Silaborative Carbocyclizations of 1,7-Enynes. Diastereoselective Preparation of Chromane Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b03479

Palladium(0)-catalyzed carbocyclization of 1,7-enynes mediated by (chlorodimethylsilyl)pinacolborane proceeds with 1,8-addition of the silicon and boron functions to give functionalized cyclohexane derivatives with boron attached to the exocyclic olefin. A variety of chromane dervatives are accessible by this method. In contrast to the analogous reactions with 1,6-enynes, the configuration of the newly formed stereogenic center is controlled by a stereogenic center present in the substrate.

Full text of DOI:10.1021/acs.orglett.5b03479

Letter
pubs.acs.org/OrgLett
Silaborative Carbocyclizations of 1,7-Enynes. Diastereoselective
Preparation of Chromane Derivatives
You-Cai Xiao and Christina Moberg*
KTH Royal Institute of Technology, Department of Chemistry, Organic Chemistry, SE 10044 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Palladium(0)-catalyzed carbocyclization of 1,7-enynes
mediated by (chlorodimethylsilyl)pinacolborane proceeds with 1,8-
addition of the silicon and boron functions to give functionalized
cyclohexane derivatives with boron attached to the exocyclic olefin. A
variety of chromane dervatives are accessible by this method. In contrast
to the analogous reactions with 1,6-enynes, the configuration of the
newly formed stereogenic center is controlled by a stereogenic center
present in the substrate.
yclizations of 1,6-enynes catalyzed by a variety of metal
complexes have been extensively studied, and numerous
ways.12 Our previous work included cyclization of 1,6-enyne 1
C
using (dimethylphenylsilyl)pinacolborane (2a)13 to give 3
(Scheme 1).14 Dichloro-N,N-bis[2,6-(diisopropyl)phenyl]-
synthetically versatile methods for the construction of
substituted five-membered carbocycles and heterocycles have
emerged from these studies.1 In contrast, examples of
cycloisomerizations or other types of alkene−alkyne couplings
of 1,7-enynes to provide six-membered rings are more rare, and
the cyclized products are often obtained in moderate yields.2
Bismetallative cyclizations employing interelement com-
pounds,3 which contain a bond between two main group
elements, lead to cyclic products containing two reactive
functional groups.4 Further functional group transformations of
the primarily obtained products generate large structural
diversity, thereby making bisfunctionalization−cyclizations
synthetically powerful processes. Whereas such methods have
been explored for 1,6-enynes, using Si−Sn, B−Sn, and B−Si
interelement compounds,5 borastannylative carbocyclization of
1-ethenyl-2-(2-propyn-1-yloxy)benzene is the single example of
a bisfunctionalization−cyclization generating a six-membered
carbocycle.6 Instead of the desired cyclic compounds, products
from 1,2-addition of the interelement compound to the triple
bond7 are commonly obtained.6
Scheme 1. Silaborative Cyclizations
́
Cardenas and co-workers have also reported cyclizations of
imidazolium (3-chloropyridine) palladium, Pd-PEPPSI-IPr,15
served as an efficient catalyst for the process, which provided
the products in excellent yields with control of regiochemistry
as well as olefinic bond configuration, the latter being a
consequence of the mechanism of the reaction.
The present work describes the extension of this method to
1,7-enynes. For these studies, (chlorodimethylsilyl)-
pinacolborane 2b,16 which exhibits higher reactivity than 2a17
and which results in products disposed for further trans-
formations,18 was used (Scheme 2). Reaction of 4 with
compound 2b in the presence of Pd-PEPPSI-IPr did not,
however, yield the desired cyclic compound but resulted in 1,2-
1,7-enynes8 and dienynes9 with concomitant introduction of a
single reactive group. Boron−boron compounds were used in
these reactions, but as a result of the mode of activation, the
reactions led to incorporation of only one boron function; with
most substrates the product with boron at the terminal alkene
carbon atom of the starting enyne was obtained as the sole
isomer. A monofunctionalized cyclohexane derivative was also
obtained by rhodium-catalyzed silylative cyclization of 4,4-
bis(carbomethoxy)oct-7-en-1-yne, using PhMe2SiH, which gave
a low yield (34%) of a product from initial addition of Pd−Si to
the alkyne and, thus, with the silyl function at the olefinic bond
of the product.10
Silaborative cyclizations11 are particularly attractive since the
resulting products are nontoxic and possess functions with
orthogonal reactivities, which can be transformed in a variety of
Received: December 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03479
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Silaborative Cyclization of 1,7-Enyne
addition to the triple bond, evidently as a result of reductive
elimination being more rapid than insertion of the alkene into
the Pd−C bond. In contrast, use of Pd2(dba)3·CHCl3 gave
compound 5, the product from 1,8-silaboration, as a single
diastereomer in a moderate yield of 51%.
Silaborative cyclization of 1-ethynyl-2-(2-propen-1-yloxy)-
benzene (6a) provided chromane derivative 7a, also as a single
diastereomer. The effect of variation of the reaction conditions
was studied using this substrate (Table 1). Best results were
a
Figure 1. Synthesis of chromane derivatives.
Table 1. Optimization of Reaction Conditions
Scheme 3. Preparation of Tetrahydroquinoline and
Chromene
entry
catalyst
Si−B solvent temp (°C) yield (%)
b
1
2
3
4
5
6
7
8
Pd-PEPPSI-IPr
Pd-PEPPSI-IPr
2b
2b
2b
2b
2b
2b
2a
2a
THF
20
50
20
50
50
20
50
50
73
76
65
58
56
60
−
b
THF
Pd2(dba)3·CHCl3
toluene
toluene
toluene
toluene
THF
Pd2(dba)3·CHCl3/Cy3P
Pd2(dba)3·CHCl3/Ph3P
(η3-C3H5)Pd-(Ph3P)Cl
b
Pd-PEPPSI-IPr
Pd2(dba)3·CHCl3
toluene
−
a
Reaction time 48 h, 5 mol % catalyst, ligand/metal 1.2:1, 6a/2b 1.2:1.
b
2-Propanol and pyridine were added prior to workup. MeMgCl used
products, and from attempted reaction of 12 only starting
material was recovered. In analogy to 13, 1,6-enynes with
terminal olefinic substiuents were unreactive, affording low
yields of products.14 In contrast, 1,6-enyne 15 gave a
cyclopentane derivative with an all-carbon quaternary center
(16) in the presence of Pd-PEPPSI-IPr (Scheme 4).
for reduction of Pd(II).
obtained from reactions catalyzed by Pd-PEPPSI-IPr in THF
(entries 1−2); at 50 °C, 76% of cyclized product was isolated.
With this substrate, reaction in the presence of Pd2(dba)3·
CHCl3 resulted in a lower yield (entry 3). Catalysts prepared
from Pd2(dba)3·CHCl3 and a phosphine ligand or (η3-
C3H5)Pd(PPh3)Cl also gave inferior results (entries 4−6).
Even at 50 °C, no cyclized product was obtained from
attempted addition of the less reactive silylborane 2a (entries 7
and 8).
Since chromanes and chromenes19 display useful biological
properties, it was of interest to examine whether substrates
functionalized in the aromatic ring underwent the cyclization
and at the same time study the influence of substituents on the
reactivity. The reactions proceeded smoothly using substrates
with both electron-donating and electron-withdrawing sub-
stituents to give products 7b−g; no major impact of the
electronic properties on the reactivity was observed (Figure 1).
By use of the same procedure, the N-tosyl analogue of 6a, 8,
afforded hydroquinoline derivative 9 in good yield, and
cyclization of enyne 10 produced an isomeric chromane,
11,20 employing catalytic Pd2(dba)3·CHCl3 (Scheme 3).
Attempted cyclizations of 1,7-enynes 12−14 under the
conditions specified in Table 1, entry 2, did not result in the
desired product; from 13 and 14 the compounds from 1,2-
addition to the triple bond were instead obtained as the single
Scheme 4. Cyclization of Substituted 1,6-Enyne
Only a few diastereoselective2a,c,k,p or enantioselective1d,2a,j
cyclizations of 1,7-enynes to cyclohexane derivatives have been
reported. We were pleased to observe that the relative
configuration of the newly formed center could be controlled
by substituents at sp3-centers of the 1,7-enyne. Thus,
cyclization of rac-17 gave a 5:1 diastereomeric mixture of 18
(Scheme 5). Chiral 1,6-enynes reacted with lower selectivity.
B
DOI: 10.1021/acs.orglett.5b03479
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Thus, under the same conditions, rac-19 gave cyclopentane
derivative 20 as a 1.7:1 mixture of diastereomers.
into the carbon−palladium bond and final reductive elimination
(Scheme 7).
Scheme 5. Cyclization of Chiral 1,7- and 1,6-Enynes
Scheme 7. Mechanism for Silaborative Cyclization
The stereochemistry of products 23 and 24 can be
rationalized by assuming a six-membered chair formed
transition state (A, Figure 3). Assuming that the phenyl
The trans-disubstituted enynes (R*,S*)-21 and (R*,S*)-22,
with both substituents in an equatorial position, reacted with
high diastereoselectivity to give bicyclic compounds 23 and 24,
respectively, whereas cis isomer (R*,R*)-25, in which the
1
alkyne substituent according to H NMR occupies an axial
position, gave a low yield of product when subjected to the
same reaction, most likely since addition to the axial alkyne
bond is sterically unfavored (Scheme 6).
Figure 3. Proposed transition states for stereochemistry-determining
migratory insertion.
group in 17 is forced into an axial position (B, Figure 3), as a
result of steric interaction with the olefinic bond when placed in
equatorial position (C, Figure 3), the observed stereochemistry
of the product can be explained.
Scheme 6. Diastereoselective Preparation of Bicyclic
Compounds
In conclusion, we have developed an atom economic
cyclization of 1,7-enynes, which provides cyclohexane deriva-
tives containing reactive boron and silicon functional groups.
With proper reaction conditions, products from 1,2-addition to
the alkyne can usually be avoided. Cyclization of chiral
substrates proceeds with high diastereoselectivity.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03479.
The relative configurations of 18, 23, and 24 were
determined by 1H NMR spectroscopy. In 18, NOE interactions
between H6a and H2 as well as between H6a and the methylene
protons adjacent to silicon showed that the substituents are
trans oriented with the silicon substituent occupying an axial
position as also verified by the coupling constants (Figure 2). In
contrast, the corresponding substituents in 23 and 24 were
found to be cis, as shown by a NOE interaction between Ha and
Hb.
Experimental procedures, characterization data, and
1
copies of H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kimo@kth.se.
Notes
The reaction is assumed to follow a mechanism analogous to
that of similar processes, consisting of oxidative addition of the
silylborane to Pd(0) followed by addition of PdSi and B to the
alkyne and stereochemistry-determining insertion of the alkene
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Carl Trygger Foundation for
Scientific Research. We are grateful to Sigma-Aldrich for a
generous gift of Pd-PEPPSI-IPr.
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C
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DOI: 10.1021/acs.orglett.5b03479
Org. Lett. XXXX, XXX, XXX−XXX