Steric buttressing in the Pauson-Khand reactions of benzyl enynes

Article abstract of DOI:10.1016/j.tet.2017.08.053

The application of the intramolecular Pauson-Khand reaction of 1,n-enynes provides a convenient method for the construction of polycyclic frameworks but this process has largely been limited to the formation of 5,5- and 5,6-fused ring systems. In this report, we describe the application of the Pauson-Khand cyclization to 1,8-enynes embedded in an aromatic ring system wherein it is determined that the presence of steric buttresses in the form of t-butyl groups facilitates the cycloaddition. These reactions proceed in good yields with either thermal or oxidative activation and in the former case, the diastereoselectivities are high. An investigation of the tolerance of this cycloaddition to substitution around the 1,8-enyne demonstrates that only 2,2-disubstitution does not result in productive cyclization. Cycloadditions with hydroxyl groups at the propargylic position while leading to fused rings are compromised by side reactions leading to reduction and in some cases tautomerization. However, these byproducts are easily minimized through conversion of the hydroxyl group to the corresponding silyl ether.

Full text of DOI:10.1016/j.tet.2017.08.053

Tetrahedron 73 (2017) 6118e6137
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Steric buttressing in the Pauson-Khand reactions of benzyl enynes
Christian E. Madu, H.V. Rasika Dias, Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas Arlington, Arlington, TX 76019, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The application of the intramolecular Pauson-Khand reaction of 1,n-enynes provides a convenient
method for the construction of polycyclic frameworks but this process has largely been limited to the
formation of 5,5- and 5,6-fused ring systems. In this report, we describe the application of the Pauson-
Khand cyclization to 1,8-enynes embedded in an aromatic ring system wherein it is determined that the
presence of steric buttresses in the form of t-butyl groups facilitates the cycloaddition. These reactions
proceed in good yields with either thermal or oxidative activation and in the former case, the diaster-
eoselectivities are high. An investigation of the tolerance of this cycloaddition to substitution around the
1,8-enyne demonstrates that only 2,2-disubstitution does not result in productive cyclization. Cycload-
ditions with hydroxyl groups at the propargylic position while leading to fused rings are compromised by
side reactions leading to reduction and in some cases tautomerization. However, these byproducts are
easily minimized through conversion of the hydroxyl group to the corresponding silyl ether.
© 2017 Elsevier Ltd. All rights reserved.
Received 28 August 2017
Accepted 29 August 2017
Available online 4 September 2017
Keywords:
Cobalt-alkyne complex
Cycloaddition
Cyclopentenone
Diastereoselective
Oxidative
The Pauson-Khand (PK) reaction, the [2 þ 2 þ 1] co-cyclization
of an alkene, an alkyne and carbon monoxide has evolved into a
reliable method for the construction of cyclopentenones (1/3,
Scheme 1).1 In its original incarnation it involved the formation of
the dicobalt hexacarbonyl complex 2 and thermolysis to afford the
corresponding cyclopentenone (Scheme 1).2 This reaction is known
both intermolecularly and intramolecularly, and can be mediated or
catalyzed by a variety of metal complexes in addition to the classical
method with Co2(CO)8-derived complexes as initially reported by
Pauson and Khand. Photochemical variants are known and it has
even been extended to flow conditions.3 During the development of
this transformation other substrates have been found to engage in
this reaction including, allenes,4 dienes5 and even some hetero
cummulenes.4,6 However, despite these notable advances, there
still remain limitations with this cycloaddition that prevent the full
realization of its synthetic potential.7 For example, whereas there
are many examples of intramolecular cyclizations which result in
the formation of 5,5- and 5,6-fused bicyclic systems, the con-
struction of larger fused rings had not been described until quite
recently. Over the past fifteen years or so, several groups,8 including
ours have begun to identify strategies for overcoming these limi-
tations, leading to reports of the construction of medium-sized
rings annulated to the cyclopentenone.9 Our initial approach to
this problem was to use enynes which were constructed around an
aromatic scaffold10 as a means to pre-organize the reacting func-
tional groups, in essence to increase the concentration of the
reactive conformation (or conceivably decrease the concentration
of non-productive conformations).11 An advantage of this approach
was that it permitted the evaluation of additional structural ele-
ments on the aromatic ring to further reduce the conformational
degrees of freedom e using so-called steric buttressing.11bed In our
first generation studies of this approach, we employed aryl enynes
e.g., 4 and found that in the presence of ortho substituents cycli-
zation occurred to produce bridged ring systems e.g., 6 rather than
the initially expected cycloadducts (Scheme 2).11b,11c,12 In this
manuscript, we describe the extension of this chemistry to the
more conformationally flexible benzylic enynes where an addi-
tional methylene group is incorporated between the aryl ring and
the alkyne to assess the limitations of this strategy.11d
Our studies commenced by the synthesis of the parent substrate
starting from o-salicylaldehyde (7) which was allylated by treat-
ment with allyl bromide and potassium carbonate (Scheme 3). The
resulting aldehyde 8 was treated with acetylenic Grignard reagents
(R ¼ H, TMS, Ph) to provide the expected enynes 9e11 in generally
good yields. Each enyne was converted to the corresponding
Co2(CO)6-complex and then subjected to PK cyclization (Scheme 3)
under either thermal conditions (PhMe, 70 ꢀC, Condition A) or
oxidative conditions (CH2Cl2, NMO, Condition B) (Table 1).13 While
the cobalt complexes were formed uneventfully, only one of these
substrates 11 (R ¼ Ph) delivered a cyclopentenone in 31% yield
* Corresponding author.
E-mail address: lovely@uta.edu (C.J. Lovely).
http://dx.doi.org/10.1016/j.tet.2017.08.053
0040-4020/© 2017 Elsevier Ltd. All rights reserved.

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6119
Table 1
Yields from the PK reactions of the o-salicylaldehyde derived enynes 9e11.
Entry
Substrate
Conditionsa
Product
%-Yield
1
2
3
4
5
6
9
9
10
10
11
11
A
B
A
B
A
B
12
12
13
13
14
14
0
0
0
0
31
8
a
Condition A ¼ Co2(CO)8, PhMe, then 70 ꢀC; Condition B ¼ Co2(CO)8, CH2Cl2, then
NMO.
cycloaddition in a somewhat improved 50% yield. It is of note that
Perez-Castells reported unsuccessful attempts to cyclize related
substrates.8b Given that the cycloadditions of the parent substrate
were on the whole poor, we turned our attention to substrates
containing substituents ortho to the O-allyl moiety.
Scheme 1.
Starting with 4,6-di-tert-butylsalicylaldehyde (17), it was con-
verted to the allyl ether 18 in the same manner as the parent system
7 and then reaction with the same three Grignard reagents pro-
vided the corresponding propargylic alcohols 19e21 in good yields
under thermal conditions (70 ꢀC, PhMe) and 8% yield under
oxidative conditions (NMO, CH2Cl2, 0 ꢀC to rt). Interestingly, it was
found that the corresponding TBS-ether 15 underwent thermal
Scheme 2.
Scheme 3.

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C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
(Scheme 4). Initial attempts to effect PK reactions with these sub-
strates were encouraging in that cycloaddition clearly occurred, but
these reactions were complicated by the formation of several
products, including 1,4-diketones derived from isomerization of
the initial cycloadducts (see Scheme 5 and accompanying text
below for details). To simplify product analysis, the hydroxyl group
was removed reductively by treatment with TFA and Et3SiH
resulting in the formation of enynes 22e24 in essentially quanti-
tative yield (Scheme 4). Conversion of these substrates to the cobalt
complexes proceeded uneventfully and set the stage for cyclization
reactions. The terminal alkyne 22 did not provide the expected
cyclopentenone 25 under either thermal (Condition A) or oxidative
conditions (Condition B), instead undergoing simple demetallation.
On the other hand, the two internal alkynes participate in cyclo-
addition under both sets of conditions, delivering the anticipated
enones 26 and 27 in similarly moderate yields (Table 2, entries 4e5
and 7e8). The phenyl-substituted product 27 was sufficiently
crystalline allowing an X-ray structure to be obtained, which nicely
illustrated the connectivity and the formation of the 5,7-bicyclic
ring system (Fig. 1). As a further extension of this chemistry, we
were cognizant of the fact that the cobalt cluster should promote
ionization of the doubly activated hydroxyl group and that we
might be able to harness this feature and telescope the reaction
sequence.14 Accordingly, we were able to convert the cobalt com-
plexes of alcohols 20e21 directly into the reduced cycloadducts in
comparable overall yields by treating the propargylic alcohols
sequentially with Co2(CO)8, TFA/NaBH4, and then NMO (Table 2,
entries 6 and 9). Notably, the terminal alkyne 19 again failed to
provide the cyclic adduct under these modified conditions.
substrate a small amount of the expected PK product 29 was ob-
tained as a mixture of diastereomers (Scheme 5). The major prod-
uct was the diketone 28, again isolated as
a mixture of
diastereomers. Presumably, the diketone arises via a net 1,3-
hydride shift followed by tautomerization to form the diketone
(see Scheme 13 and accompanying text for further discussion). On
the other hand, the internal alkynes 20e21 were better behaved,
delivering the expected products 30 and 31, accompanied by
varying amounts of the reduction product (Table 2, entries 10e13).
In the case of the silyl-substituted system 20 under oxidative
conditions cyclopentenone 30 was obtained in 70% yield as a 2:1
mixture of stereoisomers along with 20% of the reduction product
26. Interestingly, we found that the same substrate delivered
cyclopentanone 30 as a single diastereomer under thermal condi-
tions, although the yield was somewhat attenuated. On the other
hand, the phenyl-substituted system 21 produced the reduction
product as the major cycloadduct under oxidative conditions but in
contrast under thermal conditions the expected cycloadduct was
obtained in excellent yield as a single stereoisomer. An X-ray
crystallographic structure determination on 31 revealed that this
was the exo-diastereomer (Fig. 2).
A second approach to preventing these competitive side re-
actions was to convert the alcohols 19e21 into the corresponding
silyl ethers 32e34 (Scheme 6), this was readily accomplished for all
three substrates on exposure to TBSCl. Exposure of these enynes to
Co2(CO)8 provided the corresponding cobalt complex which was
then subjected to the PK reaction under either oxidative or thermal
conditions (Table 3). Generally speaking, the cycloaddition re-
actions proceeded to produce the expected cycloadducts 35e37 in
good to excellent yields. In the case of the phenylacetylene deriv-
ative 34, accompanying the expected cyclopentenone under
oxidative conditions was the formation of a small amount of the
reduction product 27. In addition, we noted that the reaction under
thermal conditions led to higher diastereoselectivity than under
With the products derived from successful cyclization fully
characterized, we returned our attention to the parent alcohols. As
noted previously, multiple products were obtained from all three
substrates when subjected to either the thermal or oxidative con-
ditions (Scheme 5, Table 2, entries 10e13). In the case of the parent
Scheme 4.

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6121
Scheme 5.
Table 2
PK Reactions of the allyl-derived substrates 19e24.
Entry
Substrate
Conditionsa
Product (% - exo:endo)
1
2
3
4
5
6
7
8
22
22
19
23
23
20
24
24
21
20
20
21
21
A
B
C
A
B
C
A
B
C
A
B
A
B
25 (0)
25 (0)
25 (0)
e
e
e
26 (46)
26 (43)
26 (50)
27 (45)
27 (56)
27 (48)
26 (0)
26 (20)
27 (0)
27 (55)
e
e
e
e
e
9
e
10
11
12
13
30 (58 e exo)
30 (70e2:1)
31 (99 e exo)
31 (26e1:1)
a
Condition A ¼ Co2(CO)8, PhMe, then 70 C; Condition B ¼ Co2(CO)8, CH2Cl2, then
NMO. Condition C ¼ Co2(CO)8, CH2Cl2; TFA, NaBH4 then NMO.
Fig. 2. X-ray crystal structure of 31.
ray crystallography, thereby confirming the relative stereochemis-
try of cycloadduct 37. The TMS-substituted enyne 33 provided a
single cycloadduct 36 in moderate yield under oxidative conditions,
but no cyclization appeared to occur under thermal conditions. The
simple propargyl ether 32 provided the anticipated cycloadduct 35
in moderate to good yield as a mixture of diastereomers under both
conditions.
In our initial report on this chemistry, our efforts focused on
using simple allylic systems and thus we now wanted to extend our
investigation to substituted systems.15 Accordingly, we prepared
three substituted allylic systems. The two sets of methyl substituted
derivatives were prepared in a similar fashion to the parent systems
from the corresponding salicylaldehyde 17 and either methylallyl
or crotyl bromide in the presence of K2CO3 in DMF delivering the
corresponding ethers 38 and 42 in excellent yield (Scheme 7).
Subsequent treatment of the ethers with the same series of ethynyl
Grignard reagents provided the requisite enynes 39e41 and 43e45
in good yields (Scheme 7). Unfortunately, attempts to use this
strategy to obtain the related cinnamyl systems 49e50 were un-
successful, leading to the formation of dark and uncharacterizable
Fig. 1. X-ray crystal structure of 27.
oxidative conditions (10:1 vs 5:1). To confirm the stereochemistry
of the major diastereomer, the TBS ether 37 was treated with TBAF
to deliver the same alcohol exo-31 which was characterized by X-

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C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
Scheme 6.
Table 3
crystalline which permitted an X-ray crystal structure determina-
PK reaction yields of TBS-Ethers 32e34.
tion thus allowing the assignments of the relative stereochemistry
of the three chiral centers (Fig. 3). Interestingly, under thermal
conditions the cyclization was substantially more selective result-
ing in the formation of the two epimeric alcohols, favoring exo-56
(exo:endo ¼ 9:1, Table 4, entry 4). In comparison, the TMS-
substituted derivative 44 was a relatively poor substrate, result-
ing in the formation of the exo-alcohol 55 in approximately 10%
yield under both sets of conditions (Table 4, entries 5e6). The ter-
minal alkyne underwent cyclization to again produce an epimeric
mixture of 1,4-diketones 58 along with a reduction product 57
(only under oxidative conditions). In this case, the epimeric dike-
tones could be partially separated to give pure samples of both
epimers for characterization. Fortunately, we were able obtain
NOESY data on the major diketone which revealed that the ring
junction had a cis fusion. Similarly to the unsubstituted allylic
systems, the propargylic alcohols were protected as the TBS-ethers
59e61 (Scheme 9), converted to the cobalt complexes and sub-
jected to the PK reaction. The phenyl-substituted system 61 un-
derwent cyclization under both sets of conditions to give the exo-
silyl ether 65 as the major or sole product (Scheme 10 and entries 9
and 10, Table 4). The stereochemistry of the major product was
confirmed by silylating the major cycloadduct obtained from the
free alcohol 56; this material was identical to 65 obtained from 61
(Scheme 10). The TMS-substituted derivative 60 behaved similarly
in the cyclization chemistry to the unprotected system, a single
cycloadduct 64 was formed but in low yield (Scheme 10, entries 7
and 8, Table 4). Finally, the silyl ether of unsubstituted enyne 59
underwent fairly efficient cyclization (ꢁ80%) but the diaster-
eoselectivity was poor, providing essentially 1:1 mixtures of the
two epimeric silyl ethers (Scheme 10, entries 5 and 6, Table 4).
The final group of substrates that we examined were the cin-
namyl systems 49 and 50 (Scheme 11). Since the TMS-substituted
derivatives 44 and 60 performed poorly with the crotyl de-
rivatives, we only investigated the non-substituted 49 and phenyl
50 systems. Gratifyingly, we found that the phenyl-substituted
system 50 engaged effectively in a PK reaction under thermal and
oxidative conditions (Scheme 11). Thermally (Condition A), a 10:1
Entry
Substrate
Conditionsa
Product (% - exo:endo)
1
2
3
4
5
6
32
32
33
33
34
34
A
B
A
B
A
B
35 (80e1:1)
35 (52e2:1)
36 0
36 (60 e exo)
37 (95e10:1)
37 (60e5:1)
a
Condition A ¼ Co2(CO)8, PhMe, then 70 C; Condition B ¼ Co2(CO)8, CH2Cl2, then
NMO.
product mixtures from attempted allylation. However, it was found
that the required enynes could be obtained via a slightly different
sequence involving a Mitsunobu reaction of iodophenol derivative
4611a,11c with cinnamyl alcohol followed by formylation of the
resulting aryl iodide 47 by treatment with i-PrMgBr and then DMF
to deliver the aldehyde 48 (Scheme 8). Reaction of the resulting
aldehyde 48 with ethynyl Grignards provided the corresponding
enynes 49e50 in good yield (Scheme 8).
As before, once the enynes were in hand, they were converted
into the corresponding cobalt complex and subjected to PK reaction
under either thermal (Condition A) or oxidative conditions (Con-
dition B). We found that the internally substituted allyl substrates
39e41 did not participate in cyclization under either set of condi-
tions. While examples of internally substituted alkenes are known
to undergo cyclization in the PK reaction, they generally appear to
be less reactive in this chemistry. Indeed, we have found this to be
so in systems related to the ones under investigation here.11a,11c,16
On the other hand, the terminally substituted systems did engage
quite well in this cycloaddition chemistry (Scheme 9, Table 4).
Globally, the results with the phenyl acetylene derivative 41
mirrored those obtained in the parent systems in that two or three
products were obtained depending on the cyclization conditions.
Under oxidative conditions, the reduction product 52 was obtained
in 18% yield along with an almost 1:1 mixture of separable epimeric
alcohols endo-54 and exo-56 (36% and 45% respectively, Table 4,
entry 3). The alcohol produced in slightly larger amounts was nicely

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6123
Scheme 7.
after conversion to the corresponding TBS-ethers 69 and 70
(Scheme 11), the outcomes here mirrored those observed with the
crotyl systems wherein the phenyl-substituted acetylene derivative
provided a single cycloadduct 72 in moderate to excellent yield as
the exo-diastereomer. The unsubstituted system formed the ex-
pected cycloadducts 73 as essentially 1:1 mixtures of diastereomers
in much improved yields.
1. Discussion
Several issues emerged in the course of these investigations that
require further comment, specifically the diastereoselectivity of the
cycloaddition and the formation of initially unanticipated products.
1.1. Diastereocontrol
In general terms the diastereocontrol follows the patterns seen
in other PK reactions wherein the newly formed stereocenter of the
cyclopentenone and any substituents on the tether tend to end up
syn to one another,8b,17 in other words, they display exo selec-
tivity18; this is also what we observed. However, we also note that
the relative diastereoselectivity is dependent on the reaction con-
ditions with the thermal conditions resulting in the higher selec-
tivity compared to oxidative reactions. These results stand in
contrast to the formation of smaller fused rings where oxidative
conditions appear to be more selective. As we considered possible
rationales for these observations we were struck by a couple of
considerations. First, it must be borne in mind that the reaction
conditions are substantially different in terms of what might be
expected as the active metal containing species. While the full
details of the mechanism of this reaction remain to be demon-
strated experimentally,19 it is generally accepted that the reaction
involves the loss of carbon monoxide and coordination of the olefin
to the vacated coordination site on the metals, 73/74 þ 77
(Scheme 12).20 Migratory insertion affords the metallacycles 75 and
78; carbon monoxide insertion, reductive elimination and loss of
the cobalt cluster complete the reaction. Under thermal conditions,
Scheme 8.
mixture of cycloadducts was obtained, the major diastereomer was
assigned by analogy with 45 as the exo-alcohol 66. Under oxidative
conditions an essentially equal mixture of two products was ob-
tained of the reduction product 66 and the exo-alcohol 66 (Scheme
11). The terminal alkyne 49 predominantly formed the diketone
product 68 under both thermal and oxidative conditions. A small
amount of the direct PK-product 67 was obtained under thermal
conditions. Whereas the mixture of the 1,4-diketones was difficult
to separate chromatographically, a small amount of the major
adduct was obtained and characterized. A NOESY experiment
indicated that the ring fusion was cis, similar to diketone 58
(Scheme 9). Finally, cyclization of both substrates was investigated

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C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
Scheme 9.
Table 4
PK reactions of substituted Allyl systems 44e45 and 59e61.
Entry
Substrate
Conditionsa
Product (%)
1
2
3
4
5
6
7
8
9
44
44
45
45
59
59
60
60
61
61
A
B
A
B
A
B
A
B
A
B
51 (0)
51 (0)
52 (0)
52 (18)
53 (0)
55 (12)
55 (7)
56 (90)
56 (45)
62 (86e4:5)
62 (80e5:4)
63 (10)
63 (7)
64 (68)
53 (0)
54 (9)
54 (36)
10
64 (45e4:1)
a
Condition A ¼ Co2(CO)8, PhMe, then 70 C; Condition B ¼ Co2(CO)8, CH2Cl2, then
NMO.
Scheme 10.
other CO ligands are lost irreversibly which in turn means the
active cobalt species will likely be different under oxidative con-
ditions. These thoughts lead to a conclusion that one set of condi-
tions are more kinetic-like (oxidative) and the other more
thermodynamic-like (thermal). Accordingly, we hypothesize that
in the case of the oxidative conditions the alkene-coordinated
cluster is less stable and immediately undergoes the Co-insertion
and decomplexation whereas under thermal conditions this com-
plex is more stable and undergoes reversible olefin coordination
(i.e., 74 ⇔ 77) really need an equilibrium arrow here, with the rate
(and product) determining step being Co insertion and formation of
the cobaltacycles 75 and 78 (Scheme 12). Co-insertion is generally
thought to be irreversible and thus the developing interactions in
the cobaltacycle 75 and 78 drive the observed stereoselectivity,
specifically the interaction between the propargylic substituent
and substituent on the terminus of the alkyne. When R1 ¼ TMS or
Fig. 3. X-ray crystal structure of 56.
the loss of CO is expected to be relatively slow, controlled and more
importantly potentially reversible whereas in the case of oxidative
conditions, the CO is converted irreversibly to CO2 and presumably
lost to the atmosphere and the oxidant, the amine oxide leaves an
amine behind which may potentially be involved in coordination to
the metal cluster. Moreover, an excess of NMO is used meaning that

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6125
Scheme 11.
Ph, good diastereoselectivities are observed as a result of a sub-
stantial destabilizing interaction with the propargylic group,
whereas when R1 ¼ H, there is essentially no diastereoselectivity
which is consistent with minimal interaction with the propargylic
substituent.
base, acid and then ligand. It is assumed that this reduction occurs
pre-cyclization as we have already shown that the cobalt complex
can be reduced and that it is a competent cyclization precursor. It is
also worth noting that the reduction product is more prominent in
the case of the phenyl-substituted systems.
The second type of byproduct observed is the formation of the
1,4-dione 90 (Scheme 14), which is only formed from substrates
containing a terminal alkyne. In a general sense, the formation of
the dione can be understood through the participation of a cobalt
hydride species through oxidative addition 86/87, isomerization
and subsequent reductive elimination 87/88. Decomplexation
followed by tautomerization gives rise to the diketone; the facial
selectivity of the protonation dictating the stereochemistry of the
ring fusion. The precise identity of the metallic species involved is
unclear, it is also unclear whether the tautomerization occurs prior
to decomplexation of the cobalt cluster immediately after the
cycloaddition, i.e. “intramolecular” catalysis or whether it is the
result of the participation of an “intermolecular” cobalt species
derived from post cycloaddition decomplexation. These details
notwithstanding, a pathway to the diketones can be articulated
through a net 1,3-hydride shift-tautomerization sequence.
1.2. Product selectivity
In addition to the formation of the expected cycloadduct adduct,
we also observed the formation of two byproducts, resulting from
the reduction of the propargylic hydroxyl group or from tautom-
erism of the hydroxy enone to provide the dione when the free
alcohols are employed.21 Counterintuitively, perhaps, the reduction
product was observed predominantly under oxidative conditions.
As noted above, when the PK reaction is performed under oxidative
conditions, it is not entirely clear what the reactive species is, but
presumably when the hydroxyl group is syn to the cobalt cluster it
can react with a carbonyl ligand and then undergoes cobalt-
assisted decarboxylation to produce 82 via 81 (Scheme 13).
Reductive cleavage of the Co-carbon bond leading to 83 and
decomplexation completes the sequence by providing 84. Pre-
sumably, the N-methyl morpholine byproduct serves as both the
In summary, we have demonstrated that oxahydroazulenes can

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C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
Scheme 12. Rationale for the observed diastereoselectivity.
Scheme 13.
Scheme 14.

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6127
be constructed through intramolecular PK reactions in moderate to
excellent yields. High diastereoselectivities can be obtained under
thermal conditions and this outcome has been rationalized in terms
of thermodynamic-like control. Substrates containing free prop-
argylic alcohols participate in these cyclizations but lead to the
formation of other types of products, resulting from reduction at
the propargylic position and isomerization. These unwanted side
reactions can be reduced by protection of the alcohol as a silyl ether.
We have also examined the tolerance of this variant of the PK re-
action to substitution on the olefin which indicates that internal
alkenes are competent substrates but 2,2-disubstitution is not
tolerated.
Celite and SiO2 (ca. 1:1 v/v) and first washed with hexane to remove
the alkyneꢂCo2(CO)6 remaining and then washed with ethyl acetate
to remove the cyclized product. After rotary evaporation of the
filtrate, the crude product was purified by flash chromatography
(hexane/EtOAc, 20/1.5 unless indicated otherwise).
2.3.2. Oxidative Pauson-Khand method (procedure B)
1.1e1.2 equiv. of Co2(CO)8 was added to a stirred solution of
enyne in CH2Cl2 under N2 at room temperature. The reaction
mixture was stirred for 5 h. The reaction mixture was cooled to 0 ꢀC
before NMO (12 equiv) was added in three portions at 30 min in-
tervals and then left to stir for 2 h. The reaction mixture was then
poured into a sintered glass funnel packed with Celite and SiO2 (ca.
1:1) and washed with EtOAc. The crude product was purified by
flash chromatography (hexane/EtOAc, 20/1.5 unless indicated
otherwise).
2. Experimental - general methods
All reagents were purchased from commercial suppliers and
were used as received unless otherwise noted. Solvents were dried
either by distillation over appropriate drying agents: tetrahydro-
furan and diethyl ether were distilled from sodium/benzophenone
ketyl; benzene and dichloromethane were distilled over calcium
hydride or purified using Innovative Technologies Inc Pure Solv
2.3.3. Reductive PKR (procedure C)
1.1e1.2 equiv. of Co2(CO)8 was added to a stirred solution of
enyne in CH2Cl2 under N2 at room temperature. The reaction
mixture was stirred for 5 h at rt. The reaction mixture was then
cooled to 0 ꢀC before adding NaBH4. Subsequently, TFA was added
over 10 min at 0 ꢀC. The reaction mixture was decanted into 300 mL
iced water and the organic solution was separated, washed with
water and dried (Na2SO4). The organic layers were concentrated
and cooled to 0 ꢀC before NMO (12 equiv) was added and stirred for
2 h. The reaction mixture was then poured onto a sintered glass
funnel with Celite and SiO2 (ca. 1:1) and filtered. The solid packing
was washed with EtOAc to extract the cycloadduct. The filtrates
were combined and concentrated under reduced pressure. The
crude product was purified by flash chromatography (hexane/
EtOAc, 20/1.5 unless indicated otherwise).
SPS-400-05 solvent purification system. 1H and 13C NMR (
d in ppm)
spectra were recorded in CDCl3 (unless otherwise noted) at 500 and
125.8 MHz, respectively (unless otherwise noted); using a JEOL
Eclipseþ 500 spectrometer. In some cases 1H and 13C NMR spectra
were recorded at 300 and 75 MHz respectively; using a JEOL Eclipse
300 spectrometer. Residual CHCl3
NMR and carbon absorption of CDCl3 (
(
d
¼ 7.26) as reference for 1H
d
¼ 77.0) as internal reference
for 13C NMR were used. Infrared spectra were recorded either as
neat films or as KBr pellets using a Bruker Vector 22 FT-IR spec-
trometer. High resolution mass spectra (HR-MS) were measured at
the University of Florida, Gainesville, Florida. Analytical thin layer
chromatography (TLC) was performed on silica gel 60F254
aluminum precoated plates (0.25 mm layer). All chromatographic
purifications were performed using ICN silica gel (200e400 mesh).
2.3.4. 2-(2-Propenyloxy)benzaldehyde (8)
Allyl bromide (19.8 g, 160 mmol) was added to a suspension of
K2CO3 (23.0 g) and 2-hydroxybenzaldehyde (20.0 g, 160 mmol) in
DMF (100 mL) and stirred for 12 h according to the general alkyl-
ation procedure. The crude product was purified by flash chroma-
2.1. General procedure for O-alkylation reactions
The bromoalkene (11.0 mmol) was added to a suspension of
K2CO3 (14.4 mmol) and 3,5-di-tert-butyl-2-hydroxybenzaldehyde
(11.0 mmol) in DMF (50 mL) and stirred at room temperature for
12 h. The mixture was diluted with CH2Cl2 (25 mL) and washed
twice with water, dried using Na2SO4 (anhydrous) and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography (SiO2: hexane/EtOAc, 15:1 unless indicated
otherwise).
tography to give 8 as a brown oil (18.5 g, 70%). 1H NMR:
d
¼ 10.41 (s,
1H), 7.70 (dd, J ¼ 1.4, 7.8 Hz, 1H), 7.40 (dt, J ¼ 1.8, 8.7 Hz, 1H), 6.90 (t,
J ¼ 7.8 Hz,1H), 6.86 (d, J ¼ 8.7 Hz,1H), 6.95 (ddt, J ¼ 5.5,10.5,17.0 Hz,
1H), 5.33 (dd, J ¼ 1.4, 17.4 Hz, 1H), 5.21 (dd, J ¼ 1.4, 10.5 Hz, 1H), 4.52
(d, J ¼ 5.0 Hz, 2H); 13C NMR:
d
¼ 189.7, 161.0, 136.1, 132.6, 128.4,
125.1, 120.9, 118.1, 113.1, 69.2; IR (neat, cmꢃ1) ¼ 3079, 2866, 1685,
1599,1483,1286, 995, 759; HRMS (ESI): Calcd. for [MþH]þ C10H11O2
(m/z): 163.0759. Found 163.0749.
2.2. General procedure for Grignard reactions
2.3.5. 2-(1-Hydroxy-2-propynyl)-(2-propenyloxy) benzene (9)
A 0.5 M solution of ethynylmagnesium bromide (55.6 mL,
28.0 mmol) in THF was added at 0 ꢀC to a solution of 8 (3.00 g,
19.0 mmol) in THF (20 mL) under N2 atmosphere. The reaction was
worked up according to the general procedure to give 9 (3.31 g,
95%) as a brown oil after chromatographic purification. 1H NMR:
The Grignard reagent (1.5 equiv) was added to a solution of
aldehyde in dry THF (10 mL) under an N2 at 0 ꢀC. The mixture was
stirred and gradually allowed to warm up to room temperature and
stirred for an additional 3 h. The reaction was quenched by the
addition of saturated aqueous NH4Cl and then extracted with
CH2Cl2. The organic extracts were then washed with water, brine
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (SiO2, hexane/EtOAc, 4:1).
d
¼ 7.57 (dd, J ¼ 1.8, 7.3 Hz, 1H), 7.28 (dt, J ¼ 1.8, 7.3 Hz, 1H), 6.98 (dt,
J ¼ 1.0, 7.3 Hz, 1H), 6.88 (d, J ¼ 7.8 Hz, 1H), 6.05 (ddt, J ¼ 5.5, 10.5,
17.0 Hz, 1H), 5.73 (d, J ¼ 2.3 Hz, 1H), 5.45 (dq, J ¼ 1.8, 17.0 Hz, 1H),
5.30 (dq, J ¼ 1.4, 10.5 Hz, 1H), 4.58 (ddt, J ¼ 1.4, 3.2, 5.0 Hz, 2H), 3.44
(s, 1H), 2.61 (d, J ¼ 2.3, 1H); 13C NMR:
d
¼ 153.2, 133.0, 129.8, 128.7,
2.3. General procedures for the Pauson-Khand cyclization
128.0, 121.2, 118.0, 112.3, 83.4, 74.2, 69.2, 60.9; IR (neat,
cmꢃ1) ¼ 3392, 3287, 3077, 2870, 2116,1648,1601,1490,1453; HRMS
(CI): Calcd. For [Mþ] C12H12O2 (m/z): 188.0837. Found 188.0829.
2.3.1. Thermal Pauson-Khand reactions (procedure A)
1.1e1.2 equiv. of Co2(CO)8 was added to a stirred solution of
enyne in toluene under N2 and stirred for 5 h at room temperature.
The reaction mixture was then heated at 70 ꢀC overnight. The re-
action mixture was poured into a sintered glass funnel packed with
2.3.6. 2-(1-Hydroxy-3-trimethylsilyl-2-propynyl)-(-2-propenyloxy)
benzene (10)
Trimethylsilylethynylmagnesium chloride in dry THF was

6128
C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
prepared by adding ethynyltrimethylsilane (3.33 g, 34.0 mmol) to
2.0 solution of isopropylmagnesium chloride (14.0 mL,
viscous brown liquid. 1H NMR:
d
¼ 7.76 (dd, J ¼ 1.4, 7.3 Hz, 1H), 7.42
M
(dd, J ¼ 2.3, 4.1 Hz, 2H), 7.29 (m, 4H), 7.02 (t, J ¼ 7.3 Hz, 1H), 6.88 (d,
J ¼ 7.8 Hz, 1H), 6.07 (m, 2H), 5.48 (dq, J ¼ 1.4, 17.4 Hz, 1H), 5.29 (dq,
J ¼ 1.4, 10.5 Hz, 1H), 4.63 (app. t, J ¼ 4.6 Hz, 2H), 0.99 (s, 9H), 0.29 (s,
28.0 mmol) under N2 at 0 ꢀC and the mixture was stirred for 30 min
before allowing to gradually warm up to room temperature and
then stirred further for 10 min. To this thus prepared solution of
trimethylsilylethynylmagnesium chloride was added a solution of 8
(3.00 g, 19.0 mmol) in dry THF (20 mL) under N2 atmosphere
at ꢃ78 ꢀC and then stirred for 2.5 h at ꢃ78 ꢀC. The reaction was then
allowed to warm up to room temperature and stirred overnight.
The reaction was worked up according to the general procedure to
3H), 0.20 (s, 3H). 13C NMR:
d
¼ 154.9, 133.5, 131.7, 130.7, 128.8, 128.3,
128.1, 127.6, 123.5, 121.0, 117.3, 111.8, 90.7, 84.2, 69.0, 59.9, 26.0,
18.5, ꢃ4.4, ꢃ4.7; IR (neat, cmꢃ1) ¼ 3080, 2929, 2857, 2175, 1601,
1490; HRMS (ESI): Calcd. for [MþNa]þ C24H30O2SiNa (m/z):
401.1907. Found 401.1902.
give 10 (4.97 g, 93%) as a brown oil. 1H NMR (300 MHz),
d
¼ 7.56 (dd,
J ¼ 1.7, 7.6 Hz, 1H), 7.27 (dt, J ¼ 1.7, 8.3 Hz, 1H), 6.99 (dt, J ¼ 1.0,
7.2 Hz, 1H), 6.89 (d, J ¼ 8.3 Hz, 1H), 6.02 (ddt, J ¼ 4.8, 10.7, 17.2 Hz,
1H), 5.71 (s, 1H), 5.46 (dq, J ¼ 1.7, 17.2 Hz, 1H), 5.31 (dq, J ¼ 1.4,
10.7 Hz, 1H), 4.58 (ddt, J ¼ 1.7, 3.5, 5.2 Hz, 2H), 3.09 (s, 1H), 0.20 (s,
2.3.10. 10-tert-Butyldimethylsilyloxy-1-phenyl-4,4a-dihydro-
3H,10H-5-oxabenzo[f]azulen-2-one (16)
The Pauson-Khand cyclization was carried out according to the
General Procedures A and B. The enyne 15 (200 mg, 0.53 mmol) was
dissolved in 10 mL of appropriate solvent, Co2(CO)8 (200 mg,
0.58 mmol) and NMO (680 mg, 5.85 mmol) were added following
the general procedures. The crude product was purified by flash
chromatography (hexane/EtOAc, 9:1) to afford 10 (110 mg, 50%)
using procedure B as a light brown waxy solid. Procedure A gave no
cyclized product with only starting material being recovered. 1H
9H). 13C NMR (75 MHz):
d
¼ 160.0, 132.9, 129.7, 129.0, 128.2, 121.2,
117.8, 112.3, 104.7, 90.9, 69.1, 61.9, ꢃ0.1; IR (neat, cmꢃ1) ¼ 3403,
2960, 2173, 1601, 1490, 1455, 1249; HRMS (ESI): Calcd. for [MþNa]þ
C15H20O2Na (m/z): 283.1125. Found 283.1124.
2.3.7. 2-(1-Hydroxy-3-phenyl-2-propynyl)-(2-propenyloxy)
benzene (11)
1.0 M solution of phenylethynylmagnesium bromide (24.6 mL,
25.0 mmol) in THF was added at 0 ꢀC to a solution of 2 (3.00 g,
19.0 mmol) in THF (20 mL) under N2 atmosphere and worked up
according to the general procedure to give 11 (2.04 g, 47%) as a
NMR:
d
¼ 7.36 (m, 3H), 7.26 (dt, J ¼ 1.8, 9.2 Hz, 1H), 7.19 (dd, J ¼ 1.8,
7.3 Hz, 1H), 7.10 (m, 2H), 7.08 (d, J ¼ 7.3 Hz, 1H), 7.03 (d, J ¼ 7.8 Hz,
1H), 5.63 (s, 1H), 4.71 (d, J ¼ 7.5 Hz, 1H), 3.86 (m, 2H), 2.79 (dd,
J ¼ 6.4, 18.8 Hz, 1H), 2.27 (d, J ¼ 18.8 Hz, 1H), 0.80 (s, 9H), ꢃ0.07 (s,
3H), ꢃ0.18 (s, 3H); 13C NMR:
d
¼ 206.1, 172.3, 160.4, 139.0, 131.0,
brown oil. 1H NMR:
d
¼ 7.64 (dd, J ¼ 1.8, 7.8 Hz, 1H), 7.47 (dd, J ¼ 2.3,
130.9, 130.7, 130.1, 129.1, 128.4, 123.8, 122.5, 110.9, 72.6, 60.2, 40.2,
38.1, 25.8, 18.1, ꢃ4.6, ꢃ4.8; IR (neat, cmꢃ1) ¼ 2954, 1711, 1486, 1251,
1068, 836; HRMS (ESI): Calcd. For [MþH]þ C25H31O3Si (m/z):
407.2037. Found 407.2030.
7.3 Hz, 2H), 7.32 (m, 4H), 7.02 (dt, J ¼ 1.0, 7.3 Hz, 1H), 6.93 (d,
J ¼ 8.3 Hz, 1H), 6.07 (ddt, J ¼ 5.0, 10.5, 17.4 Hz, 1H), 5.96 (d,
J ¼ 6.0 Hz, 1H), 5.47 (dd, J ¼ 1.4, 17.4 Hz, 1H), 5.32 (dq, J ¼ 1.4,
10.5 Hz, 1H), 4.65 (ddt, J ¼ 1.8, 3.7, 5.0 Hz, 2H), 3.25 (d, J ¼ 6.0 Hz,
1H). 13C NMR:
d
¼ 156.0, 133.0, 131.9, 129.7, 129.3, 128.5, 128.4,
128.2, 122.9, 121.2, 117.9, 112.3, 88.7, 86.0, 69.2, 62.0; IR (neat,
cmꢃ1) ¼ 3413, 3079, 2870, 2198, 1560, 1490; HRMS (ESI): Calcd. For
[MþNa]þ C18H16O2Na (m/z): 287.1043. Found 287.1038.
2.3.11. 3,5-Di-tert-butyl-2-(-2-propenyloxy)benzaldehyde (18)
Allyl bromide (1.29 g, 11.0 mmol) was added to a suspension of
K2CO3
(2.00
g, 14.4
mmol)
and
3,5-di-tert-butyl-2-
hydroxybenzaldehyde (17) (2.50 g, 11.0 mmol) in DMF (50 mL)
and stirred at room temperature for 12 h according to the general
alkylation procedure. The crude product was purified by flash
chromatography (hexane/EtOAc, 15:1) to give 18 as a light yellow
2.3.8. 10-Hydroxy-1-phenyl-4,4a-dihydro-3H,10H-5-oxabenzo[f]
azulen-2-one (14)
The Pauson-Khand cyclization was carried out according to the
General Procedures A and B. The enyne 11 (200 mg, 0.76 mmol) was
dissolved in 10 mL of the appropriate solvent and Co2(CO)8
(285 mg, 0.83 mmol) and NMO (975 mg, 8.30 mmol) were added
following the general procedures. The crude product was purified
by flash chromatography (silica gel, n-hexane/EtOAc, 9:1) to afford
8 (17.6 mg, 8% using procedure A and 70.0 mg, 31% using procedure
oil (2.72 g, 93%). 1H NMR:
d
¼ 10.29 (s, 1H), 7.74 (d, J ¼ 2.8 Hz, 1H),
7.65 (d, J ¼ 2.8 Hz, 1H), 6.08 (ddt, J ¼ 4.6, 11.0, 17.0 Hz, 1H), 5.51 (dq,
J ¼ 1.8, 17.0 Hz, 1H), 5.31 (dq, J ¼ 1.4, 10.5 Hz, 1H), 4.47 (dt, J ¼ 1.4,
5.0 Hz, 2H), 1.42 (s, 9H), 1.31 (s, 9H); 13C NMR:
d
¼ 190.9, 159.8,
146.5, 143.1, 140.3, 132.9, 130.9, 129.4, 123.9, 117.5, 79.4, 35.4, 31.4,
30.9; IR (neat, cmꢃ1); 2962, 2871, 1690, 1472, 1231, 928; HRMS
(ESI): Calcd. for [MþH]þ C18H26O2 (m/z): Calcd. For C18H27O2 (m/z):
275.2006. Found 275.1995.
B) as a light yellow waxy solid. 1H NMR:
d
¼ 7.57 (m, 4H), 7.09 (m,
5H), 5.59 (d, J ¼ 6.0 Hz, 1H), 4.68 (dd, J ¼ 5.5, 11.5 Hz, 1H), 3.99 (m,
1H), 3.67 (app.t, J ¼ 10.5 Hz, 1H), 2.97 (d, J ¼ 6.0 Hz, 1H), 2.75 (dd,
J ¼ 7.0, 19.0 Hz, 1H), 2.09 (d, J ¼ 20.0 Hz, 1H); 13C NMR:
d
¼ 205.5,
171.1, 159.8, 140.2, 132.1, 130.6, 130.5, 130.1, 129.4, 128.5, 128.5, 125.1,
123.0, 76.7, 72.3, 39.3, 37.1; IR (neat, cmꢃ1) ¼ 3418, 3058, 2953,
1702, 1601, 1486, 1016; HRMS (ESI): Calcd. for [MþH]þ C19H17O3 (m/
z): 293.1178. Found 293.1166.
2.3.12. 4,6-Di-tert-butyl-2-(1-hydroxy-2-propynyl)-(2-
propenyloxy)benzene (19)
0.5
M solution of ethynylmagnesium bromide (30.0 mL,
15.0 mmol) THF was added to a solution of 18 (2.72 g, 9.92 mmol) in
dry THF (20 mL) under N2 atmosphere at 0 ꢀC after work-up and
purification according to the general procedure gave 19 (2.75 g,
2.3.9. 2-(-1-tert-Butyldimethylsilyloxy -3-phenyl-2-propynyl)-(2-
propenyloxy)benzene (15)
92%) as a light yellow solid, mp: 95e96 ꢀC. 1H NMR:
d
¼ 7.58 (d,
Tert-Butyldimethylsilyl chloride (1.51 g, 1.00 mmol) was added
at room temperature to a mixture of 11 (880 mg, 3.33 mmol) and
imidazole (600 mg, 1.00 mmol) in DMF (10 mL). Then the mixture
was heated at 50 ꢀC for 4.5 h. The reaction was quenched by the
addition of NaHCO3 and extracted with Et2O. The organic layer
separated, washed with water, brine and dried with Na2SO4
(anhydrous). The organic layer was concentrated to give a dark
colored liquid. The crude product was purified by flash chroma-
tography (SiO2, hexane/EtOAc, 19:1) to give 15 (1.21 g, 96%) as
J ¼ 2.8 Hz, 1H,), 7.36 (d, J ¼ 2.3 Hz, 1H,), 6.10 (ddt, J ¼ 4.6, 11.0,
17.0 Hz, 1H), 5.76 (d, J ¼ 2.3 Hz, 1H), 5.55 (dq, J ¼ 1.8, 17.0, 1), 5.30
(dq, J ¼ 1.4, 10.5, 1H), 4.59 (ddt, J ¼ 1.8, 4.6, 13.3 Hz, 1H), 4.43 (ddt,
J ¼ 1.8, 5.0, 13.3 Hz, 1H), 2.62 (d, J ¼ 1.8 Hz, 1H), 2.46 (s,1H), 1.41 (s,
9H),1.30 (s, 9H); 13C NMR:
d
¼ 153.2,146.7,142.4,133.8,125.3,123.6,
116.8, 84.6, 76.1, 74.3, 59.8, 35.6, 34.8, 31.6, 31.3 (only 15 signals out
of 16 carbon types were observed); IR (neat, cmꢃ1) ¼ 3304, 2960,
2219, 1470, 1281, 989; HRMS (CI): Calcd. for [M]þ C20H28O2 (m/z):
300.2089. Found 300.2091.

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6129
2.3.13. 4,6-Di-tert-butyl-2-(1-hydroxy-3-trimethylsilyl-2-
propynyl)-(-2-propenyloxy) benzene (20)
of the solvent. The crude product purified by flash chromatography
(hexane/EtOAc, 95:5) to give 23 as a light yellow liquid (1.87 g, 99%).
A solution of trimethylsilylethynylmagnesium chloride in dry
THF was prepared by adding ethynyltrimethylsilane (2.47 g,
25.0 mmol) to 3.0 M solution of ethylmagnesium chloride (8.40 mL,
25.0 mmol) in THF under N2 at 0 ꢀC and stirred for 30 min before
allowing the reaction to warm up to room temperature and stirred
for additional 10 min. To this thus prepared solution of trime-
thylsilylethynylmagnesium chloride, was added a solution of 18
(3.00 g, 11.0 mmol) in dry THF (20 mL) under N2 atmosphere
at ꢃ78 ꢀC. The reaction mixture was stirred for 2.5 h at ꢃ78 ꢀC
before allowing to warm up to rt. The reaction was then stirred
overnight and worked up according to the general procedure to
give 20 (3.05 g, 75%) as a light yellow solid, mp: 94e95 ꢀC. 1H NMR:
1H NMR:
d
¼ 7.47 (d, J ¼ 2.5 Hz, 1H), 7.25 (d, J ¼ 2.5 Hz, 1H), 6.05
(ddt, J ¼ 5.0,10.5,17.0 Hz,1H), 5.49 (dq, J ¼ 1.8,17.0 Hz,1H), 5.26 (dq,
J ¼ 1.8, 10.5 Hz, 1H), 4.35 (dt, J ¼ 1.8, 5.0 Hz, 2H), 3.64 (s, 2H), 1.39 (s,
9H), 1.32 (s, 9H), 0.18 (s, 9H); 13C NMR (75 MHz):
d
¼ 153.6, 145.9,
141.9, 133.9, 129.5, 125.4, 123.1, 116.5, 105.5, 86.8. 73.9, 35.5, 34.8,
31.6, 31.3, 21.4, 0.2; IR (neat, cmꢃ1) ¼ 2960, 2874, 2177; HRMS (ESI):
Calcd. For [MþH]þ C23H37OSi (m/z): 357.2608. Found 357.2618.
2.3.17. 4,6-Di-tert-butyl-2-(-3-phenyl-2-propynyl)-2-
propenyloxybenzene (24)
Triethylsilane (1.24 g, 10.7 mmol) was added at room tempera-
ture to a solution of 21 (2.0 g, 5.3 mmol) in CH2Cl2 (10 mL) under N2
atmosphere. Then trifluoroacetic acid (2.43 g, 21.3 mmol) was
added and stirred for 20 min. The reaction mixture was quenched
with aqueous NaHCO3 and extracted with CH2Cl2 (2 ꢄ 10 mL) to
give a yellow liquid. The crude product was purified by flash
chromatography (hexane/EtOAc, 95:5) to give 24 as a light yellow
d
¼ 7.61 (d, J ¼ 2.3 Hz, 1H), 7.35 (d, J ¼ 2.3 Hz, 1H), 6.09 (ddt, J ¼ 5.0,
10.5, 17.0 Hz, 1H), 5.73 (d, J ¼ 5.5 Hz, 1H), 5.52 (dq, J ¼ 1.4, 17.0 Hz,
1H), 5.28 (dq, J ¼ 1.4, 10.5 Hz,1H), 4.64 (ddt, J ¼ 1.8, 5.0,13.0 Hz,1H),
4.43 (ddt, J ¼ 1.8, 5.0, 13.0 Hz, 1H), 2.50 (d, J ¼ 5.5 Hz, 1H), 1.41 (s,
9H), 1.30 (s, 9H), 0.19 (s, 9H); 13C NMR:
d
¼ 153.4, 146.5, 142.3, 134.0,
133.9, 125.19, 124.1, 116.7, 106.0, 91.1, 76.1, 60.6, 35.6, 34.8, 31.5,
31.3, ꢃ0.09; IR (neat, cmꢃ1) ¼ 3454, 2960, 2172; HRMS (ESI): Calcd.
for [MþNa]þ C23H36O2SiNa (m/z): 395.2377. Found 395.2373.
liquid (1.87 g, 98%). 1H NMR:
d
¼ 7.52 (d, J ¼ 2.5 Hz, 1H), 7.44 (m,
2H), 7.30 (d, J ¼ 2.5 Hz, 1H), 7.29 (d, J ¼ 3.0 Hz, 3H), 6.11 (ddt, J ¼ 4.6,
11.0, 17.0 Hz, 1H), 5.55 (dq, J ¼ 1.8, 17.4 Hz, 1H), 5.32 (dq, J ¼ 1.8,
10.5 Hz, 1H), 4.46 (dt, J ¼ 1.8, 4.6 Hz, 2H), 3.83 (d, J ¼ 5.0 Hz, 2H),
2.3.14. 4,6-Di-tert-butyl-2-(1-hydroxy-3-phenyl-2-propynyl)-2-
propenyloxybenzene (21)
1.0 M solution of phenylethynylmagnesium bromide (15.0 mL,
15.0 mmol) was added at 0 ꢀC to the solution of 18 (3.00 g,
11.0 mmol) in dry THF (20 mL) under N2 atmosphere according to
the general procedure to give 21 (3.07 g, 75%) as a light yellow solid,
1.46 (s, 9H), 1.38 (s, 9H); 13C NMR:
d
¼ 153.6, 146.1, 142.0, 134.0,
131.7, 129.9, 128.3, 127.8, 125.5, 124.0, 123.2, 116.5, 88.7, 82.1, 74.1,
35.5, 34.7, 31.6, 31.3, 20.9; IR (neat, cmꢃ1) ¼ 2959, 2870, 1451, 1225,
991, 755; HRMS (ESI): Calcd. For [MþH]þ C26H33O (m/z): 361.2526.
Found 361.2538.
mp 92e93 ꢀC. 1H NMR:
d
¼ 7.69 (d, J ¼ 2.8 Hz,1H), 7.46 (m, 2H), 7.38
2.3.18. 6,8-Di-tert-butyl-1-trimethylsilyl-4,4a-dihydro-3H,10H-5-
oxabenzo[f]azulen-2-one (26)
(d, J ¼ 2.8 Hz, 1H), 7.30 (m, 3H), 6.13 (ddt, J ¼ 4.6, 11.0, 17.0 Hz, 1H),
5.98 (s, 1H), 5.55 (dq, J ¼ 1.8, 17.4 Hz, 1H), 5.32 (dq, J ¼ 1.8, 10.5 Hz,
1H), 4.65 (ddt, J ¼ 1.8, 4.6,13.3 Hz,1H), 4.50 (ddt, J ¼ 1.8, 4.6,13.3 Hz,
1H), 2.58 (d, J ¼ 5.5 Hz, 1H), 1.44 (s, 9H), 1.34 (s, 9H); 13C NMR:
The Pauson-Khand cyclization was carried out according to the
general procedures A and B. The enyne 23 (124 mg, 0.35 mmol) was
dissolved in 10 mL of the appropriate solvent. Co2(CO)8 (200 mg,
0.59 mmol) and NMO (408 mg, 3.48 mmol) were added according
to the General Procedure B. The crude product was purified by flash
chromatography (silica gel, hexane/EtOAc, 90:10) to afford 26
(75.0 mg, 56% using Procedure A and 60.0 mg, 45% using Procedure
B) as a yellow solid.
d
¼ 171.3, 153.3, 146.6, 142.4, 134.4, 133.9131.8, 128.4, 125.1, 123.9,
122.8, 116.8, 89.7, 86.1, 76.3, 60.6, 35.6, 34.8, 31.6, 31.3; IR (neat,
cmꢃ1) ¼ 3414, 2959, 2223, 1479, 1280; HRMS (ESI): Calcd. for
[MþH]þ C26H33O2 (m/z): 377.2475. Found 377.2471.
2.3.15. 4,6-Di-tert-butyl-2-prop-2-ynyl-(2-propenyloxy)benzene
(22)
General Procedure C: Co2(CO)8 (506 mg, 1.47 mmol) was added
to a solution of 20 (500 mg,1.34 mmol) in CH2Cl2 (10 mL) was under
N2 and stirred at room temperature for 5 h. The reaction mixture
was then cooled in an ice bath before adding NaBH4 (153 mg,
4.03 mmol). Subsequently, TFA (15 mL) was added over 10 min at
0 ꢀC and then worked up. The organic extracts were concentrated,
redissolved in CH2Cl2 (10 mL) and cooled to 0 ꢀC before NMO
(2.08 g. 17.8 mmol) was added in three portions and then left to stir
for 2 h. Usual work-up and purification of the crude product was
purified by flash chromatography (hexane/EtOAc, 20:1.5) to afford
Triethylsilane (1.24 g, 10.7 mmol) was added at room tempera-
ture to the solution of 19 (1.60 g, 5.30 mmol) in CH2Cl2 (10 mL)
under N2 atmosphere. Then trifluoroacetic acid (2.43 g, 21.3 mmol)
was added and stirred for 20 min. The reaction mixture was
quenched with aqueous NaHCO3 and then extracted with CH2Cl2
(2 ꢄ 10 mL) to give a yellow liquid. The crude product was purified
by flash chromatography (hexane/EtOAc 95:5) to give 22 as a light
yellow liquid (1.45 g, 96%). 1H NMR:
d
¼ 7.39 (d, J ¼ 2.8 Hz, 1H), 7.25
(d, J ¼ 2.8 Hz, 1H), 6.07 (ddt, J ¼ 5.0, 10.5, 17.0 Hz, 1H), 5.51 (dq,
J ¼ 1.8, 17.0 Hz, 1H), 5.29 (dq, J ¼ 1.8, 10.5 Hz, 1H), 4.38 (dt, J ¼ 1.4,
5.0 Hz, 2H), 3.58 (d, J ¼ 2.3 Hz, 2H), 2.12 (t, J ¼ 2.8 Hz, 1H), 1.39 (s,
23 (240 mg, 48%) as a yellow solid. mp: 89e91 ꢀC; 1H NMR:
d
¼ 7.24
(s,1H), 7.10 (s,1H), 4.54 (dd, J ¼ 5.3, 5.6 Hz,1H), 3.91 (s, 2H), 3.41 (m,
1H), 3.24 (t, J ¼ 11.4 Hz, 1H), 2.52 (dd, J ¼ 7.1, 18.8 Hz, 1H), 1.82 (dd,
J ¼ 1.6, 18.8 Hz, 1H), 1.38 (s, 9H), 1.30 (s, 9H), 0.31 (s, 9H); 13C NMR:
9H), 1.32 (s, 9H); 13C NMR:
122.9, 116.6, 83.0, 73.9, 69.7, 35.5, 34.6, 31.6, 31.3, 6.7, 5.9; IR (neat,
cmꢃ1) ¼ 3312, 2959, 2872, 2176, 1715, 1507; HRMS (CI): Calcd. For
[Mþ] C20H28Oþ (m/z): 284.2135. Found 284.2132.
d
¼ 148.9, 142.0, 133.5, 128.9, 125.0,
d
¼ 211.8, 184.9, 156.5, 146.3, 141.6, 139.2, 129.6, 125.2, 123.0, 76.0,
47.5, 38.4, 38.2, 35.2, 34.6, 31.6, 30.7, ꢃ0.03; IR (neat,
cmꢃ1) ¼ 2958.3, 1693.5, 1587.2, 1249.7; HRMS (ESI): Calcd. for
[MþNa]þ C24H36O2SiNa 407.2377, Found 407.2376.
2.3.16. 4,6-Di-tert-butyl-2-(3-trimethylsilyl-2-propynyl)-(-2-
propenyloxy) benzene (23)
2.3.19. 6,8-Di-tert-butyl-1-phenyl-4,4a-dihydro-3H,10H-5-
oxabenzo[f]azulen-2-one (27)
Triethylsilane (1.24 g, 10.7 mmol) was added at room tempera-
ture to a solution of 20 (1.98 g, 5.30 mmol) in CH2Cl2 (10 mL) under
N2 atmosphere. Then trifluoroacetic acid (2.43 g, 21.3 mmol) was
added and the reaction was stirred for 20 min. The reaction mixture
was quenched with aqueous NaHCO3 and extracted with
dichloromethane (2 ꢄ 10 mL) to give a yellow liquid after removal
The Pauson-Khand cyclization was carried out according to the
General Procedures A and B. The enyne 24 (130 mg, 0.36 mmol) was
dissolved in 10 mL of the appropriate solvent. Co2(CO)8 (136 mg,
0.40 mmol) and NMO (460 mg, 3.93 mmol) were added according
to the general procedure. The crude product was purified by flash

6130
C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
chromatography (silica gel, n-hexane/EtOAc, 9:1) to afford 27
(60 mg, 43% using procedure A and 64 mg, 46% using procedure B)
as a yellow solid.
General Procedure C: Co2(CO)8 (136 mg, 0.40 mmol) was added
to a solution of 21 (290 mg, 0.77 mmol) in CH2Cl2 (10 mL) under N2
and stirred at room temperature for 5 h. The reaction mixture was
then cooled in an ice bath before adding NaBH4 (88.0 mg,
2.31 mmol). Subsequently, TFA (10 mL) was added over 10 min at
2.3.23. 6,8-Di-tert-butyl-10-hydroxyl-4,4a-dihydro-3H,10H-5-
oxabenzo[f]azulen-2-one (29)
Yellow oil, 1H NMR:
d
¼ 7.56 (d, J ¼ 2.3 Hz,1H), 7.48 (d, J ¼ 2.3 Hz,
1H), 6.29 (s, 1H), 4.71 (dd, J ¼ 6.0, 11.5 Hz, 1H), 3.85 (td, J ¼ 2.8,
11.5 Hz, 1H), 3.55 (m, 1H), 2.93 (d, J ¼ 19.3 Hz, 1H), 2.38 (dd, J ¼ 8.3,
17.9 Hz, 1H), 2.04 (dd, J ¼ 11.0, 22.5 Hz, 1H), 1.38 (s, 9H), 1.31 (s, 9H);
13C NMR:
d
¼ 205.4, 181.9, 152.6, 147.5, 140.6, 134.3, 128.4, 122.5,
120.6, 77.4, 74.6, 42.3, 36.5, 35.1, 31.6, 30.7, 25.5; HRMS (ESI): Calcd.
0
ꢀC and then worked-up. The dried organic extracts were
for C21H28NaOþ3 (m/z): 351.1931. Found 351.1957 [MþNa]þ.
concentrated, redissolved in CH2Cl2 (10 mL) and cooled to 0 ꢀC
before NMO (1.22 g. 10.4 mmol) was added in three portions and
then left to stir for 2 h. Usual work-up and purification of the crude
product (hexane/EtOAc, 20:1.5) provided 27 (150 mg, 50%) as a
2.3.24. Cyclization 4,6-di-tert-butyl-2-(1-hydroxy-3-trimethylsilyl-
2-propynyl)-(-2-propenyloxy)benzene (20)
The Pauson-Khand cyclization of the enyne 20 (102 mg,
0.27 mmol) in 10 mL of the appropriate solvent, was carried out
following the General Procedures A and B. Co2(CO)8 (103 mg,
0.30 mmol) and NMO (230 mg, 2.74 mmol) were added according
to the general procedures and worked up as described. The crude
product was purified by flash chromatography (hexane/EtOAc,
90:10) to afford the reduced PK product 26 (21.0 mg, 20%) and the
expected PK product 30 (78.0 mg, 70% as a 1:2 mixture of exo and
endo epimers) using the oxidative Procedure B. However, when
enyne 20 was subjected to Procedure A only the exo-product of 30
(64.0 mg, 58%) was isolated.
yellow solid. mp: 160e162 ꢀC; 1H NMR:
d
¼ 7.46 (t, J ¼ 7.8 Hz, 2H).
7.40 (d, J ¼ 2.8 Hz, 1H), 7.34 (d, J ¼ 2.8 Hz, 2H), 7.30 (s, 1H), 7.14 (s,
1H), 4.67 (dd, J ¼ 5.5, 11.5 Hz, 1H), 3.91 (d, J ¼ 12.8 Hz, 1H), 3.76 (d,
J ¼ 12.8 Hz, 1H), 3.54 (m, 1H), 3.35 (t, J ¼ 11.5 Hz, 1H), 2.75 (dd,
J ¼ 7.1, 18.9 Hz,1H), 2.03 (dd, J ¼ 2.8, 18.8 Hz,1H), 1.41 (s, 9H), 1.35 (s,
9H); 13C NMR:
d
¼ 205.5,172.0,156.8,146.7,141.9, 139.7, 131.3, 129.7,
129.6,128.3,128.2,125.3,123.0, 76.2, 44.1, 36.9, 36.7, 35.2, 34.7, 31.6,
30.7; IR (neat, cmꢃ1) ¼ 2958, 1705, 1474, 758; HRMS (ESI): Calcd. for
[MþNa]þ C27H32O2Na (m/z): 411.2295. Found 411.2266.
2.3.20. Cyclization of 4,6-di-tert-butyl-2-(1-hydroxy-2-propynyl)-
(2-propenyloxy)benzene (19)
2.3.25. 6,8-Di-tert-butyl-10-hydroxy-1-trimethylsilyl-4,4a-
dihydro-3H,10H-5-oxabenzo[f] azulen-2-one (30)
A light yellow solid, mp: 110e112 ꢀC; 1H NMR:
d
¼ 7.32 (d,
The Pauson-Khand cyclization of the enyne 19 (80 mg,
0.27 mmol) in 10 mL of the appropriate solvent, was carried out
following the General Procedures A and B. Co2(CO)8 (100 mg,
0.29 mmol) and NMO (312 mg, 2.67 mmol) were added according
to the general procedures and then worked up as described. The
crude product was purified by flash chromatography (silica gel,
hexane/EtOAc, 9:1) to afford the PK product 29 (15 mg, 17% as a 1:1
mixture of epimers) and the 1,4-diketone 28 (80 mg, 80% as a 1:6
mixture of the syn- and anti-isomers) using the oxidative procedure
B. On the other hand, when the enyne was heated to 70 ꢀC for 1 day
in toluene under the thermal procedure A, it gave the PK product of
29 (10 mg, 11% in a 2:1 ratio of exo:endo epimers) along with the
diketone product 28 (44 mg, 50% as a 1:1 mixture of the syn and
anti isomers).
J ¼ 2.3 Hz, 1H), 7.17 (d, J ¼ 2.3 Hz, 1H), 5.68 (d, J ¼ 9.2 Hz, 1H), 4.58
(dd, J ¼ 6.0, 11.5 Hz, 1H), 3.96 (m, 1H), 3.37 (t, J ¼ 11.5 Hz, 1H), 3.25
(d, J ¼ 9.2 Hz, 1H), 2.55 (dd, J ¼ 7.3, 18.8 Hz, 1H), 1.82 (dd, J ¼ 2.8,
18.3 Hz, 1H), 1.37 (s, 9H) 1.30 (s, 9H), 0.29 (s, 9H); 13C NMR
(125 MHz):
d
¼ 211.4, 185.1, 155.9, 147.1, 142.5, 140.0, 132.9, 125.0,
124.9, 77.6, 75.0, 41.8, 37.7, 35.3, 34.9, 31.5, 30.7, ꢃ0.12; IR (neat,
cmꢃ1) ¼ 3396, 2958, 1710, 1606, 1471, 1367, 1236, 1013; HRMS (ESI):
Calcd. for [MþH]þ C24H37O3Si (m/z): 401.2506. Found 401.2500.
2.3.26. Cyclization of 4,6-di-tert-butyl-2-(1-hydroxy-3-phenyl-2-
propynyl)-2-propenyloxy benzene (21)
The Pauson-Khand cyclization of the enyne 21 (250 mg,
0.67 mmol) in 10 mL of the appropriate solvent, was carried out
following the General Procedures A and B. Co2(CO)8 (250 mg,
0.73 mmol) and NMO (1.22 g, 10.4 mmol) were added according to
the general procedures. Usual work-up and purification (silica gel,
hexane/EtOAc, 90:10) gave the reduced PK product 27 (142 mg,
55%) and the expected PK product 31 (70 mg, 26% as a 1:1 mixture
of epimers) using the Procedure B. Under Procedure A the reaction
only gave the exo-product 31 (255 mg, 99%).
2.3.21. 6,8-Di-tert-butyl-1,1a,4,4a-tetrahydro-3H-5-oxabenzo[f]
azulen-2,10-dione (cis-28)
Yellow waxy solid, 1H NMR:
d
¼ 7.57 (d, J ¼ 2.3 Hz, 1H), 7.49 (d,
J ¼ 2.3 Hz,1H), 4.71 (dd, J ¼ 6.0, 12.4 Hz, 1H), 3.85 (dt, J ¼ 2.8, 8.7 Hz,
1H), 3.76 (dd, J ¼ 10.1, 12.4 Hz, 1H), 3.33 (dddd, J ¼ 6.0, 8.7, 10.1,
18.8 Hz, 1H), 2.91 (d, J ¼ 18.8 Hz 1H), 2.41 (dd, J ¼ 8.3, 18.3 Hz, 1H),
2.29 (dd, J ¼ 8.7, 18.8 Hz, 1H), 2.04 (dd, J ¼ 10.1, 17.4 Hz, 1H), 1.40 (s,
9H), 1.30 (s, 9H); 13C NMR:
d
¼ 215.3, 200.9, 160.1, 144.6, 139.9,
2.3.27. 6,8-Di-tert-butyl-10-hydroxy-1-phenyl-4,4a-dihydro-
3H,10H-5-oxabenzo[f]azulen-2-one (31)
128.4, 127.5, 124.3, 51.0, 42.4, 39.5, 39.4, 35.4, 34.7, 31.5, 30.7, 30.2;
IR (neat, cmꢃ1) ¼ 2960, 2871, 1750, 1678, 1597, 1474, 1439, 1365;
HRMS (ESI): Calcd. for [MþH]þ C21H29O3 (m/z): 329.2111. Found
329.2098.
A light yellow solid, mp: 171e173 ꢀC; 1H NMR:
d
¼ 7.46 (m, 3H),
7.35 (d, J ¼ 2.8 Hz, 1H), 7.23 (m, 2H), 7.14 (d, J ¼ 2.8 Hz, 1H), 5.49 (d,
J ¼ 9.2 Hz, 1H), 4.61 (dd, J ¼ 5.7, 11.5 Hz, 1H), 4.09 (m. 1H), 3.51 (t,
J ¼ 11.9 Hz,1H), 3.15 (d, J ¼ 8.7 Hz,1H), 2.76 (dd, J ¼ 6.9,19.3 Hz, 1H),
2.03 (dd, J ¼ 2.8, 18.8 Hz, 1H), 1.40 (s, 9H), 1.32 (s, 9H); 13C NMR:
2.3.22. 6,8-Di-tert-butyl-1,1a,4,4a-tetrahydro-3H-5-oxabenzo[f]
azulen-2,10-dione (trans-28)
d
¼ 205.3, 172.3, 156.3, 147.3, 142.8, 139.6, 133.0, 130.7, 129.6, 128.5,
128.3, 125.1, 125.0, 77.9, 73.7, 38.8, 36.7, 35.3, 34.7, 31.5, 30.7; IR
(neat, cmꢃ1) ¼ 3435, 2959, 1702, 1598, 756; HRMS (ESI): Calcd. for
[MþH]þ C27H33O3 (m/z): 405.2424. Found 405.2425.
Yellow waxy solid, 1H NMR:
d
¼ 7.83 (d, J ¼ 2.3 Hz, 1H), 7.61 (d,
J ¼ 2.3 Hz, 1H), 4.25 (m, 2H), 3.67 (dd, J ¼ 11.5, 19.3 Hz,1H), 2.87 (dd,
J ¼ 11.5, 19.3 Hz, 1H), 2.66 (t, J ¼ 8.3 Hz, 2H), 2.63 (s, 1H), 2.27 (dt,
J ¼ 3.2, 14.7 Hz, 1H), 1.43 (s, 9H), 1.32 (s, 9H); 13C NMR:
d
¼ 214.4.
2.3.28. 4,6-Di-tert-butyl-2-(-1-tert-butyl-dimethylsilyloxy-2-
propynyl)-(-2-propenyloxy) benzene (32)
tert-Butyldimethylsilyl chloride (0.750 g, 5.00 mmol) was added
at room temperature to a mixture of 19 (0.500 g, 1.67 mmol) and
imidazole (0.300 g, 5.00 mmol) in DMF (10 mL). The reaction
198.7, 167.6, 146.4, 142.8, 130.0, 129.9, 124.8, 74.3, 52.0, 44.3, 39.8,
39.6, 35.6, 34.8, 31.4, 30.8; IR (neat, cmꢃ1) ¼ 2960, 2871, 1750, 1678,
1597, 1474, 1439, 1365; HRMS (ESI): Calcd. For C42H56NaOþ6 (m/z):
679.3969. Found 679.4005 [2M þ Na]þ.

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6131
mixture was heated at 50 ꢀC for 4.5 h. The reaction was quenched
by the addition of aqueous NaHCO3 and extracted with Et2O. The
organic layer was separated, washed with water and brine and
dried (Na2SO4). The organic extracts were concentrated to give a
dark liquid. The crude product was purified by flash chromatog-
raphy (hexane/EtOAc; 19:1) to give 32 as a viscous brown oil,
following the General Procedures A and B. Co2(CO)8 (91 mg,
0.27 mmol) and NMO (310 mg, 2.65 mmol) were added according
to the general procedures. Normal work-up and purification of the
crude product (hexane/EtOAc, 9:1) to afford the PK product 35
(45 mg, 52% as a 2:1 mixture of epimers) using Procedure B. Pro-
cedure A delivered the PK product 35 (68.3 mg, 80%) as a 1:1
mixture stereoisomers. Small amounts of the stereoisomers of 35
were separated by preparative thin layer chromatography to give
the exo- and endo-products.
(0.680 g, 99%). 1H NMR:
d
¼ 7.56 (d, J ¼ 2.8 Hz, 1H), 7.28 (d,
J ¼ 2.8 Hz,1H), 6.06 (ddt, J ¼ 4.6,11.0,17.0 Hz,1H), 5.69 (d, J ¼ 2.3 Hz,
1H), 5.55 (dq, J ¼ 1.8, 17.4 Hz, 1H), 5.29 (dq, J ¼ 1.4, 10.5 Hz, 1H), 4.48
(ddt, J ¼ 1.8, 4.6,13.8 Hz,1H), 4.42 (ddt, J ¼ 1.8, 4.6,13.8 Hz,1H), 2.49
(d, J ¼ 1.8 Hz, 1H), 1.39 (s, 9H), 1.31 (s, 9H), 0.82 (s, 9H), 0.07 (s,
2.3.32. 6,8-Di-tert-butyl-10-t-butyldimethylsilyloxy-4,4a-dihydro-
3H,10H-5-oxabenzo[f]azulen-2-one (exo-35)
3H), ꢃ0.08 (s, 3H); 13C NMR:
d
¼ 152.4, 146.3, 141.5, 135.5, 133.9,
124.2, 124.0, 116.1, 85.9, 75.8, 72.6, 59.3, 35.5, 34.8, 31.6, 31.1, 25.8,
18.3, ꢃ4.8, ꢃ5.0; IR (neat, cmꢃ1) ¼ 3299, 2956, 2867, 2175, 1466,
1252, 1069; HRMS (ESI): Calcd. for [MþH]þ C26H43O2Si (m/z):
415.3027. Found 415.3045.
Brown waxy solid, 1H NMR (300 MHz):
d
¼ 7.55 (d, J ¼ 2.1 Hz,
1H), 7.26 (d, J ¼ 2.4 Hz,1H), 6.25 (s,1H), 5.75 (s,1H), 4.51 (dd, J ¼ 6.2,
11.4 Hz, 1H), 3.52 (m, 1H), 3.09 (t, J ¼ 11.7 Hz, 1H), 2.58 (dd, J ¼ 6.9,
18.6 Hz, 1H), 1.87 (dd, J ¼ 2.8, 18.6 Hz, 1H), 1.34 (s, 9H), 1.31 (s, 9H),
1.00 (s, 9H), 0.07 (s, 6H), 13C NMR (75 MHz):
d
¼ 206.6, 182.8, 153.8,
2.3.29. 4,6-Di-tert-butyl-2-(-1-tert-butyldimethylsilyloxy-3-
trimethylsilyl-2-propynyl)-(2-propenyloxy)benzene (33)
146.6,140.9,133.0,127.4, 123.4,120.5, 75.8, 71.1, 43.1, 37.4, 35.0, 31.7,
30.8, 25.9, 18.4, ꢃ4.9, ꢃ5.1, only 20 carbons were observed out of 21
carbon types; IR (neat, cmꢃ1) ¼ 2954, 2862, 1718, 1623, 1475; HRMS
(ESI): Calcd. for [MþH]þ C27H43O3Si (m/z): 443.2976. Found
443.3002.
tert-Butyldimethylsilyl chloride (0.500 g, 3.31 mmol) was added
at room temperature to a mixture of 20 (0.410 g, 1.10 mmol) and
imidazole (0.440 g, 3.31 mmol) in DMF (10 mL). Then the mixture
was heated at 50 ꢀC for 4.5 h. The reaction was quenched by the
addition of aqueous NaHCO3 and extracted with Et2O. The organic
layer was separated, washed with water and brine and dried
(Na2SO4). The organic extracts were concentrated to give a dark
liquid. The crude material was purified by flash chromatography
(hexane/EtOAc; 19:1) to give 33 as a viscous brown oil (0.510 g,
2.3.33. 6,8-Di-tert-butyl-10-t-butyldimethylsilyloxy-4,4a-dihydro-
3H,10H-5-oxabenzo[f]azulen-2-one (endo-35)
Brown waxy solid, 1H NMR (300 MHz):
d
¼ 7.29 (d, J ¼ 2.1 Hz,
1H), 7.11 (d, J ¼ 2.4 Hz,1H), 6.06 (s, 1H), 5.61 (s, 1H), 4.49 (dd, J ¼ 5.2,
11.0 Hz, 1H), 3.73 (m, 1H), 3.73 (t, J ¼ 11.0 Hz, 1H), 2.62 (dd, J ¼ 6.9,
18.9 Hz, 1H), 1.95 (dd, J ¼ 2.1, 18.6 Hz, 1H), 1.36 (s, 9H), 1.30 (s, 9H),
0.85 (s, 9H), 0.04 (s, 3H), ꢃ0.19 (s, 3H); 13C NMR (75 MHz):
95%). 1H NMR:
d
¼ 7.57 (d, J ¼ 2.3 Hz, 1H), 7.28 (d, J ¼ 2.3 Hz, 1H),
6.05 (ddt, J ¼ 4.6, 10.5, 17.4 Hz, 1H), 5.70 (s, 1H), 5.51 (dq, J ¼ 1.8,
17.4 Hz,1H), 5.29 (dq, J ¼ 1.8, 10.5 Hz, 1H), 4.48 (dt, J ¼ 1.4, 5.0 Hz,
2H), 1.39 (s, 9H), 1.32 (s, 9H), 0.83 (s, 9H), 0.15 (s, 9H), 0.10 (s, 3H),
d
¼ 207.8, 181.2, 155.4, 145.7, 142.2, 132.2, 128.1, 124.9, 124.3, 75.2,
40.7, 38.0, 35.3, 34.6, 31.6, 30.6, 25.8, 18.3, ꢃ4.76, ꢃ4.8; IR (neat,
cmꢃ1) ¼ 2952, 2860, 1716, 1620, 1472; HRMS (ESI): Calcd. for
[2M þ Na]þ C54H84NaO6Siþ2 (m/z): 907.5699. Found 907.5636.
0.07 (s, 3H); 13C NMR (75 MHz):
d
¼ 152.7, 146.0, 141.4, 135.6, 134.1,
124.7, 123.9, 116.0, 107.7, 85.9, 75.7, 60.2, 35.5, 34.8, 31.6, 31.2, 25.9,
18.4, ꢃ0.1, ꢃ4.4, ꢃ4.7; IR (neat, cmꢃ1) ¼ 2960, 2173, 1470, 1252,
1070; HRMS (CI): Calcd. for [Mþ] C29H50O2Si2 (m/z): 486.3344.
Found 486.3355.
2.3.34. Cyclization of 4,6-di-tert-butyl-2-(-1-tert-butyl-
dimethylsilyloxy-3- trimethylsilyl -2-propynyl)-(-2-propenyloxy)
benzene (33)
2.3.30. 4,6-Di-tert-butyl-2-(-1-tert-butyl-dimethylsilyloxy -3-
phenyl-2-propynyl)-(-2-propenyloxy)benzene (34)
The Pauson-Khand cyclization of the enyne 33 (100 mg,
0.21 mmol) in 10 mL of the appropriate solvent, was carried out
following the General Procedures A and B. Co2(CO)8 (141 mg,
0.41 mmol) and NMO (530 mg, 4.52 mmol) were added according
to the general procedures, work-up and purification (hexane/
EtOAc, 90:10) provided only the exo-isomer of the PK product 36
(58 mg, 61% yield). On the other hand, subjection of enyne 33 to
thermal conditions resulted in no formation of any cycloadduct.
tert-Butyldimethylsilyl chloride (0.410 g, 2.71 mmol) was added
at room temperature to a mixture of 31 (0.340 g, 0.900 mmol) and
imidazole (0.300 g, 2.71 mmol) in DMF (10 mL). The mixture was
heated at 50 ꢀC for 4.5 h. The reaction was quenched by the addition
of aqueous NaHCO3 and extracted with Et2O. The organic layer was
separated, washed with water and brine, dried with Na2SO4
(anhydrous). The organic layer was concentrated to give a dark
colored liquid. The crude product was purified by flash chroma-
tography (hexane/EtOAc; 19:1) to give 34 as viscous brown liquid
2.3.35. 6,8-Di-tert-butyl-10-t-butyldimethylsilyloxy-1-
trimethylsilyl-4,4a-dihydro-3H,10H-5-oxabenzo[f]azulen-2-one
(36)
(0.420 g, 95%). 1H NMR:
d
¼ 7.65 (d, J ¼ 2.5 Hz, 1H), 7.41 (d,
J ¼ 2.5 Hz, 1H), 7.40 (d, J ¼ 4.0 Hz, 1H), 7.27e7.30 (m, 4H), 6.09 (ddt,
J ¼ 4.6, 10.5, 17.4 Hz, 1H), 5.93 (s, 1H), 5.56 (dq, J ¼ 1.8, 17.0 Hz, 1H),
5.29 (dq, J ¼ 1.8, 10.5 Hz,1H), 4.56 (ddt, J ¼ 1.8, 4.6, 13.8 Hz,1H), 4.50
(ddt, J ¼ 1.8, 4.1, 13.8 Hz, 1H), 1.42 (s, 9H), 1.33 (s, 9H), 0.86 (s, 9H),
Yellow, waxy paste, 1H NMR:
d
¼ 7.26 (d, J ¼ 2.5 Hz, 1H), 7.07 (d,
J ¼ 2.3 Hz, 1H), 5.78 (s, 1H), 4.51 (dd, J ¼ 4.6, 11.9 Hz, 1H), 4.18 (dd,
J ¼ 4.6, 8.7 Hz, 1H), 3.89 (m, 1H), 3.52 (t, J ¼ 11.5 Hz, 1H), 2.56 (dd,
J ¼ 6.9, 18.8 Hz, 1H), 1.94 (d, J ¼ 17.9 Hz, 1H), 1.34 (s, 9H), 1.29 (s, 9H),
0.82 (s, 9H), 0.23 (s, 9H), 0.03 (s, 3H), ꢃ0.21 (s, 3H); 13C NMR:
0.14 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz):
d
¼ 152.5, 146.2, 141.5,
135.8, 134.0, 131.7, 128.3, 124.5, 123.9, 123.3, 116.5, 91.4, 84.7, 75.8,
60.1, 35.5, 34.8, 31.6, 31.2, 25.9, 18.4, ꢃ4.4, ꢃ4.8 (only 23 signals
were observed out of 24 carbon types); IR (neat, cmꢃ1) ¼ 2959,
2864, 1600, 1362, 1063; HRMS (CI): Calcd. for [Mþ] C32H46O2Si (m/
z): 490.3262. Found 490.3277.
d
¼ 212.6, 186.9, 157.1, 145.0, 141.9, 138.5, 131.4, 126.3, 124.0, 75.4,
38.8, 38.7, 35.3, 34.5, 31.5, 30.4, 25.8, 18.2, 14.2, 11.0, ꢃ0.2, ꢃ4.6; IR
(neat, cmꢃ1) ¼ 3433.6, 2956.3, 2859.6, 1732.2, 1698.8, 1594.5,
1477.2, 1250.8; HRMS (ESI): Calcd. for [MþH]þ C30H51O3Si2 (m/z):
515.3371. Found 515.3389.
2.3.31. Cyclization of 4,6-di-tert-butyl-2-(-1-tert-butyl-
2.3.36. Cyclization of 4,6-di-tert-butyl-2-(-1-tert-
butyldimethylsilyloxy -3-phenyl-2-propynyl)-(-2-propenyloxy)
benzene (34)
dimethylsilyloxy-2-propynyl)-(-2-propenyloxy) benzene (35)
The Pauson-Khand cyclization of the enyne 32 (80 mg,
0.19 mmol) in 10 mL of the appropriate solvent, was carried out
The Pauson-Khand cyclization of the enyne 34 (101 mg,

6132
C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
0.21 mmol) in 10 mL of the appropriate solvent, was carried out
following the General Procedures A and B. Co2(CO)8 (141 mg,
0.41 mmol) and NMO (529 mg, 4.52 mmol) were added according
to the general procedures and after work-up and purification as
usual gave the reduced PK product 27 (11.2 mg, 11%) and the PK
product 37 (62.9 mg, 60% as a 1:5 mixture of epimers) using the
oxidative Procedure B. Procedure A delivered only 37 (101 mg, 95%
as a 1:10 mixture of epimers) was isolated. The isomers were
separated by preparative thin layer chromatography.
2.3.41. 3,5-Di-tert-butyl-2-(3-methyl-2-propenyloxy)
benzaldehyde (42)
Crotyl chloride (95% trans, 1.16 g, 18.0 mmol) was added to a
suspension of K2CO3 (2.00 g, 14.4 mmol) and 3,5-di-tert-butyl-2-
hydroxybenzaldehyde (1.00 g, 4.26 mmol) in DMF (10 mL) and
stirred for 12 h according to the general alkylation procedure. The
crude product was purified by flash chromatography (hexane/
EtOAc, 15:1) to give 42 (1.22 g, 99%) as a brown oil. The proton NMR
spectrum indicated that it was a 5:1 mixture of the E/Z-isomers. 1H
NMR data of the major isomer:
d
¼ 10.29 (s, 1H), 7.69 (d, J ¼ 2.7 Hz,
1H), 7.58 (d, J ¼ 2.3 Hz, 1H), 5.88 (m, 1H), 5.80 (m, 1H), 4.39 (dd,
J ¼ 1.4, 6.0 Hz, 2H), 1.78 (dd, J ¼ 1.4, 6.4 Hz, 3H), 1.42 (s, 9H), 1.31 (s,
2.3.37. 6,8-Di-tert-butyl-10-t-butyldimethylsilyloxy-1-phenyl-
4,4a-dihydro-3H,10H-5-oxabenzo[f]azulen-2-one (exo-37)
9H); 13C NMR:
d
¼ 191.2, 160.0, 146.4, 143.1, 130.9, 130.7, 129.5,
Yellow oil, 1H NMR:
d
¼ 7.39 (m, 3H), 7.31 (d, J ¼ 2.3 Hz, 1H),
126.0, 123.8, 79.7, 35.4, 34.8, 31.4, 31.0, 18.0; IR (neat, cmꢃ1) ¼ 2958,
1690, 1593, 1460, 1374, 1220, 970; HRMS (ESI): Calcd. For [MþNa]þ
C19H28NaOþ2 (m/z): 311.1981. Found 311.1951.
7.21(dd, J ¼ 1.8, 7.8 Hz, 2H), 7.05 (d, J ¼ 2.8 Hz, 1H), 5.55 (s, 1H), 4.62
(dd, J ¼ 5.0, 11.9 Hz, 1H), 4.01 (m, 1H), 3.54 (t, J ¼ 10.5 Hz, 1H), 2.78
(dd, J ¼ 7.3, 18.8 Hz, 1H), 2.10 (d, J ¼ 18.8 Hz, 1H), 1.38 (s, 9H), 1.32 (s,
9H), 0.77 (s, 9H), ꢃ0.12 (s, 3H), ꢃ0.33 (s, 3H); 13C NMR:
d
¼ 206.3,
2.3.42. 4,6-Di-tert-butyl-2-(-1-hydroxy-2-propynyl)-1-(-2-
butenyloxy)benzene (43)
173.9,157.3,145.6,142.4,138.2,132.0,131.0,129.5,128.3,126.1,126.1,
124.3,124.2, 74.2, 39.2, 37.3, 35.4, 34.6, 31.5, 30.5, 25.8,18.2, ꢃ4.8; IR
(neat, cmꢃ1) ¼ 2959, 1709, 849; HRMS (ESI): Calcd. for C33H47O3Si
(m/z): 519.3289. Found 519.3295 [MþH].
A 0.5 M solution in THF of ethynylmagnesium bromide (12.7 mL,
6.35 mmol) was added at 0 ꢀC to the solution of 42 (1.22 g,
4.23 mmol) in dry THF (10 mL) under N2 atmosphere according to
the general Grignard Procedure to give 43 as a viscous brown liquid
2.3.38. 6,8-Di-tert-butyl-10-t-butyldimethylsilyloxy-1-phenyl-
4,4a-dihydro-3H,10H-5-oxabenzo[f]azulen-2-one (endo-37)
(1.32 g, 99%). 1H NMR (300 MHz):
d
¼ 7.56 (d, J ¼ 2.3 Hz,1H), 7.35 (d,
J ¼ 2.7 Hz, 1H), 5.91 (q, J ¼ 6.2 Hz, 1H), 5.81 (dt, J ¼ 1.0, 5.5 Hz, 1H),
5.77 (d, J ¼ 2.1 Hz, 1H), 4.51 (ddt, J ¼ 1.0, 5.5, 11.7 Hz, 1H), 4.34 (ddt,
J ¼ 1.0, 5.9, 11.7 Hz, 1H), 2.61 (d, J ¼ 2.4 Hz, 1H), 1.78 (d, J ¼ 5.2 Hz,
Yellow oil, 1H NMR:
d
¼ 7.69 (d, J ¼ 2.5 Hz, 1H), 7.29e7.23 (m,
6H), 5.90 (s, 1H), 4.62 (dd, J ¼ 5.5, 11.5 Hz, 1H), 3.53 (m, 1H), 3.23 (t,
J ¼ 11.5 Hz, 1H), 2.75 (dd, J ¼ 6.9, 18.8 Hz, 1H), 1.94 (dd, J ¼ 2.3,
18.8 Hz, 1H), 1.41 (s, 9H), 1.37 (s, 9H), 0.60 (s, 9H), ꢃ0.14 (s,
3H), 1.40 (s, 9H), 1.32 (s, 9H); 13C NMR (75 MHz):
d
¼ 153.3, 146.6,
142.4, 133.7, 129.8, 126.7, 125.3, 123.5, 84.4, 76.3, 74.2, 60.1, 35.6,
34.8, 31.5, 31.3,18.0; IR (neat, cmꢃ1) ¼ 3298, 2958, 2103, 1602, 1277;
HRMS (ESI): Calcd. for [2M þ Na]þ C42H60O4Naþ (m/z): 651.4384.
Found 651.4334.
3H), ꢃ0.28 (s, 3H); 13C NMR (125 MHz):
¼ 205.4,173.7,146.5,141.1,
d
138.2, 134.0, 132.2, 130.4, 127.7, 127.2, 126.2, 123.0, 120.9, 72.2, 61.8,
42.2, 36.6, 35.1, 35.0, 31.6, 30.8, 25.6, 18.1, ꢃ5.5; IR (neat,
cmꢃ1) ¼ 2959, 1709, 1623, 849; HRMS (ESI): Calcd. for [MþH]þ
C33H47O3Si (m/z): 519.3289. Found 519.3250.
2.3.43. 4,6-Di-tert-butyl-2-(-1-hydroxy-3- trimethylsilyl -2-
propynyl)-1-(-2- butenyloxy) benzene (44)
2.3.39. 3,5-Di-tert-butyl-2-(2-methyl-2-propenyloxy)benzaldehyde
(38)
A solution of trimethylsilylethynylmagnesium chloride in dry
THF was prepared by adding ethynyltrimethylsilane (2.47 g,
25.0 mmol) to 3.0 M solution of ethylmagnesium chloride (8.27 mL,
25.0 mmol) THF under N2 at 0 ꢀC and stirred for 30 min before
allowing the reaction to warm up to room temperature. The reac-
tion was further stirred for 10 min at room temperature. To this
aliquot of trimethylsilylethynylmagnesium chloride was added a
solution of 42 (2.27 g, 7.87 mmol) in THF (20 mL) under N2 atmo-
sphere at ꢃ78 ꢀC and stirred for 2.5 h at ꢃ78 ꢀC before allowing it to
warm up to rt. This was then stirred overnight and then worked up
according to the general procedure to give 44 (3.00 g, 99%) as a light
3-Chloro-2-methylpropene (1.16 g, 18.0 mmol) was added to a
suspension of K2CO3 (2.00 g, 14.4 mmol) and 3,5-di-tert-butyl-2-
hydroxybenzaldehyde (1.00 g, 4.26 mmol) in DMF (10 mL) and
stirred for 12 h according to the general alkylation procedure. The
crude product was purified by flash chromatography (hexane/
EtOAc, 15:1) to give 38 (1.21 g, 98%) as a light yellow solid: mp:
49e51 ꢀC, 1H NMR (500 MHz):
1H), 7.65 (d, J ¼ 2.7 Hz, 1H), 5.55 (s, 1H), 5.35 (s, 1H), 4.36 (s, 2H),
1.85 (s, 3H), 1.42 (s, 9H), 1.31 (s, 9H); 13C NMR (125 MHz):
d
¼ 10.29 (s, 1H), 7.74 (d, J ¼ 2.7 Hz,
d
¼ 191.2,
yellow waxy solid; 1H NMR:
d
¼ 7.54 (d, J ¼ 2.7 Hz, 1H), 7.27 (d,
159.6, 146.5, 143.1, 140.4, 130.9, 129.4, 123.6, 110.2, 82.2, 35.4, 34.8,
31.4, 30.9, 19.6; IR (neat, cmꢃ1) ¼ 2962, 2869, 1688, 1597, 1478, 993,
896; HRMS (CI): Calcd. For [M]þ C19H28O2þ (m/z): 288.2084. Found
288.2082.
J ¼ 2.3 Hz, 1H), 5.84 (m, 1H), 5.75 (m, 1H), 5.68 (s, 1H), 4.47 (dd,
J ¼ 6.0, 11.5 Hz, 1H), 4.35 (dd, J ¼ 6.0, 11.5 Hz, 1H), 1.71 (d, J ¼ 6.4 Hz,
3H), 1.34 (s, 9H), 1.25 (s, 9H), 0.12 (s, 9H); 13C NMR:
d
¼ 153.5, 146.3,
142.2, 134.1, 129.6, 126.8, 125.1, 124.0, 106.0, 90.9, 76.2, 60.8, 35.5,
34.7, 31.5, 31.3, 18.0, ꢃ0.1; IR (neat, cmꢃ1) ¼ 3361, 2960, 2172, 1462;
HRMS (ESI): Calcd. For [2M þ Na]þ C48H76O4Si2Naþ (m/z): 795.5178.
Found 795.5212.
2.3.40. 4,6-Di-tert-butyl-2-(-1-hydroxy-3-phenyl-2-propynyl)-(2-
methyl-2-propenyloxy) benzene (41)
A 1.0 M solution of phenylethynylmagnesium bromide (15.6 mL,
16.0 mmol) in THF was added to a solution of 38 (3.00 g, 10.0 mmol)
in THF (20 mL) under N2 atmosphere at 0 ꢀC according to the
general procedure 3.1.2 to give 41 (4.00 g, 98%) as a light yellow
2.3.44. 4,6-Di-tert-butyl-2-(-1-hydroxy-3-phenyl-2-propynyl)-(2-
butenyloxy)benzene (45)
solid, mp: 49e51 ꢀC. 1H NMR:
d
¼ 7.71 (d, J ¼ 2.7 Hz, 1H), 7.45 (m,
A 1.0 M solution in THF of phenylethynylmagnesium bromide
(15.6 mL, 16.0 mmol) was added to the solution of 42 (3.0 g,
10.0 mmol) in dry THF (20 mL) under N2 atmosphere at 0 ꢀC ac-
cording to the general Grignard Procedure to give 45 (3.00 g, 74%)
2H), 7.37 (d, J ¼ 2.7 Hz, 1H), 7.30 (m, 3H), 6.01 (s, 1H), 5.30 (s, 1H),
5.05 (s, 1H), 4.59 (d, J ¼ 13.1 Hz, 1H), 4.41 (d, J ¼ 13.1 Hz, 1H), 2.62 (s,
1H), 1.89 (s, 3H), 1.45 (s, 9H), 1.37 (s, 9H); 13C NMR:
d
¼ 153.4, 146.6,
142.4, 141.5, 134.3, 131.8, 128.6, 128.4, 125.1, 123.9, 122.8, 111.4, 90.0,
86.1, 78.6, 60.5, 35.6, 34.9, 31.6, 31.3, 19.7; IR (neat, cmꢃ1) ¼ 3452,
2963, 2908, 2224, 1658, 1599; HRMS (ESI): Calcd. for [MþNa]þ
C27H34O2Naþ (m/z): 413.2451. Found 413.2442.
as a light yellow oil; 1H NMR:
d
¼ 7.75 (d, J ¼ 2.3 Hz, 1H), 7.49 (m,
2H), 7.44 (d, J ¼ 2.7 Hz, 1H), 7.32 (m, 3H), 6.03 (d, J ¼ 4.0 Hz, 1H),
5.98 (m, 1H), 5.88 (m, 1H), 4.59 (dd, J ¼ 6.0, 7.3 Hz, 1H), 4.44 (dd,
J ¼ 6.0, 7.3 Hz, 1H), 2.85 (d, J ¼ 5.0 Hz, 1H), 1.80 (d, J ¼ 5.5 Hz, 3H),

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6133
1.44 (s, 9H), 1.37 (s, 9H); 13C NMR:
d
¼ 153.4, 146.5, 142.4, 134.4,
(ESI) Calcd. for [MþNa]þ C26H36O2Naþ (m/z): 399.2295. Found
131.8, 129.8, 128.5, 128.4, 126.9, 125.2, 123.8, 122.8, 89.9, 86.1, 76.4,
60.8, 35.6, 34.8, 31.6, 31.4, 18.0; IR (neat, cmꢃ1) ¼ 3357, 2955, 2179,
1463, 1374, 1223; HRMS (ESI): Calcd. for [MþNa]þ C27H34O2Na (m/
z): 413.2451. Found 413.2461.
399.2293.
2.3.48. 4,6-Di-tert-butyl-2-(1-hydroxy-3-phenyl-2-propynyl)-1-
(-3-phenyl-2-propenyloxy) benzene (50)
1.0 M solution of phenylethynylmagnesium bromide (8.59 mL,
8.59 mmol) in THF was added at 0 ꢀC to a solution of 48 (2.00 g,
5.71 mmol) in dry THF (20 mL) under N2 atmosphere. The reaction
mixture was allowed to warm up to room temperature and stirred
for 3 h. The reaction was quenched with NH4Cl and extracted with
CH2Cl2. The organic extract was washed with water, dried (Na2SO4)
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (SiO2, hexane/EtOAc,10:1) to give
22b (2.0 g, 78%) as a white solid. Mp: 133e134 ꢀC; 1H NMR
2.3.45. 1,5-Di-tert-butyl-3-iodo-2-(3-phenyl-2-propenyloxy)
benzene (47)
A solution of diethyl azodicarboxylate (15.7 g, 90.4 mmol) in dry
THF (50 mL) was added dropwise to a solution of iodophenol 4611c
(10.0 g, 30.1 mmol), cinnamyl alcohol (8.08 g, 60.2 mmol) and PPh3
(23.7 g, 90.4 mmol) in dry THF (100 mL) at 0 ꢀC and stirred for 3 h.
The solvent was removed in vacuo at the end of the reaction. The
crude product was purified by flash chromatography (hexane) to
give the product 47 (12.4 g, 92%) as a white solid, mp: 120e122 ꢀC;
(500 MHz):
d
¼ 7.25e7.70 (m, 12H), 6.84 (d, J ¼ 16.0 Hz, 1H), 6.49
1H NMR (300 MHz):
d
¼ (E-isomer) 7.69 (d, J ¼ 2.4 Hz, 1H),
(dt, J ¼ 5.5, 15.6 Hz, 1H), 6.04 (s, 1H), 4.81 (ddd, J ¼ 1.8, 5.5, 12.8 Hz,
7.26e7.50 (m, 6H), 6.82 (d, J ¼ 15.8 Hz, 1H), 6.50 (dt, J ¼ 5.5, 16.2 Hz,
1H), 4.65 (ddd, J ¼ 1.8, 5.5, 12.8 Hz,1H), 2.60 (s, 1H), 1.45 (s, 9H), 1.36
1H), 4.69 (d, J ¼ 5.5 Hz, 2H), 1.43 (s, 9H), 1.31 (s, 9H); 13C NMR
(s, 9H); 13C NMR (75 MHz):
d
¼ 153.3, 146.7, 142.4, 136.8, 134.4,
(75 MHz):
d
¼ 155.1, 148.2, 143.9, 136.9, 135.4, 132.6, 128.7, 127.9,
132.2, 131.8, 128.7, 128.6, 128.5, 128.4, 127.9, 126.7, 125.3, 125.2,
123.9, 89.8, 86.2, 76.1, 60.7, 35.7, 34.8, 31.6, 31.4; IR (neat,
cmꢃ1) ¼ 3441, 2961, 1599, 1444, 1362, 1222, 1159, 1119, 965, 883,
756; HRMS (ESI): Calcd. for [MþNa]þ C24H31O2 (m/z): 475.2608.
Found 475.2613.
126.7, 125.3, 124.9, 93.4, 73.9, 34.5, 34.0, 31.5, 31.3; IR (neat,
cmꢃ1) ¼ 3100, 2960, 2872, 1772, 1434, 1394, 1234, 1087, 963; HRMS
(CI): Calcd. for [Mþ] C23H29IO (m/z): 448.1257. Found 448.1218.
2.3.46. 3,5-Di-tert-butyl-2-(3-phenyl-2-propenyloxy)
benzaldehyde (48)
2.3.49. Cyclization of 4,6-di-tert-butyl-2-(1-hydroxy-3-phenyl-2-
propynyl)-1-(-3-methyl-2-propenyloxy) benzene (45)
A
solution
of
1,5-di-tert-butyl-3-iodo-2-(3-phenyl-2-
propenyloxy)benzene 47 (5.00 g, 11.2 mmol) in dry THF (20 mL)
was cooled to ꢃ30 ꢀC and 2.0 M solution of i-propylmagnesium
chloride (1.38 g, 13.5 mmol) in THF was added and the reaction
mixture stirred for 20 min at ꢃ30 ꢀC. The reaction was then allowed
to warm up to room temperature and stirred for 20 min. Next the
reaction mixture was cooled to 0 ꢀC and DMF (1.30 mL, 16.7 mmol)
was added dropwise. The reaction was warmed up to room tem-
perature and stirred for 2 h. The reaction was quenched with water
and extracted with CH2Cl2. The organic layer was separated,
concentrated under reduced pressure and dried (MgSO4). The
crude product was purified by flash chromatography (SiO2, hexane/
EtOAc, 5:1) to give 48 (4.51 g, 98%) as a white solid, mp:
The Pauson-Khand cyclization of the enyne 45 (63 mg,
0.16 mmol) was carried out following the General Procedures A and
B in 5 mL of the appropriate solvent. Co2(CO)8 (61 mg, 0.18 mmol)
and NMO (189 mg, 1.62 mmol) were added according to the general
procedures, work-up and purification (hexane/EtOAc, 87:13) as
usual provided the reduced PK product 52 (12 mg, 18%), the endo-
product 54 (26 mg, 36%) and the exo-product 56 (31 mg, 45%) for
procedure B. Procedure A produced the endo-product 54 (6.1 mg,
9%) and the exo-PK product 56 (60 mg, 90%).
2.3.50. 6,8-Di-tert-butyl-1-phenyl-3-methyl-4,4a-dihydro-3H,10H-
5-oxabenzo[f]azulen-2-one (52)
123e125 ꢀC; 1H NMR (300 MHz):
d
¼ (E-isomer) 10.37 (s, 1H), 7.73
Light yellow solid, mp: 80e82 ꢀC; 1H NMR:
d
¼ 7.45 (t, J ¼ 7.3 Hz,
(d, J ¼ 2.4 Hz,1H), 7.65 (d, J ¼ 2.4 Hz,1H), 7.26e7.47 (m, 5H), 6.80 (d,
J ¼ 15.8 Hz,1H), 6.50 (dt, J ¼ 5.5,16.2 Hz,1H), 4.64 (d, J ¼ 5.9 Hz, 2H),
2H), 7.38 (t, J ¼ 6.9 Hz,1H), 7.34 (d, J ¼ 7.3 Hz, 2H), 7.28 (d, J ¼ 2.3 Hz,
1H,), 7.14 (d, J ¼ 1.8 Hz, 1H), 4.72 (dd, J ¼ 5.5, 11.5 Hz, 1H), 3.87 (d,
J ¼ 12.8 Hz,1H), 3.77 (d, J ¼ 12.8 Hz,1H), 3.37 (t, J ¼ 11.5 Hz,1H), 3.10
(m, 1H), 1.96 (dd, J ¼ 2.8, 8.7 Hz, 1H), 1.42 (s, 9H), 1.36 (d, J ¼ 7.8 Hz,
1.46 (s, 9H), 1.33 (s, 9H); 13C NMR (75 MHz);
d
¼ 191.0, 159.8, 146.6,
143.2, 136.4, 133.0, 131.0, 129.4, 128.8, 128.1, 126.8, 124.1, 124.0, 79.4,
35.5, 34.8, 31.4, 31.0; IR (neat, cmꢃ1) ¼ 3049, 2920, 1667, 1592, 1485,
1362, 1231, 915, 755, 687; HRMS (ESI): Calcd. for [MþH]þC24H31O2
(m/z): 351.2319. Found 351.2325.
3H), 1.34 (s, 9H); 13C NMR (125 MHz):
d
¼ 207.7, 169.9, 157.0, 146.7,
141.8, 138.4, 131.5, 129.7, 128.3, 128.1, 125.3, 123.0, 75.5, 52.9, 42.4,
36.5, 35.2, 34.7, 31.6, 30.7, 15.3 (21 carbons were observed out of 22
carbon types); IR (Neat, cmꢃ1) ¼ 2957, 1705, 1466, 752; HRMS (ESI):
Calcd. for [MþH]þ C28H35O2 (m/z): 403.2632. Found 403.2636.
2.3.47. 4,6-Di-tert-butyl-2-(1-hydroxy-2-propynyl)-1-(-3-phenyl
-2-propenyloxy) benzene (49)
A 0.5 M solution of ethynylmagnesium bromide (17.2 mL,
8.61 mmol) in THF was added at 0 ꢀC to the solution of 48 (2.00 g,
5.71 mmol) in dry THF (20 mL) under N2 atmosphere. The reaction
mixture was allowed to warm up to rt and stirred for 3 h. The re-
action was quenched with NH4Cl and extracted with CH2Cl2. The
organic extract was washed with water, dried (Na2SO4) and
concentrated under reduced pressure. The crude product was pu-
rified by flash chromatography (SiO2, hexane/EtOAc, 10:1) to give
49 (3.11 g, 99%) as a yellow solid, mp: 136e138 ꢀC; 1H NMR
2.3.51. 6,8-Di-tert-butyl-10-hydroxy-3-methyl-1-phenyl-4,4a-
dihydro-3H,10H-5-oxabenzo[f]azulen-2-one (54, endo-product)
Yellow oil, 1H NMR:
d
¼ 7.37 (m, 3H), 7.34 (d, J ¼ 2.8 Hz, 1H), 7.20
(dd, J ¼ 1.8, 8.3 Hz, 2H), 7.14 (d, J ¼ 2.8 Hz, 1H), 5.53 (s, 1H), 4.73 (dd,
J ¼ 5.5, 11.5 Hz, 1H), 4.13 (d, J ¼ 7.3 Hz, 1H), 4.10 (d, J ¼ 7.3 Hz, 1H),
3.64 (t, J ¼ 11.0 Hz, 1H), 2.83 (ddd, J ¼ 7.3, 7.8, 11.5 Hz, 1H), 1.40 (s,
9H), 1.32 (s, 9H), 1.16 (d, J ¼ 7.8 Hz, 3H); 13C NMR:
d
¼ 208.8, 171.5,
156.4, 147.3, 142.7, 138.5, 132.8, 130.9, 129.7, 128.4, 128.3, 125.3,
124.9, 73.5, 42.0, 41.7, 35.3, 34.7, 31.5, 30.7, 14.3, 10.5; IR (Neat,
cmꢃ1) ¼ 3434, 3055, 2960, 2870, 1703, 1477, 1444; HRMS (ESI):
Calcd. for [2M þ Na]þ C56H68NaO6 (m/z) 859.4908, Found 859.4955.
(300 MHz):
d
¼ 7.26e7.61 (m, 7H), 6.81 (d, J ¼ 15.6 Hz, 1H), 6.46 (dt,
J ¼ 5.4, 16.2 Hz, 1H), 5.84 (s, 1H), 4.74 (ddd, J ¼ 1.5, 5.7, 13.2 Hz, 1H),
4.58 (ddd, J ¼ 1.5, 5.7, 13.2 Hz, 1H), 2.64 (d, J ¼ 1.2 Hz, 1H), 2.52 (s,
1H), 1.44 (s, 9H), 1.34 (s, 9H); 13C NMR (75 MHz):
d
¼ 153.3, 146.8,
2.3.52. 6,8-Di-tert-butyl-10-hydroxy-3-methyl-1-phenyl-4,4a-
dihydro-3H,10H-5-oxabenzo [f]azulen-2-one (56, exo product)
142.4,136.7, 133.8,132.2, 128.7, 127.9, 126.7, 125.4, 125.0, 123.6, 84.5,
76.1, 74.4, 59.9, 35.7, 34.9, 31.6, 31.4; IR (neat, cmꢃ1) ¼ 3550, 3279,
2962, 2159, 1476, 1362, 1230, 1159, 1118, 1021, 965, 884, 748; HRMS
Yellow solid, mp: 158e160 ꢀC, 1H NMR:
7.34 (d, J ¼ 2.8 Hz,1H), 7.23 (d, J ¼ 6.5 Hz, 2H), 7.18 (d, J ¼ 2.8 Hz,1H),
d
¼ 7.42e7.35 (m, 3H),

6134
C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
5.53 (d, J ¼ 8.3 Hz,1H), 4.76 (dd, J ¼ 5.0,11.0 Hz,1H), 4.12 (dd, J ¼ 7.3,
14.2 Hz,1H), 3.60 (m,1H), 3.54 (t, J ¼ 11.0 Hz,1H,), 3.14 (d, J ¼ 8.7 Hz,
1H), 1.41 (s, 9H), 1.38 (d, J ¼ 7.3 Hz, 3H), 1.32 (s, 9H); 13C NMR:
[2M þ Na]þ C44H60NaOþ6 (m/z) 707.4282, Found 707.4352.
2.3.58. 6,8-Di-tert-butyl-3-methyl-4,4a-dihydro-3H,10H-5-
oxabenzo[f]azulen-2-one (57)
d
¼ 207.5, 170.0, 156.5, 147.3, 142.7, 138.5, 132.9, 130.9, 129.6, 128.4,
128.3,125.2,124.9, 73.5, 60.5, 47.7, 42.5, 35.3, 34.7, 31.5, 30.7,15.2; IR
(Neat, cmꢃ1) ¼ 3498, 2955, 1701, 1468; HRMS (ESI): Calcd. for
[MþH]þ C28H35O3 419.2581, Found 419.2577.
Light yellow oily waxy solid, 1H NMR:
d
¼ 7.25 (d, J ¼ 2.5 Hz, 1H),
7.06 (d, J ¼ 2.5 Hz, 1H), 6.0 (s, 1H), 4.59 (dd, J ¼ 5.5, 11.5 Hz, 1H), 3.94
(d, J ¼ 13.3 Hz, 1H), 3.73 (d, J ¼ 13.3 Hz, 1H), 3.24 (t, J ¼ 11.9 Hz, 1H),
3.03 (m 1H), 1.86 (ddd, J ¼ 3.2, 7.3, 14.7 Hz, 1H), 1.38 (s, 9H), 1.29 (s,
2.3.53. Cyclization of 4,6-di-tert-butyl-2-(1-hydroxy-3-
trimethylsilyl-2-propynyl)-1-(3-methyl-2-propenyloxy) benzene
(43)
The Pauson-Khand cyclization of the enyne 43 (200 mg,
0.52 mmol) was carried out following the General Procedures A and
B in 5 mL of the appropriate solvent. Co2(CO)8 (195 mg, 0.57 mmol)
and NMO (606 mg, 5.18 mmol) were added according to the general
procedures, work-up and purification by flash chromatography
(hexane/EtOAc, 87:13) afforded the PK product 55 (15 mg, 7%) for
Procedure B whereas Procedure A gave 55 (25 mg, 12%).
9H), 1.23 (d, J ¼ 7.3 Hz, 3H); 13C NMR:
¼ 210.0, 176.5, 156.6, 146.6,
d
141.6, 129.2, 128.4, 125.2, 123.3, 75.0, 54.1, 43.6, 38.6, 35.1, 34.6, 31.6,
30.7, 14.9; IR (neat, cmꢃ1) ¼ 2959, 1707, 1620, 1468, 1232, 1000;
HRMS (ESI): Calcd. for [MþH]þ C22H31O2 (m/z): 327.2319. Found
327.2312.
2.3.59. 4,6-Di-tert-butyl-2-(-1-tert-butyl-dimethylsilyloxy-2-
propynyl)-(2-butenyloxy) benzene (59)
tert-Butyldimethylsilyl chloride (2.20 g, 14.3 mmol) was added
at room temperature to a mixture of 42 (1.50 g, 4.78 mmol) and
imidazole (0.980 g, 14.3 mmol) in DMF (10 mL). The reaction
mixture was heated at 50 ꢀC for 4.5 h. The reaction was quenched
by the addition of aqueous NaHCO3 and extracted with Et2O. The
organic layer was separated, washed with water and brine and
dried (Na2SO4). The organic layer was concentrated to give a dark
liquid. The crude product purified by flash chromatography (hex-
ane/EtOAc; 19:1) to give 59 as viscous brown oil, (2.03 g, 99%). 1H
2.3.54. 6,8-Di-tert-butyl-10-hydroxy-3-methyl-1-trimethylsilyl-
4,4a-dihydro-3H,10H-5-oxabenzo[f]azulen-2-one (55)
Yellow liquid, 1H NMR:
d
¼ 7.32 (d, J ¼ 2.8 Hz, 1H), 7.18 (d,
J ¼ 2.8 Hz, 1H), 5.69 (s, 1H), 4.65 (dd, J ¼ 5.0, 11.0 Hz, 1H), 3.50 (ddd,
J ¼ 3.2, 5.0, 11.0 Hz, 1H), 3.47 (t, J ¼ 11.0 Hz, 1H), 1.85 (ddd, J ¼ 3.2,
7.3, 14.7 Hz, 1H),1.38 (s, 9H),1.29 (s, 9H), 1.23 (d, J ¼ 7.8 Hz, 3H), 0.29
(s, 9H); 13C NMR (125 MHz):
d
¼ 213.5, 182.6, 156.2, 146.9, 142.4,
NMR:
d
¼ 7.58 (d, J ¼ 2.8 Hz, 1H), 7.28 (d, J ¼ 2.8 Hz, 1H), 5.94 (dq,
139.0, 132.7, 125.1, 124.9, 75.0, 60.5, 50.6, 43.6, 35.3, 34.7, 31.5, 30.7,
15.0, ꢃ0.09; IR (neat, cmꢃ1) ¼ 3498, 2960, 1697, 1590, 1478; HRMS
(CI): Calcd. for [Mþ] C25H38O3Si (m/z): 414.2590. Found 414.2593.
J ¼ 6.4, 15.1 Hz, 1H), 5.81 (dt, J ¼ 6.0, 15.1 Hz, 1H), 5.73 (d,
J ¼ 2.3 Hz,1H), 4,28 (ddt, J ¼ 1.4, 5.5, 10.5 Hz, 1H), 4.21 (ddt, J ¼ 1.4,
5.5, 12.4 Hz, 1H), 2.49 (d, J ¼ 2.3 Hz, 1H), 1.81 (dd, J ¼ 6.5, Hz, 3H),
1.41 (s, 9H), 1.33 (s, 9H), 0.85 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H); 13C
2.3.55. Cyclization of 4,6-di-tert-butyl-2-(-1-hydroxy-2-propynyl)-
1-(-2-butenyloxy) benzene (42)
NMR:
d
¼ 152.6, 146.2, 141.5, 135.6, 128.8, 126.9, 124.1, 124.0, 86.0,
76.0, 72.6, 59.5, 35.5, 34.8, 31.6, 31.2, 25.8, 18.3, 18.0, ꢃ4.8, ꢃ5.0; IR
(neat, cmꢃ1) ¼ 3311, 2960, 2934, 2118, 1649, 1474; HRMS (ESI):
Calcd. for [MþNa]þC27H44O2SiNa (m/z): 451.3003. Found 451.3010.
The Pauson-Khand cyclization of the enyne 42 (420 mg,
1.34 mmol) was carried out following General Procedures A and B
in 5 mL of the appropriate solvent. Co2(CO)8 (500 mg, 1.46 mmol)
and NMO (1.72 g, 14.7 mmol) were added according to the general
procedures, usual work-up and purification by flash chromatog-
raphy (hexane/EtOAc, 87:13) delivered the reduced PK product 57
(131 mg, 30%) and the 1,4-diketone 58 (253 mg, 58% as a 1:3
mixture of syn and anti isomers) using Procedure B. Procedure A
only gave 57 (146 mg, 32%, 1:2 mixture of syn and anti isomers).
Preparatory TLC was used to separate the syn- and anti-products.
2.3.60. 4,6-Di-tert-butyl-2-(-1-tert-butyl-dimethylsilyloxy-3-
trimethylsilyl -2-propynyl)-(2-butenyloxy)benzene (60)
tert-Butyldimethylsilyl chloride (0.940 g, 6.22 mmol) was added
at room, 6.22 mmol) in DMF (10 temperature to a mixture of 44
(0.800 g, 2.07 mmol) and imidazole (0.400 g mL). The reaction
mixture was heated at 50 ꢀC for 4.5 h. The reaction was quenched
by the addition of aqueous NaHCO3 and extracted with Et2O. The
organic layer was separated, washed with water and brine and
dried (Na2SO4). The organic layer was concentrated to give a dark
colored liquid. The crude product was purified by flash chroma-
tography (hexane/EtOAc, 19:1) to give 60 as viscous brown oil,
2.3.56. 6,8-Di-tert-butyl-3-methyl-1,1a,4,4a-tetrahydro-1H,3H-5-
oxabenzo[f]azulen-2,10-dione (syn-58)
Brown solid, mp: 134e136 ꢀC, 1H NMR:
d
¼ 7.56 (d, J ¼ 2.8 Hz,
1H). 7.49 (d, J ¼ 2.8 Hz, 1H), 4.84 (dd, J ¼ 6.45, 11.9 Hz, 1H), 3.81 (dt,
J ¼ 1.8, 8.7 Hz, 1H), 3.70 (t, J ¼ 11.9 Hz, 1H), 3.16 (dt, J ¼ 1.8, 19.3 Hz,
1H), 2.93 (m, 1H), 2.25 (dd, J ¼ 8.3, 19.3 Hz, 1H), 1.94 (m, 1H), 1.42 (s,
(1.02 g, 98%). 1H NMR:
1H), 5.94 (dq, J ¼ 6.4, 15.5 Hz, 1H), 5.81 (dt, J ¼ 6.0, 15.6 Hz, 1H), 5.73
(s, 1H), 4.52 (d, J ¼ 4.5 Hz, 2H), 1.81 (d, J ¼ 6.5 Hz, 3H), 1.40 (s, 9H),
1.30 (s, 9H), 0.85 (s, 9H), 0.16 (s, 9H), 0.12 (s, 3H), 0.02 (s, 3H); 13C
d
¼ 7.58 (d, J ¼ 3.0 Hz, 1H), 7.28 (d, J ¼ 3.0 Hz,
9H), 1.30 (s, 9H), 1.09 (d, J ¼ 6.9 Hz, 3H); 13C NMR:
¼ 217.0, 200.5,
d
160.3, 144.4, 139.9, 128.3, 128.0, 124.3, 76.8, 50.0, 48.6, 44.4, 37.4,
35.4, 34.6, 31.5, 30.2, 12.8; IR (neat, cmꢃ1) ¼ 2960, 1748, 1680, 1463,
757; HRMS (ESI): Calcd. for [MþH]þ.C22H31O3 (m/z) 343.2268,
Found 343.2272.
NMR:
d
¼ 152.9, 145.6, 141.4, 135.7, 128.7, 127.2, 124.6, 123.8, 107.8,
89.4, 76.0, 60.3, 35.5, 34.8, 31.6, 31.2, 25.8, 18.4,
18.1, ꢃ0.1, ꢃ4.4, ꢃ4.6; IR (neat, cmꢃ1) ¼ 2959, 2216, 1469, 1251;
HRMS (ESI): Calcd. For [MþNa]þ C30H52O2Si2Na (m/z): 523.3398.
Found 523.3412.
2.3.57. 6,8-Di-tert-butyl-3-methyl-1,1a,4,4a-tetrahydro-1H,3H-5-
oxabenzo[f]azulen-2,10-dione (anti-58)
2.3.61. 4,6-Di-tert-butyl-2-(-1-tert-butyl-dimethylsilyloxy -3-
phenyl-2-propynyl)-(-2-butenyloxy)benzene (61)
Yellow waxy solid, 1H NMR:
d
¼ 7.53 (d, J ¼ 2.5 Hz, 1H,), 7.39 (d,
J ¼ 2.5 Hz, 1H), 4.45 (dd, J ¼ 2.3, 12.8 Hz, 1H), 3.99 (dd, J ¼ 3.7,
12.3 Hz, 1H), 3.59 (dt, J ¼ 8.7, 10.5 Hz, 1H), 2.95 (tt, J ¼ 2.8, 8.7 Hz,
1H), 2.49 (t, J ¼ 8.7 Hz, 1H), 2.41 (ddd, J ¼ 1.8, 8.7, 10.5 Hz, 1H), 2.33
(dd, J ¼ 8.3, 19.3 Hz, 1H), 1.25 (s, 9H), 1.22 (s, 9H), 1.21 (d, J ¼ 2.3 Hz,
tert-Butyldimethylsilyl chloride (1.16 g, 7.69 mmol) was added at
room temperature to a mixture of 45 (1.00 g, 2.60 mmol) and
imidazole (0.460 g, 7.69 mmol) in DMF (10 mL). The reaction
mixture was heated at 50 ꢀC for 4.5 h. The reaction was quenched
by the addition of aqueous NaHCO3 and extracted with Et2O. The
organic layer was separated, washed with water and brine and
dried (Na2SO4). The organic layer was concentrated to give a dark
3H); 13C NMR:
d
¼ 215.9, 202.7, 158.8, 145.1, 140.1, 128.6, 125.2,
125.0, 74.0, 51.1, 45.3, 45.1, 39.8, 35.2, 34.7, 31.5, 30.2, 10.3; IR (neat,
cmꢃ1) ¼ 2960, 1742, 1678, 1463, 755; HRMS (ESI): Calcd. for

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6135
liquid. The crude product was purified by flash chromatography
(hexane/EtOAc, 19:1) to give 61 as viscous brown liquid (1.28 g,
J ¼ 9.5 Hz,1H), 3.51 (d, J ¼ 3.5 Hz,1H), 2.15 (d, J ¼ 5.0 Hz, 1H),1.40 (s,
9H), 1.38 (d, J ¼ 5.0 Hz, 3H), 1.33 (s, 9H), 0.78 (s, 9H), ꢃ0.11 (s,
98%). 1H NMR:
d
¼ 7.67 (d, 1H, J ¼ 3.0 Hz), 7.47 (m, 2H), 7.31 (d, 1H,
3H), ꢃ0.27 (s, 3H); 13C NMR:
d
¼ 208.4, 171.5, 157.4, 145.4, 142.1,
J ¼ 3.0 Hz), 7.29 (m, 3H), 6.01 (m, 1H), 5.98 (s, 1H), 5.86 (m, 1H), 4.46
137.2, 131.7, 131.1, 129.4, 128.2, 126.3, 124.2, 75.1, 73.8, 48.4, 43.2,
35.4, 34.6, 31.7, 31.6, 30.5, 25.8, 18.2, 15.1, ꢃ4.75, ꢃ4.79; IR (neat,
cmꢃ1) ¼ 2957, 1709, 1465, 1066, 841; HRMS (ESI): Calcd. for
(dd, 2H, J ¼ 5.5, 11.0 Hz), 1.83 (d, 3H, J ¼ 6.5 Hz), 1.42 (s, 9H), 1.34 (s,
9H), 0.89 (s, 9H), 0.17 (s, 3H), 0.04 (s, 3H); 13C NMR:
d
¼ 152.7, 146.1,
141.5, 135.9, 131.7, 128.9, 128.3, 127.1, 124.5, 123.8, 123.4, 91.5, 84.6,
76.0, 60.2, 35.6, 34.8, 31.6, 31.2, 25.9, 25,8, 18.4, 18.1, ꢃ4.4, ꢃ4.7, IR
(neat, cmꢃ1) ¼ 2960, 2300, 1560, 1475, 1252, 1064; HRMS (ESI):
Calcd. for [MþNa]þ C33H48O2SiNa (m/z): 527.3316. Found 527.3345.
C34H49O3Si (m/z): 533.3445. Found 533.3468.
2.3.65. Cyclization of 4,6-di-tert-butyl-2-(1-hydroxy-3-phenyl-2-
propynyl)-1-(-3-phenyl-2-propenyloxy) benzene (50)
The Pauson-Khand cyclization of the enyne 50 (110 mg,
0.240 mmol) was carried out following the General Procedures A
and B in 5 mL of the appropriate solvent. Co2(CO)8 (92 mg,
0.27 mmol) and NMO (310 mg, 2.65 mmol) were added according
to the general procedures, work-up and purification by flash
chromatography (SiO2, hexane/EtOAc, 87:13) produced the reduced
PK-product 65 (50 mg, 45%) and the exo-PK product 66 (60 mg, 51%)
for the Procedure B, Procedure gave only the PK-product 66
(110 mg, 90%, 1:10 mixture of the epimers).
2.3.62. 6,8-Di-tert-butyl-10-t-butyldimethylsilyloxy-3-methyl-
4,4a-dihydro-3H,10H-5-oxa benzo[f]azulen-2-one (62)
The Pauson-Khand cyclization of the enyne 59 (200 mg,
0.470 mmol) was carried out following the general procedures A
and B in 5 mL of the appropriate solvent. Co2(CO)8 (180 mg,
0.530 mmol) and NMO (620 mg, 5.30 mmol) were added according
to the general procedures, normal work-up and purification was
purified by flash chromatography (hexane/EtOAc, 87:13) affording
the PK product 62 (170 mg, 80%, as a 5:4 mixture epimers) for
Procedure B, Procedure A gave PK product 52 (180 mg, 85%, as a 5:4
mixture of isomers) as a brown waxy solid; 1H NMR (300 MHz):
2.3.66. 6,8-Di-tert-butyl-1,3-diphenyl-4,4a-dihydro-3H,10H-5-
oxabenzo[f]azulen-2-one (65)
d
¼ 7.29 (d, J ¼ 2.5 Hz, 1H), 7.13 (d, J ¼ 2.5 Hz, 1H), 6.06 (s, 1H), 5.63
Yellow waxy solid, 1H NMR (300 MHz):
d
¼ 7.27e7.51 (m, 10H),
(s, 1H), 4.59 (dd, J ¼ 5.1, 11.4 Hz, 1H), 3.72 (app. t, J ¼ 10.2 Hz, 1H),
3.20 (d, J ¼ 3.5 Hz, 1H), 2.07 (d, J ¼ 3.9 Hz, 1H), 1.31 (s, 9H), 1.30 (s,
9H), 1.23 (d, J ¼ 3.9 Hz, 3H), 0.86 (s, 9H), 0.07 (s, 6H); 13C NMR
7.25 (d, J ¼ 2.1 Hz, 1H), 7.19 (d, J ¼ 2.4 Hz,1H), 4.78 (dd, J ¼ 4.5,
10.2 Hz, 1H), 3.96 (d, J ¼ 13.2 Hz, 1H), 3.84 (d, J ¼ 12.9 Hz, 1H), 3.55
(m, 1H), 3.48 (t, J ¼ 11.4 Hz, 1H), 3.13 (d, J ¼ 3.0 Hz, 1H), 1.42 (s, 9H),
(75 MHz):
d
¼ 210.2, 178.9, 153.9, 145.5, 142.0, 131.9, 127.1, 124.3,
1.37 (s, 9H), 13C NMR (75 MHz):
d
¼ 204.7, 170.7, 157.0, 146.8, 141.9,
120.6, 75.4, 71.1, 49.6, 44.1, 35.3, 34.6, 31.6, 30.7, 25.8, 18.3,
14.6, ꢃ4.7, ꢃ4.8; IR (neat, cmꢃ1) ¼ 2957, 1712, 1624, 1474; HRMS
(ESI): Calcd. for [MþH]þ C28H45O3Si (m/z): 457.3132. Found
457.3131.
138.8, 138.6, 131.3, 129.8, 129.5, 129.1, 128.4, 128.3, 128.2, 127.4,
125.3, 123.1, 75.4, 54.2, 53.8, 36.6, 35.2, 34.7, 31.6, 30.7; IR (neat,
cmꢃ1) ¼ 3059, 3029, 2961, 2869, 1707, 1638, 1599, 1476; HRMS
(ESI): Calcd. For C33H36O2Na (m/z): 487.2608. Found 487.2625
[MþNa]þ.
2.3.63. 6,8-Di-tert-butyl-10-t-butyldimethylsilyloxy-3-methyl-1-
trimethylsilyl-4,4a-dihydro-3H,10H-5- oxabenzo[f]azulen-2-one
(63)
2.3.67. 6,8-Di-tert-butyl-10-hydroxy-1,3-diphenyl-4,4a-dihydro-
3H,10H-5-oxabenzo[f] azulen-2-one (66)
The Pauson-Khand cyclization of the enyne 60 (100 mg,
0.200 mmol) was carried out following the General Procedures A
and B in 5 mL of the appropriate solvent. Co2(CO)8 (75 mg,
0.22 mmol) and NMO (260 mg, 2.20 mmol) were added according
to the general procedures, usual work-up and purification by flash
chromatography (SiO2, hexane/EtOAc, 87:13) to afford only the exo-
PK product 63 (7.8 mg, 7%) for the oxidative method. Thermal
method gave also the exo-product 63 (10.4 mg, 10%) as a brown
Yellow solid, mp: 173e175 ꢀC. 1H NMR:
d
¼ 7.36 (m, 6H), 7.25 (m,
5H), 7.22 (d, J ¼ 2.3 Hz, 1H), 5.60 (s, 1H), 4.81 (dd, J ¼ 5.5, 11.5 Hz,
1H), 4.10 (m, 1H), 3.68 (t, J ¼ 11.5 Hz,1H), 3.17 (d, J ¼ 2.8 Hz,1H), 1.41
(s, 9H),1.35 (s, 9H); 13C NMR (75 MHz):
d
¼ 204.5,170.9,156.4,147.4,
142.8, 138.7, 138.2, 132.7, 130.7, 129.7, 129.1, 128.6, 128.3, 128.2,
127.5, 125.2, 125.1, 73.5, 60.5, 54.2, 48.6, 35.4, 34.8, 31.5, 30.7; IR
(neat, cmꢃ1) ¼ 3450, 3058, 2956, 1700, 1638, 1600, 1477, 1361, 1266;
HRMS (ESI): Calcd. for [MþNa]þ C33H36O3Na (m/z): 503.2557.
Found 503.2548.
waxy solid, 1H NMR:
d
¼ 7.26 (d, J ¼ 2.5 Hz, 1H), 7.06 (d, J ¼ 2.5 Hz,
1H), 5.78 (s,1H), 4.58 (dd, J ¼ 4.6,11.5 Hz,1H), 3.71 (t, J ¼ 9.5 Hz,1H),
3.34 (m, 1H), 2.06 (m, 1H), 1.34 (s, 9H), 1.30 (s, 9H), 1.23 (d,
J ¼ 5.0 Hz, 3H), 0.83 (s, 9H), 0.21 (s, 9H), 0.06 (s, 3H), ꢃ0.14 (s, 3H);
2.3.68. Cyclization of 4,6-di-tert-butyl-2-(1-hydroxy-2-propynyl)-
1-(-3-phenyl-2-propenyloxy) benzene (49)
13C NMR:
d
¼ 214.6, 177.1, 168.7, 163.0,155.4, 138.6, 121.7, 114.5, 82.2,
The Pauson-Khand cyclization of the enyne 49 (200 mg,
0.530 mmol) was carried out following the general procedures A
and B in 5 mL of the appropriate solvent. Co2(CO)8 (200 mg,
0.590 mmol) and NMO (680 mg, 5.85 mmol) were added according
to the general procedures. The reaction mixture was filtered using a
sintered glass funnel packed with a short layer of Celite and SiO2.
The crude product was purified by flash chromatography (SiO2,
hexane/EtOAc, 87:13) to afford the diketone product 68 (130 mg,
51%, 5:1 ratio of the syn- and trans-isomers), for the oxidative
method. The thermal method gave the 68 (90 mg, 41%, 3:1 ratio of
the syn and trans-isomers) and the normal PK product 67 (10 mg,
5%).
71.8, 44.5, 35.4, 34.5, 33.2, 31.5, 30.4, 30.3, 29.8, 25.8, 18.2,
6.1, ꢃ0.2, ꢃ4.5; IR (neat, cmꢃ1) ¼ 2957, 1709, 1465, 1066, 841; HRMS
(ESI): Calcd. for [MþH]þ C31H53O3Si2 (m/z): 529.3528. Found
529.3500.
2.3.64. 6, 8-di-tert-butyl-10-t-butyldimethylsilyloxy-3-methyl-1-
phenyl-4,4a-dihydro-3H,10H-5-oxabenzo[f]azulen-2-one (64)
The Pauson-Khand cyclization of the enyne 61 (210 mg,
0.400 mmol) was carried out following the General Procedures A
and B in 5 mL of the appropriate solvent. Co2(CO)8 (150 mg,
0.440 mmol) and NMO (510 mg, 4.36 mmol) were added according
to the general procedures, usual a purification by flash chroma-
tography (SiO2, hexane/EtOAc, 87:13) provided the PK product 64
(100 mg, 45%, 1:4 mixture of the diastereomers) for Procedure B,
Procedure A gave 64 (151 mg, 68%) as a brown waxy solid, 1H NMR:
2.3.69. 6,8-Di-tert-butyl-3-phenyl-1,1a,4,4a-tetrahydro-3H-5-
oxabenzo[f]azulen-2,10-dione (68)
For the major Isomer (obtained pure) as a yellow waxy solid. 1H
d
¼ 7.36 (m, 3H), 7.31 (d, J ¼ 2.5 Hz, 1H), 7.21 (d, J ¼ 7.0 Hz, 2H), 7.09
NMR (300 MHz):
7.29 (m, 3H), 7.08 (d, J ¼ 6.9 Hz, 2H), 4.67 (dd, J ¼ 6.2, 12.0 Hz, 1H),
d
¼ 7.62 (d, J ¼ 2.4 Hz, 1H), 7.50 (d, J ¼ 2.4 Hz, 1H),
(d, J ¼ 2.5 Hz, 1H), 5.60 (s, 1H), 4.68 (dd, J ¼ 5.0, 12.0 Hz, 1H), 3.68 (t,

6136
C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
3.94 (dt, J ¼ 1.2, 8.6 Hz, 1H), 3.73 (t, J ¼ 12.0 Hz, 1H), 3.53 (ddt,
J ¼ 6.2, 8.6, 19.2 Hz, 1H), 3.29 (d, J ¼ 19.2 Hz, 1H), 3.12 (d, J ¼ 12.9 Hz,
1H), 2.40 (dd, J ¼ 8.4, 18.9 Hz, 1H), 1.39 (s, 9H), 1.32 (s, 9H); 13C NMR
2.3.73. 6,8-Di-tert-butyl-10-t-butyldimethylsilyloxy-1,3-diphenyl-
4,4a-dihydro-3H,10H-5-oxabenzo[f]azulen-2-one (71)
The Pauson-Khand cyclization of the enyne 70 (200 mg,
0.35 mmol) was carried out following the General Procedures A and
B in 10 mL of the appropriate solvent. Co2(CO)8 (140 mg, 0.41 mmol)
and NMO (490 mg, 4.19 mmol) were added according to General
Procedures A and B, usual work-up and purification by flash chro-
matography (hexane/EtOAc, 87:13) yielded only the exo-PK prod-
ucts of 71 (140 mg, 67%) for Procedure B, similarly Procedure A gave
the exo-PK product 71 (180 mg, 86%) as a yellow viscous liquid. 1H
(75 MHz):
d
¼ 214.0, 200.4, 160.5, 144.5, 140.0, 136.0, 129.1, 128.5,
128.4, 128.1, 127.8, 124.3, 76.7, 56.4, 49.7, 48.4, 38.2, 35.4, 34.7, 31.5,
30.2, 29.8; IR (neat, cmꢃ1) ¼ 3099, 2959, 2869, 2360, 1750, 1676,
1597, 1438; HRMS (ESI): Calcd. for C27H33Oþ3 (m/z): 405.2424. Found
405.2432 [MþH]þ.
2.3.70. 6,8-Di-tert-butyl-10-hydroxy-3-phenyl-4,4a-dihydro-
3H,10H-5-oxabenzo[f] azulen-2-one (67)
NMR (500 MHz):
d
¼ 7.16e7.42 (m, 12H), 4.71 (s, 1H), 4.75 (dd,
J ¼ 4.6,11.5 Hz, 1H), 4.10 (m, 1H), 3.83 (t, J ¼ 10.0 Hz,1H), 3.31 (s, 1H),
Yellow waxy solid, 1H NMR (300 MHz):
d
¼ 7.19e7.36 (m, 7H),
1.42 (s, 9H),1.37 (s, 9H), 0.81 (s, 9H), ꢃ0.05 (s, 3H), ꢃ0.24 (s, 3H); 13
C
6.20 (s, 1H), 5.56 (s, 1H), 4.69 (dd, J ¼ 5.4, 11.4 Hz, 1H), 4.21 (dd,
J ¼ 3.6, 5.4 Hz, 1H), 3.96 (m, 1H), 3.57 (t, J ¼ 10.8 Hz, 1H), 3.08 (d,
J ¼ 3.3 Hz, 1H), 1.38 (s, 9H), 1.32 (s, 9H); 13C NMR (75 MHz):
NMR (75 MHz);
d
¼ 205.3, 172.5, 157.4, 145.6, 142.3, 138.7, 137.2,
131.9, 130.9, 129.6, 129.1, 128.4, 128.3, 128.2, 127.3, 126.3, 124.3, 73.9,
60.5, 54.6, 49.2, 35.5, 34.6, 31.6, 30.5, 25.8, 18.2, 14.3, ꢃ4.8; IR (neat,
cmꢃ1) ¼ 3098, 2955, 1712, 1600, 1477, 1361, 1254; HRMS (ESI):
Calcd. For [MþH]þ C39H51O3Si (m/z): 595.3602. Found 595.3605.
d
¼ 206.4, 177.8, 147.4, 142.6, 129.1, 128.9, 128.4, 128.1, 127.5, 125.4,
125.0, 111.2, 89.8, 77.3, 75.6, 50.4, 35.3, 34.8, 31.5, 30.7, 29.8; IR
(neat, cmꢃ1) ¼ 3451, 2959, 2926, 2869, 2360,1712,1476,1362,1269;
HRMS (ESI): Calcd. For [MþNa]þ C27H32NaO3 (m/z): 427.2244.
Found 427.2216.
2.3.74. 6,8-Di-tert-butyl-10-t-butyldimethylsilyloxy-3-phenyl-
4,4a-dihydro-3H,10H-5-oxa benzo[f]azulen-2-one (72)
The Pauson-Khand cyclization of the enyne 69 (200 mg,
0.410 mmol) was carried out following the General Procedures A
and B in 10 mL of the appropriate solvent. Co2(CO)8 (153 mg,
0.450 mmol) and NMO (525 mg, 4.49 mmol) were added according
to the general procedures, normal work-up and purification by
flash chromatography (SiO2, hexane/EtOAc, 87:13) produced the PK
product 72 (150 mg, 71%, 1:0.8 mixture of the epimers) for Pro-
cedure B, the thermal conditions also gave the PK product 72
(180 mg, 86%, 1:1 ratio of epimers) as a viscous yellow liquid. 1H
2.3.71. 4,6-Di-tert-butyl-2-(1-tert-butyldimethylsilyloxy -2-
propynyl)-1-(-3-phenyl -2-propenyloxy) benzene (69)
tert-Butyldimethylsilyl chloride (1.20 g, 7.98 mmol) was added
at room temperature to a mixture of the 49 (1.0 g, 2.66 mmol) and
imidazole (0.54 g, 7.98 mmol) in DMF (10 mL). Then the mixture
was heated at 50 ꢀC for 4.5 h. The reaction was quenched by the
addition of aqueous NaHCO3 and extracted with Et2O. The organic
layer separated, washed with water and brine, dried with anhy-
drous Na2SO4 and then concentrated to give a dark liquid. Purifi-
cation was by flash chromatography (hexane/EtOAc; 19:1) to give
NMR:
d
¼ (1:1 mixture of exo- and endo-compound) 7.62 (d,
J ¼ 2.3 Hz, 1H), 7.27e7.36 (m, 8H), 7.19e7.15 (m, 5H), 6.38 (s, 1H),
6.17 (s, 1H), 5.83 (s, 1H), 5.69 (s, 1H), 4.67 (dd, J ¼ 6.4, 11.5 Hz, 1H),
4.59 (dd, J ¼ 6.4,11.9 Hz,1H), 3.82 (broad s, 2H), 3.62 (m,1H), 3.32 (t,
J ¼ 11.9 Hz, 1H), 3.24 (s, 1H), 3.02 (d, J ¼ 3.2 Hz, 1H), 1.41 (s, 9H), 1.38
(s, 9H), 1.35 (s, 9H), 1.34 (s, 9H), 1.06 (s, 9H), 0.89 (s, 9H), 0.16 (s, 3H),
69 (1.29 g, 99%) as dark red oil. 1H NMR:
d
¼ 7.59 (d, J ¼ 2.8 Hz, 1H),
7.46 (d, J ¼ 7.8 Hz, 2H), 7.34 (t, J ¼ 7.8 Hz, 2H), 7.30 (d, J ¼ 2.3 Hz,1H),
7.29 (d, J ¼ 7.3 Hz, 1H), 6.85 (d, J ¼ 16.0 Hz, 1H), 6.44 (dt, J ¼ 5.1,
16.0 Hz, 1H), 5.76 (s, 1H), 4.62 (dd, J ¼ 5.1, 13.8 Hz, 2H), 2.52 (s, 1H),
0.13 (s, 3H),0.12 (s, 3H), ꢃ0.10 (s, 3H); 13C NMR:
d
¼ 207.0, 205.8,
1.42 (s, 9H), 1.33 (s, 9H), 0.82 (s, 9H), 0.07 (s, 3H), ꢃ0.06 (s, 3H); 13
C
181.6,179.5,155.8,155.7, 153.9,146.7, 145.6,142.1,141.0,138.4,138.3,
132.7, 131.6, 129.1,129.0,128.2,127.9, 127.4,127.3,127.2,126.3,125.5,
124.4, 123.5, 120.6, 75.1, 71.1, 55.9, 54.9, 52.8, 50.8, 35.4, 35.1, 34.6,
NMR (75 MHz):
d
¼ 152.4, 146.4, 141.6, 136.9, 135.5, 131.5, 128.7,
127.8, 126.7, 125.3, 124.2, 124.1, 85.9, 75.7, 72.8, 59.5, 35.6, 34.8, 31.6,
31.2, 25.8, 18.3, ꢃ4.7, ꢃ4.9; IR (neat, cmꢃ1) ¼ 3308, 3027, 2963,
2223, 1601, 1472, 1362, 1289, 1159, 1119, 1068, 965; HRMS (ESI):
Calcd. For C32H47O2Si (m/z): 491.3340. Found 491.3343 [MþH]þ.
31.7,
31.6,
30.9,
30.6,
26.0,
25.8,
18.5,
18.3,
14.3, ꢃ4.7, ꢃ4.7, ꢃ4.8, ꢃ5.1; IR (neat, cmꢃ1) ¼ 3105, 2955, 1710,
1625, 1476, 1390, 1361, 1254, 1230; HRMS (ESI): Calcd. for [MþH]þ
C33H47O3Siþ (m/z), 519.3289. Found 519.3296.
2.3.72. 4,6-Di-tert-butyl-2-(1-tert-butyldimethylsilyloxy-3-phenyl
-2-propynyl)-1-(3-phenyl-2-propenyloxy) benzene (70)
2.4. X-ray crystallographic data
tert-Butyldimethylsilyl chloride (1.00 g, 6.64 mmol) was added
at room temperature to a mixture of 50 (1.00 g, 2.21 mmol) and
imidazole (450 mg, 6.64 mmol) in DMF (10 mL). The reaction
mixture was then heated at 50 ꢀC for 4.5 h. The reaction was
quenched with aqueous NaHCO3 and extracted with Et2O. The
organic layer separated, washed with water and brine, dried
(Na2SO4) and concentrated to give a dark liquid. The crude product
was purified by flash chromatography (hexane/EtOAc, 19:1) to give
A suitable crystal covered with a layer of hydrocarbon/Paratone-
N oil was selected and mounted on a Cryo-loop, and immediately
placed in the low temperature nitrogen stream. The X-ray intensity
data for compounds 27, 31 and 56 were measured at 100(2) K on a
SMART APEX II CCD area detector system equipped with an Oxford
Cryosystems 700 series cooler, a graphite monochromator, and a
Mo K
a
fine-focus sealed tube (
l
¼ 0.71073 Å). Intensity data were
processed using the Bruker ApexII program suite. Absorption cor-
rections were applied by using SADABS. All the calculations for the
structure determination were carried out using the SHELXTL
package (version 6.14). Initial atomic positions were located by
direct methods using XS, and the structures of the compounds were
refined by the least-squares method using SHELXL.22 All the non-
hydrogen atoms were refined anisotropically. X-ray structural fig-
ures were generated using Olex2.23 The hydrogen atoms of hydroxy
groups were located in a Fourier difference synthesis and refined
satisfactorily. All the remaining hydrogen atoms of compounds 27,
31 and 56 were placed at calculated positions and refined using a
70 (1.23 g, 98%) as dark brown oil. 1H NMR:
d
¼ 7.73 (d, J ¼ 2.8 Hz,
1H), 7.29e7.51 (m, 11H), 6.92 (d, J ¼ 16.0 Hz, 1H), 6.53 (dt, J ¼ 5.0,
15.6 Hz, 1H), 6.06 (s, 1H), 4.77 (ddd, J ¼ 1.8, 5.5, 15.0 Hz, 1H), 4.70
(ddd, J ¼ 1.8, 5.5, 15.0 Hz, 1H), 1.49 (s, 9H), 1.40 (s, 9H), 0.92 (s, 9H),
0.20 (s, 3H), 0.09 (s, 3H); 13C NMR:
d
¼ 152.6, 146.3, 141.6, 137.0,
135.9, 131.8, 131.6, 128.7, 128.3, 128.3, 127.8, 126.7, 125.5, 124.6,
124.0, 123.3, 91.5, 84.9, 75.8, 60.4, 35.6, 34.9, 31.7, 31.3, 26.0,
18.4, ꢃ4.3, ꢃ4.6; IR (neat, cmꢃ1) ¼ 3102, 2928, 2709, 2223, 1946,
1659,1599,1472; HRMS (ESI): Calcd. for [MþNa]þ C38H50O2SiNa (m/
z): 589.3472. Found 589.3505.

C.E. Madu et al. / Tetrahedron 73 (2017) 6118e6137
6137
ꢀ
ꢀ
10. (a) Perez-Serrano L, Blanco-Urgoiti J, Casarrubios L, Domínguez G, Perez-
riding model. The CCDC 1552430e1552432 contain the supple-
mentary crystallographic data. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html or
from the Cambridge Crystallographic Data Centre (CCDC), 12 Union
Road, Cambridge, CB2 1EZ, UK).
Castells J. J Org Chem. 2000;65:3513e3519;
(b) Arnaiz E, Blanco-Urgoiti J, Abdi D, Domínguez G, Castells JP. J Orgmet Chem.
2008;693:2431e2437;
ꢀ
(c) Xing P, Huang Z-g, Jin Y, Jiang B. Tetrahedron Lett. 2012;54:699e702.
11. (a) Lovely CJ, Seshadri H. Synth Commun. 2001;31:2479;
(b) Lovely CJ, Seshadri H, Wayland B, Cordes AW. Org Lett. 2001;3:2607;
(c) Madu CE, Seshadri H, Lovely CJ. Tetrahedron. 2007;63:5019;
(d) Madu CE, Lovely CJ. Synlett. 2007:2011.
12. Comer E, Rohan E, Deng L, Porco JA. Org Lett. 2007;9:2123e2126.
13. (a) Shambayati S, Crowe WE, Schreiber SL. Tetrahedron Lett. 1990;31:
5289e5292;
(b) Jeong N, Chung YK, Lee BY, Lee SH, Yoo S-E. Synlett. 2001:204e206.
14. Akimura N, Fujii A, Kamada F, et al. Synthesis. 2016:3931e3940.
15. We also investigated lengthening the tether between the ether oxygen and the
olefin, but these substrates did not engage in productive PK reactions and thus
are not included herein.
Acknowledgements
We are grateful to the Robert A. Welch Foundation (Y-1289 and
Y-1362) for supporting our research in this area. The NSF (CHE-
0234811 and CHE-0840509) is thanked for partial funding of the
purchase of NMR spectrometers employed in this work.
16. Madu CE, Lovely CJ. Org Lett. 2007;9:4697.
17. Fustero S, Lazaro R, Aiguabella N, Riera A, Simon-Fuentes A, Barrio P. Org Lett.
2014;16:1224e1227.
18. (a) Magnus P, Principe LM. Tetrahedron Lett. 1985;26:4851e4854;
(b) Jiang B, Xu M. Org Lett. 2002;4:4077e4080.
19. (a) Gimbert Y, Lesage D, Milet A, Fournier F, Greene AE, Tabet J-C. Org Lett.
2003;5:4073e4075;
Appendix A. Supplementary data
ꢀ
ꢀ
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.08.053.
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