Gold-catalyzed cycloisomerization reactions of boronated enynes

Article abstract of DOI:10.1016/j.tetlet.2010.11.051

Gold (I) complexes generated from a mixture of gold and silver salts were found to be highly reactive for the cycloisomerization reactions of boronated enynes. Both alkynyl pinacol boronates and alkenyl pinacol boronates were tolerated, affording products

Full text of DOI:10.1016/j.tetlet.2010.11.051

Tetrahedron Letters 52 (2011) 321–324
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold-catalyzed cycloisomerization reactions of boronated enynes
⇑
Jack Chang Hung Lee, Dennis G. Hall
Department of Chemistry, Gunning-Lemieux, Chemistry Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
a r t i c l e i n f o
a b s t r a c t
Article history:
Gold (I) complexes generated from a mixture of gold and silver salts were found to be highly reactive for
the cycloisomerization reactions of boronated enynes. Both alkynyl pinacol boronates and alkenyl pinacol
boronates were tolerated, affording products in moderate to high yields. Interestingly, the ratio of the dif-
ferent endo- and exo-products was heavily dependent on the position of the boronate functionality. Fur-
ther applications including Suzuki–Miyaura cross coupling and oxidation reactions could be carried out,
affording a variety of synthetically useful products.
Received 23 September 2010
Revised 2 November 2010
Accepted 9 November 2010
Available online 16 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Transition metal catalyzed cycloisomerization reactions have
become increasingly important in modern day organic chemistry
due to their ability to increase structural complexity in an atom
economical manner.1 The high functional group compatibility of
these cycloisomerizations has extended the applications of these
reactions to various structural motifs, such as boronated enynes.
Schreiber and co-worker have described an innovative approach
of performing enyne metathesis on enynes generated in situ from
the corresponding boronic esters.2 On the other hand, Renaud et al.
have described methods carrying out ring closing metathesis or
enyne metathesis from the corresponding boronated dienes or bor-
onated enynes (Scheme 1, Eq. 1).3 More recently, Carboni and co-
workers demonstrated that palladium catalyzed enyne cycloiso-
merization could be carried out on boronated enynes (Scheme 1,
Eq. 2),4 affording a diene functionality that could undergo the
Diels–Alder cycloaddition/allylboration sequence to afford tricyclic
core structures in a one pot fashion. In the same report, two exam-
ples of rhodium and platinum catalyzed cycloisomerization reac-
tions could also be carried out affording different products. As
part of our program aimed at expanding the synthetic utility of
unsaturated boronates,5 we became interested in gold-catalyzed
cycloisomerization reactions with boronated enynes (Scheme 1,
Eq. 3). Interest in gold-catalyzed reactions has increased tremen-
dously in recent years mainly due to their high efficiency towards
alkyne activation.6 Various nucleophiles have been shown to react
remarkably well with gold activated alkynes, affording a range of
diverse products under mild conditions with both great efficiency
and chemoselectivity. Due to our interest in broadening the scope
of reactions tolerating the boronate functionality, we planned a
study of gold-catalyzed enyne cyclomerization reactions with bor-
onated enynes. Alkynyl boronates are easily accessible through
Brown’s methodology.7 As a result, we focused our initial study
on alkynyl pinacol boronate 1a (Table 1). Following the typical pro-
cedure described by the Echavarren group,8 the desired product 2a
could be accessed with a 20% or 32% yield depending on the silver
salt used. It was found that a significant amount of protodeboro-
nated product was obtained as the by-product (Table 1, entries
1–2). Altering the gold sources proved to be ineffective, either
affording the undesired deboronated products or the unconverted
starting materials (Table 1, entries 3–4). Various solvents were also
tested, and dichloromethane was the most effective, delivering the
product with a relatively higher yield (Table 1, entries 5–8). Even-
tually it was found that lowering the reaction time to 3 h and the
catalyst loading to 5 mol % decreases the amount of the deboronat-
ed side product and increases the yield of the desired product 2a to
PCy3
Cl
H
Ph
Ru
B(OR)2
Cl
PCy3
B(OR)2
X
(1)
X
CH2Cl2 or benzene
B(OR)2
Pd2(dba)3•CHCl3
PPh3, AcOH
B(OR)2
X
(2)
(3)
X
toluene
R1
Au-catalyzed
cycloisomerization
R2
R1
R2
X
X
O
R1/R2: H/ Bpin, or
R1/R2: Bpin/H
Bpin =
BH
O
⇑
Corresponding author. Tel.: +1 780 492 3141; fax: +1 780 492 8231.
E-mail address: dennis.hall@ualberta.ca (D.G. Hall).
Scheme 1. Cycloisomerization reactions involving boronated enynes.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.051

322
J. C. H. Lee, D. G. Hall / Tetrahedron Letters 52 (2011) 321–324
Table 1
conditions. We found that 2a underwent <10% protodeauration
over a period of 1 day, thus indicating that transmetallation/proto-
deauration sequence was only a minor pathway leading to the loss
of the boronate moiety. By analyzing the potential intermediates
through the proposed mechanism (Scheme 2, Eq. 5 is the originally
proposed mechanism for the endo-product,9a,b and Eq. 6 is another
potential pathway proposed in 20079c), we surmised that the pina-
col boronate could potentially participate in a competitive elimina-
tion event with the gold species, resulting in a mixture of the
desired product 2a with the protodeboronated product (Scheme 2,
Eq. 6, path a). In order to circumvent this problem, we turned to
alkenyl pinacol boronates, where the proposed intermediate would
avoid competitive elimination with the gold species, thus poten-
tially favoring the desired product.
Indeed, boronated enyne 1b experienced little problem under-
going the desired cycloisomerization reaction to give a mixture
of endo- or exo-products 2b and 3b in a 6:1 ratio (Table 2, entry
1).10 Interestingly, the endo-product, which is usually the minor
product when malonate substrates were used in the original pub-
lications,8 becomes the major product in this case. By switching the
position of the boronate, the ratio can then be reversed to favor the
exo-product 3c in a 5:1 ratio over the endo-product 2c (Table 2, en-
try 2). Trisubstituted alkenyl boronate 1d also works well, afford-
ing the exo-product with a 79% yield without any observation of
the endo-isomer (Table 2, entry 3). Switching one of the malonate
esters to a ketone was somewhat tolerated, lowering the yield to
51% (Table 2, entry 4), while changing the malonate moiety to a
tosylamino group completely suppressed the reactivity of the com-
pound (Table 2, entry 5). Unfortunately, the alkyne substituent
proves to be very crucial, and replacing the substituent from
hydrogen to a phenyl ring also depresses the reactivity of the sub-
strate (Table 2, entry 6). It is important to note here that prolonged
reaction times in some cases lead to a significant amount of pro-
todeboronated by-products, implying that transmetallation/proto-
deauration sequence could play a larger role depending on the
substrates.9
Optimization of reaction conditions for the cycloisomerization reaction of boronated
enyne 1aa
pinB
Cat. (20 mol%)
solvent
TsN
25 °C
Bpin
NTs
2a
endo
1a
Entry
1
Cat.
Solventb
CH2Cl2
Yieldc (%)
AuPPh3Cl
AgBF4
AuPPh3Cl
AgSbF6
AuCl3
AuCl
AuPPh3Cl
AgSbF6
AuPPh3Cl
AgSbF6
AuPPh3Cl
AgSbF6
AuPPh3Cl
AgSbF6
20
32
2
CH2Cl2
e
3
4
5
CH2Cl2
CH2Cl2
Toluene
—
—
e
15
6
7
8
9
MeOH
THF
Trace
d
—
e
CH3CN
CH2Cl2
—
AuPPh3Cl
AgSbF6
45f
a
Reaction procedure: enyne (0.3 mmol) and the catalysts (0.06 mmol each) were
mixed in the indicated solvent (1 mL), stirred at 25 °C for 5 h.
b
Dry, distilled solvents were employed.
Isolated yields of product after purification by flash column chromatography.
Deboronated product was isolated.
No conversion.
c
d
e
f
5 mol % catalyst loading, 3 h (the optimized conditions).
45% (Table 1, entry 9). Remarkably, no exo-product (Scheme 2, Eq.
4) was observed and only the endo-product was isolated in this
reaction. This result is unprecedented because the original studies
by the Echavarren group suggested that only enynes with unsub-
stituted alkynes could generate the endo-product.8c Despite this
interesting observation, 25% of the deboronated product could still
be isolated. To probe the potential possibility that product 2a could
participate in a transmetallation/protodeauration sequence,9 we
subjected the isolated dienyl boronate 2a back into the reaction
To broaden the synthetic utility of these cycloisomerization
products, we then carried out various transformations with these
newly acquired dienyl boronates. Suzuki–Miyaura cross coupling
reaction with iodobenzene afforded the desired cross coupling
exo-cyclization pathway (not observed)
R2
H
R1
R1
R2
R3
AuL
Z
R1
R2
Z
(4)
R3
R1
Z
R3
R3
AuL
Z
R2
LAu
endo-cyclization pathway
R2
R3
R1
R2
R1
Z
Z
AuL
AuL
R3
R1
(5)
R3
R1
Z
Z
R3
AuL
(Z = NTs, R1=R2=CH ,
R3 = Bpin)
R1
R2
2a
R2
3
R2
R3
H
R1
a
b
R1
R2
R2
Z
a
Au
Z
R1
R2
(6)
R3
Z
b
R3
R3
AuL
Z
R1
R2
LAu
Z
when R3 = Bpin
2a
Scheme 2. Mechanistic proposal for the formation of exo- and endo-products along with deboronated side products.

J. C. H. Lee, D. G. Hall / Tetrahedron Letters 52 (2011) 321–324
323
Table 2
Substrate scope for the cycloisomerization of alkenyl boronatesa
R3
R2
R3
R1
AuPPh3Cl (2 mol%)
AgSbF6 (2 mol%)
R2
R2
R1
X
X
R3
CH2Cl2
R1
exo 3
X
endo 2
Entry
1
Enyne
t (h)
Products
pinB
Yieldb (%)
X = C(CO2Me)2
R1 = H
Bpin
MeO2C
MeO2C
R2 = Bpin
0.5
90% (2b:3b = 6:1)
95% (2c:3c = 1:5)
CO2Me
3 = H
MeO2C
2b
R
3b
1b
Bpin
X = C(CO2Me)2
R1 = Bpin
MeO2C
MeO2C
2
3
R
2 = H
0.5
0.5
Bpin
CO2Me
R3 = H
3c
MeO2C
1c
2c
Bpin
X = C(CO2Me)2
R1 = CH3
R2 = Bpin
R3 = H
MeO2C
MeO2C
79%
Me
1d
2d
pinB
Bpin
X = MeOCCCO2Me
R1 = H
MeOC
CO2Me
4
5
R2 = Bpin
0.5
12
51% (2e:3e = 6:1)
MeO2C
R3 = H
1e
MeOC
3e
Bpin
2e
X = NTs
R1 = H
R2 = Bpin
R3 = H
1f
pinB
pinB
TsN
c
—
NTs
3f
2f
Ph
Ph
X = C(CO2Me)2
R1 = H
Bpin
MeO2C
MeO2C
c
6
R2 = Bpin
R3 = Ph
12
—
CO2Me
MeO2C
1g
3g
2g
a
b
c
Reaction procedure: enyne (0.3 mmol) and the catalysts (0.006 mmol each) were mixed in the indicated solvent (3 mL), stirred at 25 °C for 30 min.
Isolated yields of product after purification by flash column chromatography. Products 2 and 3 are inseparable.
No conversion.
products 4 and 5 with a 55% yield in larger than 10 to 1 ratio, while
direct oxidation of the pinacol boronates 2c and 3c (1:5 ratio) ren-
dered the a,b-unsaturated ketone 6 (Scheme 3), where the remote
olefin had been isomerized into the internal position under the ba-
sic conditions employed. These synthetic applications indicate the
advantages of carrying out cycloisomerization reactions with bor-
onated enynes and the versatility of organoboron reagents, where
a plethora of reactions could be planned to access various different
functionalities.
Ph
Bpin
MeO2C
MeO2C
MeO2C
MeO2C
PhI
Pd(OAc)2
PPh3
K3PO4
4
5
2b
dioxane/H2
O
reflux, 15 h
Bpin
Ph
MeO2
C
MeO2C
MeO2C
MeO2C
3b
In summary, we have successfully developed a protocol for
gold-catalyzed cycloisomerization reactions with boronated eny-
nes. Both alkynyl boronates and alkenyl boronates reacted effec-
tively and provided the desired products in an atom economical
manner with a large increase in structural complexity. This gold-
catalyzed cycloisomerization protocol generates diene products
that differ from the previously reported enyne metathesis or palla-
dium catalyzed cycloisomerization reactions, thus complementing
the existing synthetic tools for organic chemists. With the versatile
boronate functionality installed in the products, these synthetically
useful intermediates can then be either elaborated into biologically
active natural products, or be used as a platform for diversity-
oriented synthesis towards the development of important
pharmaceuticals.
2b:3b
(
= 6:1)
55% (4:5 > 10:1)
Bpin
CO2Me
MeO2C
MeO2C
MeO2C
NaBO3
2c
THF/H2O
25 °C, 30 min
O
6
MeO2C
MeO2C
3c
2c:3c
75%
Bpin
(
= 1:5)
Scheme 3. Suzuki–Miyaura coupling and oxidation reactions of the corresponding
cycloisomerized boronated products.

324
J. C. H. Lee, D. G. Hall / Tetrahedron Letters 52 (2011) 321–324
Carosi, L.; Hall, D. G. Angew. Chem., Int. Ed. 2007, 46, 5913–5915; (i) Lee, J. C. H.;
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This research was generously funded by the Natural Sciences
and Engineering Research Council (NSERC) of Canada and the Uni-
versity of Alberta. J.L. thanks the U of A for a Queen Elizabeth II
Graduate Scholarship.
Supplementary data
Supplementary data (experimental procedures, NMR spectra)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.11.051.
References and notes
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doi:10.1002/anie.201003349.
10. Typical experimental procedure for cycloisomerization of boronated enynes: A
solution of boronated enyne (0.3 mmol) in dichloromethane (1.5 mL) was
added to
a mixture of AuPPh3Cl (2.0 mol %) and AgSbF6 (2.0 mol %) in
2. (a) Micalizio, G. C.; Schreiber, S. Angew. Chem., Int. Ed. 2002, 41, 152–154; (b)
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dichloromethane (1.5 mL). The mixture was stirred at room temperature for
30 min, before being filtered through a silica gel plug. The resulting solution
was then evaporated in vacuo to afford the crude product. The residue was
purified by silica gel column chromatography (EtOAc/hexane = 3:17) to give
the title 2d as a colourless oil in pure form. 1H NMR (400 MHz, CDCl3) d 7.22 (d,
J = 18.2 Hz, 1H), 5.38 (d, J = 18.1 Hz, 1H), 3.72 (s, 3H), 3.15 (br s, 2H), 3.08 (br s,
2H), 1.83 (br s, 3H), 1.26 (s, 12H); 13C NMR (100 MHz, CDCl3) d 172.5, 142.1,
139.0, 132.6, 83.1, 57.0, 52.8, 46.8, 40.5, 24.7, 13.8; (the boron-bound carbon
was not detected due to quadrupolar relaxation) 11B NMR (128 MHz, CDCl3) d
29.9; IR (microscope, cm-1) 2979, 2955, 1737, 1642, 1603; HRMS (ESI) for
C
18H27BO6: calcd 350.1901; found 350.1907.