Stereocontrolled 1,3-phosphatyloxy and 1,3-halogen migration relay toward highly functionalized 1,3-dienes

Article abstract of DOI:10.1021/ja301243t

A double migratory cascade reaction of α-halogen-substituted propargylic phosphates to produce highly functionalized 1,3-dienes has been developed. This transformation features 1,3-phosphatyloxy group migration followed by 1,3-shifts of bromine and chlorine as well as the unprecedented 1,3-migration of iodine. The reaction is stereodivergent: (Z)-1,3-dienes are formed in the presence of a copper catalyst, whereas gold-catalyzed reactions exhibit inverted stereoselectivity, producing the corresponding E products.

Full text of DOI:10.1021/ja301243t

Communication
pubs.acs.org/JACS
Stereocontrolled 1,3-Phosphatyloxy and 1,3-Halogen Migration
Relay toward Highly Functionalized 1,3-Dienes
Roohollah Kazem Shiroodi, Alexander S. Dudnik, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
S
* Supporting Information
ABSTRACT: A double migratory cascade reaction of α-
halogen-substituted propargylic phosphates to produce
highly functionalized 1,3-dienes has been developed. This
transformation features 1,3-phosphatyloxy group migration
followed by 1,3-shifts of bromine and chlorine as well as
the unprecedented 1,3-migration of iodine. The reaction is
stereodivergent: (Z)-1,3-dienes are formed in the presence
of a copper catalyst, whereas gold-catalyzed reactions
exhibit inverted stereoselectivity, producing the corre-
sponding E products.
Table 1. Optimization of the Reaction Conditions
rocesses involving 1,n-halogen migrations are powerful
P
tools for obtaining valuable functionalized synthons for
organic chemistry.1−6 Among known methods are the base-
mediated 1,2-migration of halogen atoms to the anionic center
(the halogen dance reaction);1 migrations via halonium,2 allyl
cation,3 and α-halo metal carbene4 intermediates; halogen shifts
during radical processes;5 and metal-mediated alkyne−vinyl-
idene isomerizations.6 Furthermore, various migrations of a
range of other functionalizable groups are well-precedented.7
However, double migration reactions employing two functio-
nalizable groups are exceedingly rare.8 Herein we report a
double 1,3-phosphatyloxy and 1,3-halogen migration relay
leading toward highly functionalized 1,3-dienes. This cascade
transformation features stereodivergent formation of (Z)- and
(E)-dienes and 1,3-shifts of bromine and chlorine atoms as well
as the unprecedented 1,3-migration of iodine (eq 1).
a
b
entry
catalyst (mol %)
Ph3PAuOTf (5)
solvent T (°C) 2a:3a
yield, %
1
2
DCE
DCE
DCE
DCE
DCM
PhH
rt
−
−
−
−
−
0
0
0
0
0
Ph3PAuSbF6 (5)
Ph3PAuBF4 (5)
AgOTf (10)
PtCl2 (5)
rt
3
rt
4
50
40
50
40
80
80
100
50
80
0
5
d
6
AuI (5)
1:6
ND
d
7
AuCl3 (5)
PhH
1:1.5
1:2
ND
c
d
8
LAuCl2 (5)
DCE
DCE
PhMe
DCE
DCE
PhMe
ND
9
Ph3PAuCl (5)
1:9
65
96
50
85
0
10
11
12
13
(p-F3CC6H4)3PAuCl (5)
[CuOTf]2·PhH (10)
[CuOTf]2·PhH (10)
none
1:9
24:1
100:0
−
a
b
c
Determined by 1H NMR analysis. Isolated yields. L = 2-
d
pyridinecarboxylato. Yield was not determined.
Similarly, silver and platinum catalysts provided no reaction as
well (entries 4 and 5). However, the use of gold(I) and
gold(III) halides unexpectedly produced a mixture of the
stereoisomeric 1,3-dienes 2a and 3a, the products of a double
1,3-/1,3-migration sequence (entries 6−8), with no 1,3-diene A
observed. The use of Ph3PAuCl as the catalyst resulted in good
E stereoselectivity of the reaction and moderate yield (entry 9).
Use of a more electron-deficient phosphine ligand led to (E)-
diene 3a in an excellent yield and good stereoselectivity (entry
10). Further catalyst screening led to another surprising
observation: use of [CuOTf]2·PhH as the catalyst (entry 11)
provided the 1,3-/1,3-migration product 2a with excellent Z
selectivity! Gratifyingly, performing the reaction at a higher
We have previously shown that propargylic esters and
phosphates can undergo a facile double 1,3-/1,2-migratory
cascade to produce (E)-1,3-dienes7e (eq 2). We hypothesized
that it should be possible to expand the scope of the migrating
group to halogen (MG = Hal), thus aiming at the synthesis of
difunctionalized 1,3-dienes A (eq 3).
To this end, the isomerization of α-bromo propargylic
phosphate 1a was examined under a variety of conditions
(Table 1).9 We found 1a to be unaffected by the original
catalytic system (entry 1). Likewise, employing gold(I)
complexes with alternative counterions such as SbF6 or BF4
did not provide product formation at all (entries 2 and 3).
Received: February 7, 2012
Published: April 10, 2012
© 2012 American Chemical Society
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Communication
temperature resulted in the efficient and exclusive formation of
(Z)-1,3-diene 2a (entry 12). In addition, a control experiment
indicated that no product formation occurred in the absence of
a catalyst (entry 13).
Inspired by these observations, we first investigated the scope
of the Cu-catalyzed Z-selective reaction under the optimized
conditions (Table 2). Acyclic compounds 1a−c underwent this
diene products 2f and 2g as the sole stereoisomers in excellent
yields (entries 6 and 7). Similarly, substrates 1h−j bearing six-
membered rings furnished the desired products in good
yields.10 Remarkably, compound 1j underwent a 1,3-iodine
migration in this tandem transformation to produce the (Z)-
diene 2j as a single stereoisomer in moderate yield (entry 10).
To the best of our knowledge, this is the first example of 1,3-
migration of iodine.
Next, we investigated the Au-catalyzed cascade 1,3-
phosphatyloxy/1,3-halogen double migration reaction leading
to (E)-1,3-diene products (Table 3). Several halogenated
Table 2. Cu-Catalyzed Synthesis of (Z)-Dienes
Table 3. Au-Catalyzed Synthesis of (E)-Dienes
a
b
c
The major stereoisomer is shown. Isolated yields. Determined by
1H NMR analysis.
propargylic phosphates bearing acyclic substituents were
converted into the corresponding (E)-dienes in excellent yields
with good to excellent selectivities (entries 1−4). Likewise,
exocyclic (E)-dienes 3d and 3n could also be efficiently
obtained via this transformation. Finally, cyclohexyl-containing
substrate 1j underwent this cascade transformation with
exclusive 1,3-migration of the iodine atom to produce the
corresponding (E)-1,3-diene 3j in high yield, albeit with a lower
level of stereocontrol.
We propose the following plausible mechanism for these
cascade transformations (Scheme 1). First, coordination of the
metal to the π system of the alkyne 4 enables 1,3-migration of
the phosphatyloxy group to produce cyclic intermediate 5,
which upon elimination of the metal produces allenyl
phosphate 6 or 8.7d−g In the case of the Au catalyst, π-allyl
cation 711 is produced upon halogen abstraction from 6.
Subsequent delivery of a halide from the gold halide species to
7 occurs anti to the phosphate group, giving the (E)-diene 3.
Alternatively, in the case of copper catalysis, additional
coordination of the metal to the phosphate group of allene
a
b
c
d
The major stereoisomer is shown. Isolated yields. Z:E = 19:1. Z:E
= 9:1.
tandem transformation to produce dienes 2a−c efficiently
(entries 1−3). Chlorine-containing compound 1b gave a better
yield of the isomerization product than did its bromine-bearing
analogue 1a. Propargylic phosphate 1d possessing a cyclic
substituent was also effectively converted into the correspond-
ing exocyclic diene 2d in both good yield and stereoselectivity.
Likewise, heterocyclic compound 1e also provided 1,3-diene 2e
solely as the Z isomer in good yield. To our delight, cyclic-
ketone-derived substrates 1f−j provided the corresponding
products in moderate to excellent yields. Notably, these
substrates possessing a hydrogen atom adjacent to a halogen
provided 1,3-dienes 2f−j, the products of exclusive migration of
the halogen atom rather than the hydrogen atom. Isomerization
of substrates 1f and 1g containing five-membered rings gave the
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Miyaura−Suzuki cross-coupling reaction of the vinyl bromide
moiety. Thus, the diene 13 underwent the Kumada cross-
coupling reaction of the phosphatyloxy moiety in the presence
of an iron catalyst15 to give diene 14. Finally, a sequential
Miyaura−Suzuki reaction on the vinyl bromide14 and
phosphate16 groups of diene 2f furnished highly functionalized
diene 15 in good overall yield (Scheme 2).
Scheme 1. Proposed Mechanism for the Double
Phosphatyloxy/Halogen Migration Relay
In summary, a stereocontrolled isomerization of α-halo-
substituted propargylic phosphates into valuable highly
functionalized 1,3-dienes has been developed. This method-
ology features a double 1,3-phosphatyloxy and 1,3-halogen
migration relay. Depending on the choice of catalyst, synthesis
of either (Z)- or (E)-1,3-dienes could be achieved selectively in
typically high yields. Thus, (Z)-dienes could be obtained
exclusively in the presence of a copper catalyst, whereas the use
of a gold catalyst afforded predominantly (E)-dienes. Notably,
these transformations feature an unprecedented 1,3-migration
of iodine atoms. Finally, the synthetic utility of the obtained
1,3-dienes was demonstrated in efficient Diels−Alder and cross-
coupling reactions.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and characterization data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
takes place (8). Halogen abstraction by copper produces
phosphate-coordinated π-allyl complex 9.12 In this way,
subsequent delivery of the halogen is directed by the phosphate
group and occurs syn to it, producing the corresponding
isomeric Z product 2.13
AUTHOR INFORMATION
■
Corresponding Author
vlad@uic.edu
Next, the synthetic utility of the 1,3-dienes obtained via the
Cu-catalyzed isomerization reaction was examined (Scheme 2).
Notes
The authors declare no competing financial interest.
a
9
,
Scheme 2. Selected Transformations of (Z)-1,3-Dienes 2
ACKNOWLEDGMENTS
We thank the National Institutes of Health (GM-64444) for
financial support of this work.
■
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