008, 64, 5815–5849.
(3) (a) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc.
2008, 130, 416–7. (b) Trost, B. M.; Maulide, N.; Livingston, R. C. J. Am.
Chem. Soc. 2008, 16502–16503. (c) Fustero, S.; Moscardo, J.; Jimenez,
D.; Perez-Carrion, M. D.; Sanchez-Rosello, M.; Del Pozo, C. Chemistry
2008, 14, 9868–72. (d) Wu, W.; Su, W. J. Am. Chem. Soc. 2011, 133,
11924–11927.
(4) (a) Xiao, J.; Li, X. Angew. Chem., Int. Ed. 2011, 50, 7226–7236.
(b) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132,
3258–3259. (c) Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132,
8550–8551. (d) Lu, B.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2010, 132,
14070–14072. (e) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133,
8482–8485. (f) Cui, L.; Zhang, G.; Peng, Y.; Zhang, L. Org. Lett. 2009,
11, 1225–1228. (g) Luo, Y.; Zhang, G.; Hwang, E. S.; Wilcoxon, T. A.;
Zhang, L. Beilstein J. Org. Chem. 2011, 7, 596–600. (h) Shapiro, N. D.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160–4161. (i) Li, G.; Zhang,
L. Angew. Chem., Int. Ed. 2007, 46, 5156–5159. (j) Fang, R.; Yang, L.
Organometallics 2012, 31, 3043–3055.
r
10.1021/ol4000789
Published on Web 02/04/2013
2013 American Chemical Society

a nucleophilic oxygen atom to an alkyne group (Scheme 1a).
Gold-catalyzed oxygen transfers are synthetically useful and
attract much attention.4 In 2009, Asensio and co-workers
applied the oxygen transfer concept in their intermolecular
gold-catalyzed addition of sulfoxides to alkynes which
allowed preparation of diverse sulfur containing arenes
(Scheme 1b).5 A similar approach was employed by Zhang
and co-workers in their synthesis of 2-alkylindoles from N-
arylhydroxylamines and terminal alkynes (Scheme 1c).6
We selected the reaction of 4-hydroxyhex-1-yne 1a with
N-hydroxybenzotriazole 2a as our model reaction (Table 1).
To our delight, when we treated 1(1 equiv) with 2a (1.1 equiv)
in the presence of a standard gold catalyst, i.e., Ph3PAuCl
(5%) with AgOTf (5%), we acquired a near-quantitative
isolated yield of the vinyl ether 3aa, using DCE (dichloro-
ethane) as solvent at rt (Table 1, entry 1). Reducing the load-
ing of gold catalyst to 1% did not reduce the yield, although
it lengthened the reaction time (Table 1, entry 2). When we
reduced the amount of 2a from 1.5 to 1.1 equiv, either in DCE
or acetonitrile, the reaction yields were still excellent, although,
the reaction was slower in acetonitrile (Table 1, entries 3ꢀ4).
With optimized conditions in hand, we studied the reaction
scope for synthesis of other vinyl ethers 3 (Table 2).
Terminal alkynes bearing aliphatic substituents (Table 2,
entries 1, 3, 5, 7, 9) afforded good to excellent yields of the
expected products. Functional groups such as a hydroxyl
group (Table 2, entries 1 and 7), methoxy groups (Table 2,
entry 5), and alkenes (Table 2, entry 6) were well tolerated.
In the case of aromatic alkynes, the reaction also gave
high yields (Table 2, entries 2, 4). When we reacted 1,6-
heptadiyne with 2.2 equiv of 2a, an excellent yield of
3ha was obtained (Table 2, entry 8). When substituted
N-hydroxybenzotriazoles (Table 2, entries 10ꢀ13) were
screened, we found that N-hydroxybenzotriazoles substi-
tuted with electron-donating groups (Table 2, entries 12,
13) or with electron-withdrawing groups (Table 2, entries
10, 11) also gave excellent yields of product 3. Moreover,
when we used N-hydroxy-7-azabenzotriazole, we also iso-
lated high yields of the expected 7-azabenzotriazole deri-
vatives (Table 2, entries 14ꢀ16). We alsoinvestigated use of
an allene substrate (Table 2, entry 17). In this case, when
Scheme 1. Gold-Catalyzed Oxygen Transfer Reactions
Figure 1. ORTEP-3 diagram of 3od showing 50% ellipsoids.
˚
Selected bond lengths (A) O1ꢀN1, 1.3697(18); O1ꢀC6,
1.418(2); C6ꢀC7, 1.313(3); N1ꢀN2, 1.345(2); N2ꢀN3, 1.309(2).
Table 1. Reaction Optimization for Synthesis of Vinyl Ether 3
entry
equiv of 2
solvent
time (h)
isolated yield (%)
Figure 2. ORTEP-3 diagram of 4e illustrating two unique con-
formers present in the asymmetric unit shown at 50% ellipsoids.
A third molecule identical to the top conformer in the asym-
metric unit has been omitted for clarity. Additionally, only
H atoms attached to N atoms are shown. Selected bond lengths
1
1.5
1.5
1.1
1.1
DCE
6
24
8
quantitative
quantitative
99%
2a
3
DCE
DCE
4
CH3CN
16
quantitative
˚
(A): O1ꢀC8, 1.2238(19); C6ꢀC7, 1.504(2); C7ꢀC8, 1.516(2);
a Ph3PAuCl (1%), AgOTf (1%).
N1ꢀN2, 1.3497(17); N2ꢀN3, 1.3130(19).
Org. Lett., Vol. 15, No. 4, 2013
725

Table 2. Synthesis of Vinyl Ether Intermediates
a 2.2 equiv of 2a were used.
726
Org. Lett., Vol. 15, No. 4, 2013

allene 1k was treated with N-hydroxybenzotriazole 2a, we
obtained 3qa in lower yield (17%); the majority of un-
reacted allene 1k was recovered, indicating that an allene is
less reactive than the corresponding alkyne under these con-
ditions. Interestingly, 1-hydroxyindazole (2e),7 N-hydroxy-4-
quinolone (2f),8 and N-hydroxyquinazolinediones (2g)9 did
not react with alkynes under the same conditions (Table 2,
entries 18ꢀ20). The reasons for this are not clear to us at this
point. Furthermore, we also examined a few N-oxides such as
benzo[c]cinnoline N-oxide, and benzofuroxan, but they did
not show any reactivity with alkynes under the same condi-
tions. Moreover, we also tested the reaction of internal
alkynes such as 2-decyne and 5-decyne with N-hydroxyben-
zotriazole (2a), but their reactions were very sluggish.
Scheme 2. Scope for 3,3-Sigmatropic Rearrangements of 3
In nearly all cases the reaction proceeds regioselectively.
However, reaction of propargyl alcohol 1g (Table 2, entry
7) also led to formation of a minor regioisomer 3ga0 (12%
yield), possibly due to steric reasons. The structure of 3od
was confirmed by X-ray crystallography (Figure 1).
Next, we investigated the use of vinyl ethers 3 as useful
synthetic intermediates. We first investigated 3,3-sigma-
tropic rearrangements of 3, which would lead to formation
of new CꢀC bonds affording functionalized benzotria-
zoles. We investigated the effects of Lewis acids, bases,
solvents, and temperature and found dioxane/100 °C was
optimal for rearrangement. We found that 3,3-sigmatropic
rearrangement of vinylethers3gives the 7-substituted1-H-
benzotriazoles 4 as the major product, but we also isolated
the N-substituted ketones 5 as minor side products. A
detailed mechanism explaining the formation of 5 is not
clear yet. The structure of 4e was confirmed unambigu-
ously by X-ray crystallography (Figure 2). Depending on
recrystallization conditions, either tautomer of 4e could be
obtained. In order to determine some of the scope of
this transformation, we investigated several different vinyl
ether substrates (Scheme 2). Conversion into the expected
7-substituted benzotriazoles 4 proceeded with moderate to
good yield (40ꢀ75%).
(eq 1). By contrast, many similar literature fluorination
methods are known to suffer from poor regioselectivity.11
In conclusion, we have developed a high yielding gold-
catalyzed synthesis of HOBt derived vinyl ethers 3 and
briefly explored their synthetic utility. Thus, 3,3-sigma-
tropic rearrangement of 3 gives access to functionalized
N-heterocycles, while electrophilic fluorination of 3
gives high yielding regioselective access to a functiona-
lized fluoroketone. We are now exploring other synthetic
applications of these useful intermediates 3.
Acknowledgment. We are grateful to the National
Science Foundation for financial support (CHE-1111316).
And we acknowledge the support provided by the CREAM
Mass Spectrometry Facility (University of Louisville)
funded by NSF/EPSCoR (EPS-0447479). M.S.M. thanks
the Department of Defense (W81XWH) from the Teleme-
dicine and Advanced Technology Research Center of the US
Army, the Department of Energy (DEFG02-08CH11538),
and the Kentucky Reasearch Challenge Trust Fund for the
upgrade of our X-ray facilities.
Encouraged by the utility of HOBt vinyl ethers in the
synthesis of functionalized benzotriazoles, we explored their
use in the synthesis of R-fluoroketones. Fluoroketones
are known to be important intermediates and targets in
medicinal chemistry.10 However their regioselective synth-
esis is often nontrivial. We were pleased to discover that
the reaction of 3 with Selectfluor gave the functionalized
fluoroketone 6 regioselectively and in 83% isolated yield
Supporting Information Available. CCDC-918814 and
918815 contain the supplementary crystallographic in-
formation for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Experimental procedure, compound characterization,
and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(5) Cuenca, A. B.; Montserrat, S.; Hossain, K. M.; Mancha, G.;
ꢀ
ꢀ
Lledos, A.; Medio-Simon, M.; Ujaque, G.; Asensio, G. Org. Lett. 2009,
11, 4906–4909.
(6) (a) Wang, Y.; Ye, L.; Zhang, L. Chem. Commun. 2011, 47, 7815–
7817. (b) Wang, Y.; Liu, L.; Zhang, L. Chem. Sci. 2013, 4, 739–746.
(7) Lehmann, F.; Koolmeister, T.; Odell, L. R.; Scobie, M. Org. Lett.
2009, 11, 5078–5081.
(8) Loudon, J. D.; Tennant, G. Q. Rev., Chem. Soc. 1964, 18, 389–413.
(9) Spence, T. W. M.; Tennant, G. J. Chem. Soc., Perkin Trans. 1
1972, 0, 97–102.
(10) (a) Wang, W.; Jasinski, J.; Hammond, G. B.; Xu, B. Angew.
Chem., Int. Ed. 2010, 49, 7247–7252. (b) Guo, Y.; Twamley, B.; Shreeve,
J. n. M. Org. Biomol. Chem. 2009, 7, 1716–1722. (c) Kim, K.-Y.; Kim,
B. C.; Lee, H. B.; Shin, H. J. Org. Chem. 2008, 73, 8106–8108. (d)
Prakash, G. K. S.; Beier, P. Angew. Chem., Int. Ed. 2006, 45, 2172–2174.
(11) de Haro, T.; Nevado, C. Adv. Synth. Catal. 2010, 352, 2767–2772.
The authors declare no competing financial interest.
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