Steric buttressing in the Pauson-Khand reactions of aryl enynes

Article abstract of DOI:10.1016/j.tet.2007.03.131

A variety of aryl enynes have been constructed from o-iodophenol derivatives containing ortho-tert-butyl groups via O-alkylation and a Sonogashira cross-coupling reaction. These substrates undergo efficient thermal and oxidative intramolecular Pauson-Khand reactions leading to the formation of sterically congested cyclopentenones, as well as the formation of medium-sized rings, although in the latter case with unusual regioselectivity. Incorporation of a TMS moiety on the alkyne group in a higher homolog led to cyclization via the normal mode, albeit in relatively low yield.

Full text of DOI:10.1016/j.tet.2007.03.131

Tetrahedron 63 (2007) 5019–5029
Steric buttressing in the Pauson–Khand reactions of aryl enynes
*
Christian E. Madu, Hemalatha Seshadri and Carl J. Lovely
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019-0065, United States
Received 19 February 2007; revised 16 March 2007; accepted 21 March 2007
Available online 27 March 2007
Abstract—Avariety of aryl enynes have been constructed from o-iodophenol derivatives containing ortho-tert-butyl groups via O-alkylation
and a Sonogashira cross-coupling reaction. These substrates undergo efficient thermal and oxidative intramolecular Pauson–Khand reactions
leading to the formation of sterically congested cyclopentenones, as well as the formation of medium-sized rings, although in the latter case
with unusual regioselectivity. Incorporation of a TMS moiety on the alkyne group in a higher homolog led to cyclization via the normal mode,
albeit in relatively low yield.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
workers.10 The logic behind this selection was twofold: (a)
the substrates should be rapidly constructed, and (b) there
are several natural product targets, for example, the hamiger-
ans15,16 that in principle could be accessed through success-
ful realization of this chemistry. Initial experiments along
these lines were conducted using enynes derived from
o-iodophenol via a Sonogashira cross-coupling and O-alkyl-
ation. When these substrates were subjected to cyclization
under oxidative conditions (formation of the Co2(CO)6 com-
plex and then treatment with N-methylmorpholine oxide,
NMO),17 cyclizations occurred with the simple allyl systems
(R2¼R3¼H, Scheme 1), although the efficiency was attenu-
ated with the TMS-substituted alkyne (R1¼TMS, Scheme
1).14 It was also found that substitution on the olefin, or in-
crease of the tether length (i.e., homoallyl) led to poor or
no conversion to the cycloadduct.14 As a result of these inves-
tigations, it became apparent that not only were medium-
sized rings problematic, but also the formation of congested
cyclopentenones via this method were difficult.
The Pauson–Khand (PK) reaction, the [2+2+1] co-cycliza-
tion of an alkene, alkyne (as the dicobalt hexacarbonyl com-
plex), and carbon monoxide has evolved into an excellent
method for the construction of cyclopentenones.1,2 This
reaction is known both inter- and intramolecularly, and can
be mediated or catalyzed by a variety of metal complexes
as well as by Co2(CO)8 as initially reported by Pauson and
Khand.1 In addition to developments with catalysts or medi-
ators of this reaction, the reaction has been extended to a
variety of substrates including allenes,3 dienes,4 and carbo-
diimides.5 Despite these notable advances, there are several
limitations with this cycloaddition that prevent the full real-
ization of its synthetic potential. For example, the literature
is replete with examples of the intramolecular variant lead-
ing to the formation of 5,5- and 5,6-fused systems,6,7 but
the generation of larger fused bicyclic systems is less well-
known.8,9 When this project was initiated there were no ex-
amples of medium-sized ring synthesis by this method8 until
the Krafft group10 and shortly thereafter our own group
disclosed some success in this area.11 Although since these
initial reports, several other studies have appeared in the
literature.11–13
R1
O
2: R1 = H (75%)
3: R1 = TMS (26%)
4: R1 = Ph (73%)
R1
O
O
Our initial approach to this problem was to investigate the
use of scaffolding elements that reduced the conformational
degrees of freedom of the tethers containing the reactive
functionality (olefin and alkyne). It was expected that this
tactic should sufficiently reduce the entropic penalty associ-
ated with cycloaddition to allow the reaction to proceed. The
first substrate that we selected for investigation was aromatic
rings, an approach also employed by Krafft and co-
O
5: R2 = Ph, R3 = H (16%)
6: R2 = CH3, R3 = H (48%)
7: R2 = H, R3 = CH3 (0%)
R2
R2
1
R3
R3
O
Scheme 1. See Ref. 14.
During the course of these initial studies, we became aware
of a report from Sammes and co-workers describing the
use of steric buttressing elements (ortho alkyl moiety) to
coax recalcitrant intramolecular 1,3-dipole cycloadditions of
* Corresponding author. Tel.: +1 817 272 5446; fax: +1 817 272 3808;
e-mail: lovely@uta.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.131

5020
C. E. Madu et al. / Tetrahedron 63 (2007) 5019–5029
Table 1. Conditions and yields of alkylations of phenol 10
azides with pendant dipolarophiles into substantially more
efficient reactions.18 Indeed, the Sammes lab has reported
several applications of steric buttressing to facilitate other-
wise sluggish reactions.18 Given the similarity of the situa-
tions, we became intrigued as to whether a similar approach
might lead to enhancements of both the rates and efficiencies
of PK cyclizations under investigation in our lab. It is the
investigation of this tactic that is the subject of this paper.
Entry
Conditions
Product
Yield (%)
R1
Br
K2CO3, DMF
O
1
2
11, R1¼TMS
98
100
12, R1¼H
R1
2. Results and discussion
HO
DEAD, PPh3
Ph
To explore this idea, 2,4-di-tert-butylphenol (8) was identi-
fied as a suitable precursor, as it provided both a suitable
(and large) buttressing element, and the incorporation of an
iodo moiety ortho to the hydroxy group was described in the
literature.19 It should be noted that the 4-tert-butyl substitu-
ent does not play any role in constraining the conformational
mobility of the enyne, but it does block the 4-position toward
electrophilic substitution, rendering the preparation of sub-
strates more convenient. Simply treatment of the phenol
with NIS or I2/NaOH provided large quantities of the o-iodo-
phenol in good yields (9, Scheme 2), which then served as
the departure point for construction of the cyclization sub-
strates.19 Sonogashira reaction with the TMS-substituted
acetylene provided the phenyl acetylene derivative 10 in ex-
cellent yield (Scheme 2).20 Alkylation was achieved readily
at this stage with allyl halide derivatives and base, or in the
case of the cinnamyl moiety, this was incorporated via Mit-
sunobu chemistry (Table 1). In all cases, the expected prod-
ucts 11, 13, and 15 were obtained in excellent yields.
Subsequent treatment of the alkylated products with metha-
nolic K2CO3 provided the desilylated congeners 12, 14, and
16 in high yield.
O
Ph
3
4
13, R1¼TMS
14, R1¼H
95
93
R1
Cl
K2CO3, NaI,
DMF
O
5
6
15, R1¼TMS
16, R1¼H
98
100
R1
O
R1
R2
1. Co2(CO)8
R3
2. Heat or NMO
R2
O
O
R3
11-16
17-22
Scheme 3.
Table 2. PK-cyclization yields under thermal and oxidative conditions
I
NIS, DMF
68%
Entry
Product
Conditions
Thermal (%) Oxidative (%)
OH
OH
R1
O
8
9
H
TMS
Pd(PPh3)2Cl2,
CuI, Et3N, dioxane
93%
O
TMS
R1
1
2
17, R1¼H
91
93
80
96
Table 1
18, R1¼TMS
OH
R2
R1
O
O
R3
Ph
11, 13, 15: R1 = TMS
12, 14, 16: R1 = H
10
K2CO3,
MeOH/THF
O
Scheme 2.
3
4
19, R1¼H
73
71
91
81
20, R1¼TMS
R1
O
With this selection of enynes in hand, we began to investi-
gate both their oxidative and thermal PK reactions. In order
to establish the general viability of these substrates, the
parent enyne 12 was converted into the corresponding
Co2(CO)6 complex by treatment with a slight excess of
Co2(CO)8 in CH2Cl2 and then treated with NMO. We imme-
diately noted that this substrate underwent reaction substan-
tially faster than 1 (R2¼R3¼H, Scheme 1), which lacks the
O
5
6
21, R1¼H
91
92
81
97
22, R1¼TMS

C. E. Madu et al. / Tetrahedron 63 (2007) 5019–5029
5021
ortho-tert-butyl moiety, as the complex rapidly disappeared
X
by TLC analysis. On work up and purification we were
delighted to find that the expected cycloadduct had been
formed in 80% yield (entry 1, Table 2). In our initial study,11
we reported that this substrate did not engage in the cycload-
dition on thermal activation, when in fact this substrate does
engage in the PK reaction under thermal activation in PhMe,
provided that the temperature is maintained atw70 ꢀC (our
previous reactions were conducted at reflux temperatures).21
In this case the cycloadduct was obtained in 91% yield. As
the parent substrate engaged effectively in the cycloaddition,
our attention turned to cyclizations of more substituted de-
rivatives (Scheme 3). Two general types of derivative were
investigated, those containing substituted allyl derivatives
(entries 3 and 5, Table 2) and those with TMS-substituted
moiety (entries 2, 4, and 6, Table 2). As can be seen in Table
2, all of these derivatives engage in the cycloaddition reac-
tion under both thermal or oxidative conditions, leading to
the expected adduct in excellent yield, uniformly higher
than the parent substrate lacking the tert-butyl groups. Of
particular note is 15 (providing 22), which contains both
a TMS and methyl moiety and in the corresponding enyne
that lacks steric buttressing elements (1, R1¼TMS, R2¼H,
R3¼Me, Scheme 1), no cyclization occurs, but in the pres-
ence of a tert-butyl group, the reaction proceeds in high
efficiency.
H
OH
I
Pd(PPh3)2Cl2,
CuI, Et3N, dioxane
94%
OH
OH
NaBH4,
TFA, CH2Cl2
96%
23: X = OH
24: X = H
9
HO
X
O
1. Co2(CO)8
2. Heat or NMO
Δ = 75%
[O] = 33%
O
O
27
25: X = OH
26: X = H
1. Co2(CO)8
2. Heat or NMO
Δ = 84%
[O] = 65%
O
Br
O
O
OH
O
28
29: Hamigeran B
Scheme 4.
A major aim of this investigation was to establish the utility
of this reaction for the assembly of complex natural prod-
ucts. Although not widespread in nature, there are several
examples of naturally occurring molecules that contain aryl
rings with a pendant five-membered ring. The hamigerans
and tintinnadiol are among these.22,23 As a preliminary eval-
uation of the PK reaction as a viable approach to the former
of these targets (e.g., hamigeran B (29), Scheme 4), enynes
25 and 26 were constructed from iodophenol 9 through
Sonogashira chemistry with the butynol derivative24 and
either allylation (23/25) or reduction and then allylation
(23/26). Subjection of either enyne 25 or 26 to a thermal
PK reaction led to an efficient cyclization reaction, provid-
ing the corresponding cyclopentanone derivative (27 or 28)
in good yields. When the cyclization PK reaction of the al-
cohol derivative was performed under oxidative conditions,
the expected cycloadduct was obtained but in lower effi-
ciency. The thus formed tricyclic derivatives 27 and 28 bear
some resemblance to the hamigerans (albeit an oxa analog).
R
TMS
Ph3P, DEAD,
THF
O
OH
HO
30: R = TMS, 99%
31: R = H, 80%
K2CO3,
MeOH/THF
10
Ph3P, DEAD,
THF
HO
R
O
As indicated in the introduction, one of the long-term goals
of this project was to extend the scope of the intramolecular
PK reaction to include the construction of rings larger than
5- and 6-membered. Toward this end, the higher homologs
31 and 33 were prepared using similar protocols as described
above, although it should be noted that in the case the alkyl-
ations were carried out under Mitsunobu conditions as
attempts to employ the corresponding halides were compro-
mised by low yields (Scheme 5). The terminal trimethylsilyl
moieties were removed on treatment with base. With these
substrates (31 and 33) in hand, they were converted to their
cobalt complexes and subjected to the PK cyclization under
both oxidative and thermal conditions. As can be seen in
Schemes 6 and 7, each of the substrates provided cycload-
ducts, but there is clearly some dependence on both the sub-
strate and reaction conditions.
32: R = TMS
33: R = H, 80%
K2CO3,
MeOH/THF
Scheme 5.
In the case of the parent butenyl-containing substrate 31, un-
der oxidative conditions two products were obtained, both of
which were initially unanticipated. The major product was
the epoxy ketone 35 (confirmed by X-ray analysis) along
with the enone 34,11 interestingly, both products result as
a consequence of ‘abnormal’ regiochemistry arising from in-
sertion of the CO moiety adjacent to the aryl ring and previ-
ously unobserved orientation of the olefin (see Scheme 8).2
When the same substrate was subjected to cyclization under

5022
C. E. Madu et al. / Tetrahedron 63 (2007) 5019–5029
is rather strained, and reaction at the double bond relieves
this strain.
O
Several selectivity aspects of these cyclization reactions of
the higher homologs warrant further discussion. In general,
intermolecular PK reactions are regioselective with respect
to the alkyne component, with the larger substituent placed
adjacent to the carbonyl moiety. This observation has been
interpreted in terms of steric factors, with this mode of cyclo-
addition leading to a reduction of non-bonded interactions
between the alkyne substituent and the cobalt cluster. Elec-
tronic factors also play a role,27 with the more electron rich
substituent placed adjacent to the carbonyl moiety. Regiose-
lectivity in the olefinic moiety tends to be lower unless there
are directing groups,28 or the reaction is conducted intramo-
lecularly. In intramolecular variants of the PK reaction, the
regiochemistry of the carbonyl insertion appears to depend
on the tether length. For substrates, which lead to 5,5-,
5,6-bicyclic, and for most 5,7-systems, the CO moiety in-
serts between the two terminii of the enyne. However, for
systems that lead to larger rings, there is the possibility that
insertion can occur at either the terminii or the internal posi-
tions. Indeed, our own results11 and those from the Krafft
group amply demonstrate this possibility.10 This apparent
change in selectivity can be interpreted as a reversion to in-
termolecular selectivity (carbonyl adjacent to the larger sub-
stituent) as a result of a more flexible tether in the larger
rings. However, the mode of cyclization observed with 31
and 33 appears to be unique to the systems under investiga-
tion in this work. The mode of CO insertion, adjacent to the
aryl moiety, is consistent with the normal selectivities
observed in intermolecular variants, i.e., adjacent the largest
and most electron rich substituent. The olefin regiochemistry
is unusual, but is most likely a consequence of the structural
features of the substituted aromatic ring (vide infra).
31
Conditions
O
O
O
O
HO
O
O
O
34
Conditions
35
36
34 Yield
35 Yield
(%)
36 Yield
(%)
(%)
Co2(CO)8
then NMO
18
0
36
17
0
Co2(CO)8
then 70 °C
13
Scheme 6.
thermal conditions, a reaction also occurred leading to the
formation of the b-hydroxy ketone 36 and the epoxy ketone
35. The b-hydroxy ketone results from the Michael addition
of water to the enone 34 as demonstrated by a control reac-
tion in which the enone is treated with water in toluene at re-
flux. Although we have no direct evidence, we believe that
the epoxide results from the intermediacy of cobalt oxo spe-
cies that are formed during the course of the reaction. Krafft
and co-workers have demonstrated that the normal PK reac-
tion takes a different course in the presence of oxygen, lead-
ing to the so-called interrupted PK reaction resulting in the
formation of a non-cyclic enone.2,25 When the reaction of
the cobalt complex of 31 was conducted in an oxygen
atmosphere, the yield of the epoxide 35 increased to 63%.
Whereas attempts to convert enone 34 to the epoxide 35
under either the oxidative or thermal PK conditions were
unsuccessful, suggesting that the enone is not an intermedi-
ate.26 The higher homolog 33 also underwent cyclization
under both oxidative and thermal conditions (Scheme 7),
providing a similar type of unusual enone in 30% and
86% yield, respectively (the structure of 37 was confirmed
by X-ray crystallography).11 Interestingly, it is only with
the butenyl substrate that these abnormal products are ob-
tained, a molecular model suggests that the olefin moiety
There are four possible modes of cyclization (leading to 41,
43, 45, and 47, Scheme 8) in the intramolecular PK reaction
that are distinguished by the relative orientation of the two
reacting moieties and the locus of CO insertion. Three of
these modes of cycloaddition have now been observed ex-
perimentally (41, 43, and 47). We propose that in the present
case, the ortho-tert-butyl moiety forces the olefin moiety to
adopt a conformation such that the terminus of the olefin is
placed proximal to the internal carbon of the acetylene.
When insertion takes place to form the metallocycle, it
occurs through this conformation, subsequent CO insertion
and reductive elimination leads to the formation of the ob-
served products. Although a detailed rationalization of this
observation is still under investigation, the regiochemistry
of alkyne insertion is consistent with both the steric (bulkiest
substituent a to carbonyl) and electronic (most electron rich
substituent a to carbonyl) effects observed in the intermolec-
ular version of this reaction. Therefore, this outcome may be
simply a result of the larger tether, which allows normal
steric and electronic biases to operate27 that are otherwise
geometrically prohibitive with smaller tethers, e.g., in sub-
strates 11–16 and 25–26.
O
1. Co2(CO)8
2. Heat or NMO
O
O
Δ = 86%
[O] = 31%
As these larger systems participated in the cycloaddition
reaction, albeit with unexpected selectivity, we decided to
probe the scope of this reaction with the TMS-containing
substrates. Our motivation here was to investigate whether
37
33
Scheme 7.

C. E. Madu et al. / Tetrahedron 63 (2007) 5019–5029
5023
Y
6
O
Y
Co
4
Co
7
5
Normal
1
O
O
C7-C4
Co-C5
2
Y
40
41
6
Co
7
Co
5
Y
Y
4
Co
6
1
O
C6-C5
Co-C4
2
7
10
5
Krafft et al.
Co
1
O
4
O
O
38
2
42
43
Y
Co
Y
Co
4
O
7
6
5
O
O
C7-C5
Co-C4
2
1
Co
44
45
7
Y
6
4
Co
5
Co
X
2
O
Co
4
1
C6-C4
Co-C5
5
7
6
39
Lovely et al.11
Y
Y
X
1
2
O
46
47
Scheme 8.
the regiochemistry of the cyclization may change with the
introduction of a bulky substituent on the terminus of the al-
kyne. Under oxidative conditions, cyclization did not occur,
but under thermal conditions a reaction did take place
(Scheme 9). Two products were obtained from this reaction
when it was conducted under standard conditions under a
nitrogen atmosphere the expected enone was isolated in
14% yield, however, the major product was the diene, which
was obtained in 75% yield.29 Assignment of the stereo-
chemistry at the TMS-substituted diene was determined by
a NOESY experiment, the indicated NOE (Scheme 9) was
particularly diagnostic. Repeating this reaction under a CO
atmosphere led to a slight improvement in the yield of the
enone but no diene was observed.
3. Conclusion
In summary, we have explored the use of steric buttressing
elements in the intramolecular PK reaction. This investiga-
tion suggests that very crowded cyclopentenones can be con-
structed in excellent yields under either oxidative or thermal
activation. In a second application, access to medium-sized
rings is demonstrated, leading in some cases to a bridged ring
system previously unobserved in the intramolecular PK re-
action. An initial experiment with a internal alkyne leads
to cycloaddition via the ‘normal’ mode, but providing the cy-
clopentenone in low yields. Current efforts in our labs are fo-
cused on improving the efficiency of this last example, along
with the investigation of temporary buttressing elements.
NOE
O
TMS
TMS
H
H
R
1. Co2(CO)8
O
2. PhMe, reflux
O
O
30
48
49
Conditions
N2
48 Yield (%)
Yield (%)
75
49
14
CO
22
0
Scheme 9.

5024
C. E. Madu et al. / Tetrahedron 63 (2007) 5019–5029
4. Experimental
650. Anal. Calcd for C19H26O: C, 84.39; H, 9.69. Found:
C, 84.34; H, 9.53.
4.1. General
4.1.4. 4,6-Di-tert-butyl-2-trimethylsilylethynyl-(3-phenyl-
2-propenyloxy)benzene (13). DEAD (3.46 g, 19.9 mmol)
in THF (10 mL) was added dropwise to a solution of 10
(2.00 g, 6.60 mmol), cinnamyl alcohol (1.78 g, 13.3 mmol),
and PPh3 (5.21 g, 19.9 mmol) in THF (20 mL) and stirred
at 0 ꢀC for 6 h. The solvent was removed in vacuum and
the crude product was purified by flash chromatography
(hexane) to give the product as a white solid (2.70 g,
For general considerations see Ref. 30. All NMR spectra
were acquired in CDCl3 unless otherwise indicated.
4.1.1. 4,6-Di-tert-butyl-2-trimethylsilylethynylphenol
(10). To a stirred solution of 9 (3.54 g, 10.7 mmol) and Et3N
(5.9 mL) in dioxane (5.9 mL), (trimethylsilyl)acetylene
(1.37 g, 13.9 mmol), PdCl2(PPh3)2 (78 mg, 0.12 mmol),
and CuI (41 mg, 0.24 mmol) were added. The reaction
mixture was stirred at 55 ꢀC (bath temperature) under N2
for 5 h. Et2O (50 mL) and 1 M HCl (20 mL) were added,
and the organic layer was separated, neutralized with a satu-
rated NaHCO3 (30 mL) solution, washed with H2O, dried
(Na2SO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexane) to af-
ford 10 (3.03 g, 93%) as a solid, mp 114–116 ꢀC. 1H NMR
(500 MHz): d¼7.27 (d, J¼2.4 Hz, 1H), 7.20 (d, J¼2.4 Hz,
1H), 6.08 (s, 1H), 1.39 (s, 9H), 1.39 (s, 9H), 0.27 (s, 9H);
13C NMR (125 MHz): d¼153.6, 142.1, 134.8, 125.7,
125.6, 109.2, 76.8, 35.0, 34.3, 31.5, 29.5, 0.1; IR (KBr,
cmꢁ1): 3494, 2959, 2143, 1467, 1122, 758, 657; EIMS:
57, 73, 286 (100%), 302 (M+). Anal. Calcd for C19H30OSi:
C, 75.43; H, 9.99. Found: C, 75.32; H, 10.01.
1
95%). Mp 123–125 ꢀC; H NMR (500 MHz): d¼7.45 (d,
J¼7.3 Hz, 2H), 7.33–7.36 (m, 4H), 7.25–7.28 (m, 1H),
6.82 (d, J¼15.9 Hz, 1H), 6.50 (dt, J¼15.9, 5.7 Hz, 1H),
4.97 (dd, J¼5.7, 1.8 Hz, 2H), 1.42 (s, 9H), 1.31 (s, 9H),
0.27 (s, 9H); 13C NMR (125 MHz): d¼157.5, 145.3, 142.1,
137.0, 132.0, 129.3, 128.6, 127.7, 126.6, 125.8, 125.4, 116.5,
103.3, 98.7, 73.2, 35.3, 34.5, 31.5, 30.8, 0.2; IR (neat, cmꢁ1):
3109, 2960, 2152, 1434, 1371, 1229, 1120; LRMS (ESI):
419 (M+H), 441 (M+Na); HRMS: calcd for C28H39OSi
(M+H)+ 419.2765, found 419.2767: calcd for C28H39NaOSi
(M+Na)+ 441.2584, found 441.2589.
4.1.5. 4,6-Di-tert-butyl-2-ethynyl-(3-phenyl-2-propenyl-
oxy)-benzene (14). K2CO3 (1.32 g, 9.57 mmol) was added
to a solution of 13 (1.00 g, 2.39 mmol) in MeOH/THF
(10 mL, 1:1). The mixture was stirred at room temperature
for 4 h. The reaction mixture was concentrated under re-
duced pressure and filtered through a plug of silica gel
(EtOAc). The residue was purified by flash chromatography
(hexane/ether, 83:17) to furnish 14 (0.77 g, 93%) as a color-
less liquid: 1H NMR (500 MHz): d¼7.45 (d, J¼7.3 Hz, 2H),
7.24–7.38 (m, 5H), 6.78 (d, J¼15.8 Hz, 1H), 6.51 (dt,
J¼15.8, 5.8 Hz, 1H), 4.94 (dd, J¼5.8, 1.8, Hz, 2H), 3.34
(s, 1H), 1.42 (s, 9H), 1.31 (s, 9H); 13C NMR (125 MHz):
d¼157.8, 145.5, 142.3, 137.0, 132.2, 129.5, 128.6, 127.8,
126.7, 125.7, 125.6, 115.6, 82.0, 81.6, 73.6, 35.3, 34.5,
31.5, 30.8; IR (neat, cmꢁ1): 3298, 2959, 2103, 1658, 1578,
1435, 1368, 1230, 1121; LRMS (ESI): 347 (M+H), 369
(M+Na). Anal. Calcd for C25H30O: C, 86.66; H, 8.73.
Found: C, 86.40; H, 8.86.
4.1.2. 4,6-Di-tert-butyl-2-trimethylsilylethynyl-(2-pro-
penyl-oxy)benzene (11). Allyl bromide (1.35 g, 14.9 mmol)
was added to a suspension of K2CO3 (2.06 g, 14.9 mmol)
and 10 (1.50 g, 4.97 mmol) in DMF (20 mL). The reaction
mixture was stirred at room temperature for 8 h. This was
then quenched with water (100 mL) and extracted with
CH2Cl2, the organic layer was then separated, dried
(Na2SO4), and concentrated under reduced pressure. The
residue was then purified by flash chromatography (hex-
ane/EtOAc, 91:9) to furnish 11 (1.74 g, 98%) as a light yel-
low liquid. 1H NMR (300 MHz, CDCl3): d¼7.30 (d,
J¼2.4 Hz, 1H), 7.28 (d, J¼2.4 Hz, 1H), 6.07 (ddt, J¼17.2,
10.7, 5.2 Hz, 1H), 5.41 (dd, J¼17.2, 1.7 Hz, 1H), 5.22 (dd,
J¼10.7, 1.4 Hz, 1H), 4.77 (dd, J¼5.2, 1.4 Hz, 2H), 1.37 (s,
9H), 1.28 (s, 9H), 0.24 (s, 9H,); 13C NMR (75 MHz,
CDCl3): d¼157.5, 145.2, 142.0, 134.4, 129.2, 125.3,
116.6, 116.4, 103.2, 98.5, 73.2, 35.3, 34.5, 30.5, 30.7, 0.1;
IR (neat, cmꢁ1): 3082, 2963, 2864, 2151, 1466, 1361,
1303, 1229, 1203, 1123, 959, 843; HRMS: calcd for
C22H35OSi (M+H)+ 343.2452, found 343.2446.
4.1.6. 4,6-Di-tert-butyl-2-trimethylsilylethynyl-(2-methyl-
allyloxy)benzene (15). 3-Chloro-2-methylpropene (1.35 g,
14.9 mmol) was added to a suspension of K2CO3 (2.06 g,
14.9 mmol), NaI (2.34 g, 14.9 mmol), and 10 (1.50 g,
4.97 mmol) in DMF (20 mL). The reaction mixture was
stirred for 12 h. This was then quenched with water
(100 mL) and extracted with CH2Cl2, the organic layer was
then separated, dried (Na2SO4), and concentrated under re-
duced pressure. The residue was then purified by flash chro-
matography (hexane/EtOAc, 91:9) to furnish 15 (1.74 g,
4.1.3. 4,6-Di-tert-butyl-2-ethynyl-(2-propenyloxy)benz-
ene (12). K2CO3 (0.49 g, 3.55 mmol) was added to a solution
of 11 (0.62 g, 1.74 mmol) in MeOH/THF (10 mL, 1:1). The
mixture was stirred at room temperature for 4 h. The reac-
tion mixture was concentrated under reduced pressure and
filtered through a plug of silica gel (EtOAc). The resi-
due was purified by flash chromatography (hexane/ether,
83:17) to furnish 12 (0.50 g, quantitative) as a colorless liq-
1
98%) as a yellow liquid. H NMR (500 MHz): d¼7.32 (d,
J¼2.3 Hz, 1H), 7.30 (d, J¼2.8 Hz, 1H), 5.20 (s, 1H), 4.97
(s, 1H), 4.69 (s, 2H), 1.86 (s, 3H), 1.37 (s, 9H), 1.29 (s,
9H), 0.24 (s, 9H); 13C NMR (125 MHz): d¼157.4, 145.2,
142.1, 141.5, 129.4, 125.3, 116.4, 111.1, 103.2, 98.6, 75.5,
35.2, 34.5, 31.4, 30.7, 19.7, 0.02; IR (neat, cmꢁ1): 2961,
2151, 1436, 1249, 960; HRMS: calcd for C23H37OSi
(M+H)+ 357.2608, found 357.2613.
1
uid. H NMR (500 MHz): d¼7.38 (d, 1H, J¼2.5 Hz), 7.36
(d, 1H, J¼2.5 Hz), 6.17 (m, 1H), 5.49 (dd, 1H, J¼1.3,
10.4 Hz), 5.29 (dd, 1H, J¼1.3, 17.2 Hz), 4.81 (d, 2H,
J¼5.3 Hz), 3.31 (s, 1H), 1.42 (s, 9H), 1.32 (s, 9H); 13C NMR
(125 MHz): d¼157.7, 145.4, 142.2, 134.2, 129.5, 125.6,
116.8, 115.5, 81.9, 81.5, 73.6, 35.3, 34.5, 31.4, 30.7; IR
(neat, cmꢁ1): 3311, 2962, 2106, 1647, 1437, 1122, 742,
4.1.7. 4,6-Di-tert-butyl-2-ethynyl-(2-methylallyloxy)benz-
ene (16). K2CO3 (0.49 g, 3.55 mmol) was added to a solution

C. E. Madu et al. / Tetrahedron 63 (2007) 5019–5029
5025
of 15 (0.62 g, 1.74 mmol) in MeOH/THF (10 mL, 1:1). The
mixture was stirred at room temperature for 4 h. The reaction
mixture was concentrated under reduced pressure and fil-
tered through a plug of silica gel (EtOAc). The residue
was purified by flash chromatography (hexane/ether,
83:17) to furnish 16 (0.50 g, quantitative) as a yellow liquid.
1H NMR (300 MHz): d¼7.38 (d, J¼2.4 Hz, 1H), 7.36 (d,
J¼2.4 Hz, 1H), 5.20 (s, 1H), 5.00 (s, 1H), 4.70 (s, 2H),
3.30 (s, 1H), 1.90 (s, 3H), 1.41 (s, 9H), 1.32 (s, 9H); 13C
NMR (75 MHz): d¼157.7, 145.3, 142.2, 141.7, 129.6,
125.6, 115.5, 111.8, 81.9, 81.6, 76.0, 35.3, 34.5, 31.5,
30.7, 19.8; IR (neat, cmꢁ1): 3313, 3108, 2974, 2107, 1658,
1438, 1233, 1165, 1123, 1042; HRMS: calcd for
C20H28ONa (M+Na)+ 307.2032, found 307.2037, and calcd
for C20H29O for (M+H)+ 285.2213, found 285.2211.
solidified on standing. Mp 132–134 ꢀC; 1H NMR
(500 MHz): d¼7.41 (d, J¼2.4 Hz, 1H), 7.28 (d, J¼2.4 Hz,
1H), 4.67 (dd, J¼10.4, 5.7 Hz, 1H), 3.87 (dd, J¼10.4,
13.4 Hz, 1H), 3.15 (m, 1H), 2.62 (dd, J¼17.8, 7.0 Hz, 1H),
1.95 (dd, J¼17.8, 4.5 Hz, 1H), 1.39 (s, 9H), 1.31 (s, 9H),
0.33 (s, 9H); 13C NMR (125 MHz): d¼210.7, 177.3,
152.5, 141.1, 137.4, 133.3, 128.0, 124.5, 119.0, 70.2, 38.2,
37.2, 35.3, 34.7, 31.6, 29.8, 0.1; IR (neat, cmꢁ1): 2960,
1693, 1578, 1440, 1248, 844. Anal. Calcd for C23H34O2Si:
C, 74.54; H, 9.25. Found: C, 74.13; H, 9.33; HRMS: calcd
for C23H35O2Si (M+H)+ 371.2401, found 371.2402.
4.1.10. 6,8-Di-tert-butyl-3-phenyl-3a,4-dihydro-3H-
cyclopenta[c]chromen-2-one (19). Cyclization following
the general procedures A and B utilizing 14 (200 mg,
0.58 mmol), CH2Cl2 (10 mL) for procedure A and toluene
(10 mL) for procedure B, Co2(CO)8 (220 mg, 0.64 mmol),
and NMO (740 mg, 6.40 mmol) followed by flash chromato-
graphy (hexane/EtOAc, 90:10) to afford 19 (200 mg, 91% for
procedure A and 160 mg, 73% for procedure B) as a light yel-
low solid. Mp 155–157 ꢀC; 1H NMR (500 MHz): d¼7.49 (d,
J¼2.3 Hz, 1H), 7.47 (d, J¼2.3 Hz, 1H), 7.36 (t, J¼7.3 Hz,
2H), 7.30 (d, J¼7.3 Hz, 1H), 7.21 (d, J¼7.3 Hz, 2H), 6.47
(d, J¼1.8 Hz, 1H), 4.74 (dd, J¼5.5, 10.5 Hz, 1H), 3.96 (dd,
J¼10.5, 13.3 Hz, 1H), 3.36 (ddt, J¼1.8, 5.5, 11.5 Hz, 1H),
3.26 (d, J¼4.6 Hz, 1H), 1.39 (s, 9H), 1.35 (s, 9H); 13C
NMR (125 MHz): d¼205.6, 168.2, 153.4, 143.5, 138.7,
137.9, 129.0, 128.8, 128.6, 127.4, 121.3, 119.9, 116.8, 69.2,
56.0, 45.6, 35.3, 34.5, 30.4, 29.7; IR (neat, cmꢁ1): 3105,
2959, 2864, 1712, 1607, 1476, 1214, 1151, 1005; LRMS
(ESI): 413 [M+K], 397 [M+Na], 375 [M+H]. Anal. Calcd
for C26H30O2: C, 83.38; H, 8.07. Found: C, 83.25; H, 8.18.
Oxidative Pauson–Khand method (procedure A): the enyne
was dissolved in CH2Cl2 under N2 and 1.1 equiv of
Co2(CO)8 was added and stirred at room temperature for
5 h. It was cooled to 0 ꢀC before NMO (8–10 equiv total)
was added in three approximately equal portions at 30 min
intervals and then left to stir for 2 h. The reaction mixture
was then filtered through a pad of Celite and SiO2, and
washed with EtOAc. The filtrate was concentrated and
then the product was the purified by flash chromatography
using the indicated eluant.
Thermal Pauson–Khand method (procedure B): the enyne
was dissolved in toluene under N2 and 1.1 equiv of
Co2(CO)8 was added and stirred at room temperature for
5 h. It was then heated under N2 at 70 ꢀC until the reaction
was complete. The reaction mixture was then filtered
through a pad of Celite and SiO2, washed with hexane to
remove the alkyne–Co2(CO)6 remaining, and then washed
with ethyl acetate to get the cyclized product. The crude
product was then purified by flash chromatography using
the indicated eluant.
4.1.11. 6,8-Di-tert-butyl-3-phenyl-1-trimethylsilyl-3a,4-
dihydro-3H-cyclopenta[c]chromen-2-one (20). Cycliza-
tion following the general procedures A and B utilizing 14
(200 mg, 0.48 mmol) and the appropriate solvent (10 mL),
Co2(CO)8 (180 mg, 0.53 mmol), and NMO (620 mg,
5.26 mmol) followed by flash chromatography (hexane/
EtOAc, 90:10) to afford 20 (170 mg, 81% for procedure A
and 150 mg, 71% for procedure B) as a light yellow solid.
Mp 129–131 ꢀC; 1H NMR (500 MHz): d¼7.46 (d,
J¼2.3 Hz, 1H), 7.42 (d, J¼2.3 Hz, 1H), 7.34 (t, J¼7.3 Hz,
2H), 7.28 (d, J¼7.3 Hz, 1H), 7.19 (d, J¼6.9 Hz, 2H), 4.77
(dd, J¼5.5, 10.5 Hz, 1H), 4.01 (dd, J¼10.5, 13.3 Hz, 1H),
3.30 (dt, J¼5.5, 12.8 Hz, 1H), 3.14 (d, J¼5.0 Hz, 1H),
1.39 (s, 9H), 1.36 (s, 9H), 0.39 (s, 9H); 13C NMR
(125 MHz): d¼209.5, 174.7, 153.0, 141.5, 138.2, 137.7,
132.2, 128.9, 128.7, 128.3, 127.2, 124.7, 118.7, 69.6, 56.1,
46.2, 35.4, 34.8, 31.7, 29.8, 0.1; IR (neat, cmꢁ1): 3106,
2961, 1687, 1581, 1441, 1249, 1007, 939; ESI-MS: 447
[M+H], 469 [M+Na]; HRMS: calcd for C29H38SiO2Na
(M+Na)+ 469.2533, found 469.2579.
4.1.8. 6,8-Di-tert-butyl-3a,4-dihydro-3H-cyclopenta[c]-
chro-men-2-one (17). Cyclization following the general
procedure A utilizing 12 (180 mg, 0.63 mmol), Co2(CO)8
(0.24 g, 0.64 mmol), and NMO (0.64 g, 5.50 mmol) in
CH2Cl2 (mL) or procedure B utilizing 12 (100 mg,
0.37 mmol), toluene (5 mL), and Co2(CO)8 (140 mg,
0.41 mmol) followed by flash chromatography (hexane/
EtOAc, 90:10) afforded 17 (133 mg, 80% or 100 mg, 91%,
respectively) as a solid. Mp 179–180 ꢀC; 1H NMR
(500 MHz): d¼7.44 (d, J¼2.4 Hz, 1H), 7.39 (d, J¼2.4 Hz,
1H), 6.35 (d, J¼1.7 Hz, 1H), 4.64 (dd, J¼10.7, 5.5 Hz,
1H), 3.80 (dd, J¼13.4, 10.3 Hz, 1H), 3.28 (m, 1H), 2.67
(dd, J¼17.9, 6.9 Hz, 1H), 2.04 (dd, J¼17.9, 4.1 Hz, 1H),
1.39 (s, 9H), 1.32 (s, 9H); 13C NMR (125 MHz): d¼206.3,
170.6, 153.1, 143.3, 138.5, 128.5, 121.4, 121.2, 117.1,
69.8, 38.1, 36.5, 34.5, 35.3, 31.4, 29.7; IR (KBr, cmꢁ1):
2962, 1698, 1599, 1479, 1189, 860, 680. Anal. Calcd for
C20H26O2: C, 80.50; H, 8.78. Found: C, 80.50; H, 9.00.
4.1.12. 6,8-Di-tert-butyl-3a-methyl-3a,4-dihydro-3H-
cyclopenta[c]chromen-2-one (21). Cyclization following
the general procedure A utilizing 16 (180 mg, 0.63 mmol),
Co2(CO)8 (0.24 g, 0.70 mmol), and NMO (0.73 g,
6.3 mmol) in CH2Cl2 (10 mL) or procedure B utilizing 16
(110 mg, 0.39 mmol), toluene (5 mL), and Co2(CO)8
(130 mg, 0.38 mmol) followed by flash chromatography
(hexane/EtOAc, 90:10) to afford 21 (160 mg, 81% and
110 mg, 91%) as a solid, mp 130–132 ꢀC. 1H NMR
4.1.9. 6,8-Di-tert-butyl-1-trimethylsilyl-3a,4-dihydro-3H-
cyclopenta[c]chromen-2-one (18). Cyclization following
the general procedure B utilizing 11 (100 mg, 0.29 mmol),
toluene (5 mL), and Co2(CO)8 (110 mg, 0.32 mmol) fol-
lowed by flash chromatography (hexane/EtOAc; 90:10) to
afford 18 (100 mg, 93%) as a light yellow liquid, which

5026
C. E. Madu et al. / Tetrahedron 63 (2007) 5019–5029
(300 MHz): d¼7.43 (d, J¼2.4 Hz, 1H), 7.36 (d, J¼2.1 Hz,
1H), 6.23 (s, 1H), 4.33 (d, J¼10.4 Hz, 1H), 3.87 (d,
J¼10.7 Hz, 1H), 2.39 (d, J¼17.5 Hz, 1H), 2.20 (d,
J¼17.5 Hz, 1H), 1.40 (s, 9H), 1.31 (s, 9H), 1.30 (s, 3H);
13C NMR (CDCl3): d¼205.8, 174.9, 151.7, 143.2, 138.3,
128.4, 121.5, 120.0, 116.2, 73.9, 47.0, 38.8, 35.2, 34.4,
31.4, 29.7, 23.8; IR (neat, cmꢁ1): 3098, 2962, 1700, 1594,
1463, 1183, 1011; HRMS: calcd for C21H29O2 (M+H)+
313.2162, found 313.2164.
134.5, 125.6, 124.4, 109.9, 102.8, 74.8, 35.0, 34.9, 34.3,
31.6, 29.5, 23.3, 21.5; IR (neat, cmꢁ1): 3497, 2959, 1443,
1363, 1234, 880; HRMS: calcd for C19H29O (M+H)+
273.2213, found 273.2221.
4.1.16. 4,6-Di-tert-butyl-2-(2-methylbut-3-yn-2-ol)-(2-
methyl-allyloxy)benzene (25). 3-Chloro-2-methylpropene
(1.26 g, 13.9 mmol) was added to a suspension of K2CO3
(1.92 g, 13.9 mmol), NaI (2.08 g, 13.9 mmol), and 23
(1.00 g, 3.47 mmol) in DMF (20 mL). The reaction mixture
was stirred for 12 h. This was then quenched with water
(100 mL) and extracted with CH2Cl2, the organic layer
was then separated, dried (Na2SO4), and concentrated under
reduced pressure. The residue was then purified by flash
chromatography (hexane/EtOAc, 91:9) to furnish 25 (0.88 g,
74%) as a light yellow solid, mp 91–93 ꢀC. 1H NMR
(300 MHz): d¼7.31 (d, J¼2.7 Hz, 1H), 7.25 (d, J¼2.7 Hz,
1H), 5.25 (app. t, J¼1.0 Hz, 1H), 4.99 (app. t, J¼1.4 Hz,
1H), 4.63 (s, 2H), 2.12 (s, 1H), 1.85 (s, 3H), 1.60 (s, 6H),
1.38 (s, 9H), 1.29 (s, 9H). 13C NMR (75 MHz): d¼157.0,
145.3, 142.1, 141.9, 128.8, 125.0, 116.1, 110.7, 97.9, 80.1,
75.5, 65.8, 35.3, 34.5, 31.7, 31.4, 30.7, 29.7, 19.7; IR
(neat, cmꢁ1): 3331, 2956, 2866, 1657, 1467, 1436, 1410,
1361, 1316, 1229, 1200, 1166, 1125, 1038; HRMS: calcd
for C23H34O2Na (M+Na)+ 365.2451, found 365.2450.
4.1.13. 6,8-Di-tert-butyl-1-trimethylsilyl-3a-methyl-4-
hydro-3H-cyclopenta[c]chromen-2-one (22). Cyclization
following the general procedures B utilizing 15 (240 mg,
0.64 mmol), toluene (10 mL), and Co2(CO)8 (240 mg,
0.74 mmol) followed by flash chromatography (hexane/
EtOAc, 90:10) to afford 22 (240 mg, 92%) as a solid, mp
156–157 ꢀC. 1H NMR (500 MHz): d¼0.30 (s, 9H), 1.19 (s,
3H), 1.32 (s, 9H), 1.39 (s, 9H), 2.02 (d, J¼17.5 Hz, 1H),
2.31 (d, J¼17.2 Hz, 1H), 3.96 (d, J¼10.7 Hz, 1H), 4.32 (d,
J¼10.7 Hz, 1H), 6.23 (s, 1H), 7.24 (d, J¼2.3 Hz, 1H),
7.40 (d, J¼2.3 Hz, 1H); 13C NMR (125 MHz): d¼210.1,
181.4, 151.3, 141.2, 137.1, 132.1, 127.9, 124.8, 117.8,
74.6, 47.3, 39.0, 35.2, 34.6, 31.6, 29.7, 22.9, 0.2; IR (neat,
cmꢁ1): 2959, 1691, 1529, 1255, 1028, 938. Anal. Calcd
for C24H36O2Si: C, 74.94; H, 9.43. Found: C, 74.77; H,
9.23; HRMS: calcd for C24H37O2Si (M+H)+ 385.2557,
found 385.2559.
4.1.17. 4,6-Di-tert-butyl-2-(2-methylbut-3-ynyl)-(2-methyl-
allyloxy)benzene (26). 3-Chloro-2-methylpropene (0.15 g,
1.7 mmol) was added to a suspension of K2CO3 (0.11 g,
0.81 mmol), NaI (0.25 g, 1.7 mmol), and 24 (0.11 g,
0.40 mmol) in DMF (20 mL). The reaction mixture was
stirred for 12 h. This was then quenched with water
(100 mL) and extracted with CH2Cl2, the organic layer
was then separated, dried (Na2SO4), and concentrated under
reduced pressure. The residue was then purified by flash
chromatography (hexane/EtOAc, 91:9) to furnish 26 (0.12 g,
92%) as a light yellow oil. 1H NMR (300 MHz): d¼7.27 (d,
J¼2.7 Hz, 1H), 7.24 (d, J¼2.7 Hz, 1H), 5.21 (app. t,
J¼1.0 Hz, 1H), 4.98 (app. t, J¼1.4 Hz, 1H), 4.67 (s, 2H),
2.74–2.88 (h, J¼6.9 Hz, 1H), 1.87 (s, 3H), 1.38 (s, 9H),
1.29 (s, 9H), 1.26 (d, J¼7.2 Hz, 6H); 13C NMR (75 MHz):
d¼156.8, 145.1, 141.9, 141.7, 128.9, 124.2, 117.2, 110.9,
99.9, 75.2, 35.2, 34.5, 31.5, 30.7, 29.4, 23.0, 21.6, 19.7; IR
(neat, cmꢁ1): 2956, 2866, 1657, 1467, 1436, 1410, 1361,
1316, 1229, 1200, 1166, 1125, 1038; HRMS: calcd for
C23H34O (M+H)+ 326.2604, found 326.2585.
4.1.14. 2,4-Di-tert-butyl-6-(3-hydroxy-3-methylbut-1-
ynyl)-phenol (23). To a stirred solution of 9 (2.82 g,
8.50 mmol) and Et3N (5.9 mL) in dioxane (5.9 mL), 2-
hydroxy-2-methylbut-1-yne (2.14 g, 25.5 mmol), PdCl2-
(PPh3)2 (0.30 g, 0.43 mmol), and CuI (0.16 g, 0.84 mmol)
were added. The reaction mixture was stirred at 55 ꢀC
(bath temperature) under N2 for 5 h. Et2O (50 mL) and
1 M HCl (20 mL) were added, and the organic layer was sep-
arated, neutralized with a saturated NaHCO3 (30 mL) solu-
tion, washed with H2O, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by flash
chromatography (silica gel, hexane) to afford 23 (2.30 g,
1
94%), as a golden yellow solid. Mp 97–99 ꢀC; H NMR
(300 MHz): d¼7.27 (d, J¼2.4 Hz, 1H), 7.18 (d, J¼2.4 Hz,
1H), 6.02 (s, 1H), 2.31 (s, 1H), 1.66 (s, 6H), 1.40 (s, 9H),
1.28 (s, 9H); 13C NMR (75 MHz): d¼153.0, 142.1, 134.9,
125.8, 125.3, 108.6, 100.7, 66.0, 35.0, 34.3, 31.7, 31.5,
29.5; IR (neat, cmꢁ1): 3358, 2959, 2223, 1443, 1415,
1363, 1197; HRMS: calcd for C19H28O2Na (M+Na)+
311.1982, found 311.1985.
4.1.18. 6,8-Di-tert-butyl-1-(1-hydroxy-1-methylethyl)-3a-
methyl-3a,4-dihydro-3H-cyclopenta[c]chromen-2-one
(27). Cyclization following the general procedures A and B
utilizing 25 (110 mg, 0.32 mmol) and 5 mL of appropriate
solvent, Co2(CO)8 (120 mg, 0.35 mmol), and NMO
(410 mg, 3.51 mmol) followed by flash chromatography
(hexane/EtOAc, 90:10) to afford 27 (40 mg, 33% for proce-
dure A and 91 mg, 75% for procedure B) as a yellow liquid;
1H NMR (300 MHz): d¼7.39 (d, J¼2.4 Hz, 1H), 7.37 (d,
J¼2.4 Hz, 1H), 4.72 (s, 1H), 4.32 (d, J¼10.7 Hz, 1H),
3.96 (d, J¼11.0 Hz, 1H), 2.38 (d, J¼18.2 Hz, 1H), 2.16 (d,
J¼18.2 Hz, 1H), 1.69 (s, 3H), 1.56 (s, 3H), 1.38 (s, 9H),
1.31 (s, 9H), 1.16 (s, 3H); 13C NMR (75 MHz): d¼207.9,
166.4, 151.1, 141.0, 138.5, 136.7, 127.4, 125.8, 116.6,
74.7, 71.4, 46.0, 36.2, 35.2, 34.5, 31.5, 31.4, 29.6, 27.8,
22.6; IR (neat, cmꢁ1): 3393, 2956, 2869, 1680, 1603,
4.1.15. 2,4-Di-tert-butyl-6-(3-methylbut-1-ynyl)phenol
(24). To a stirred solution of 23 (0.10 g, 0.35 mmol) and
NaBH4 (0.13 g, 3.50 mmol) in CH2Cl2 (5 mL), at 0 ꢀC was
added TFA (3 mL) over a period of 10 min. The reaction
mixture was then decanted into iced water (100 mL) and
extracted with CH2Cl2 (20 mL), and the organic layer was
separated, neutralized with a saturated NaHCO3 (30 mL) so-
lution, washed with H2O, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by flash
chromatography (hexane) to afford 24 (0.09 g, 96%) as
a golden yellow oil. 1H NMR (500 MHz): d¼7.23 (d,
J¼2.8 Hz, 1H), 7.17 (d, J¼2.8 Hz, 1H), 6.03 (s, 1H), 1.28
(s, 9H), 2.86 (sept, J¼6.9 Hz, 1H), 1.40 (s, 9H), 1.30 (d,
J¼6.9 Hz, 6H); 13C NMR (125 MHz): d¼152.8, 141.9,

C. E. Madu et al. / Tetrahedron 63 (2007) 5019–5029
5027
1467, 1438, 1025; HRMS: calcd for C24H35O3 (M+H)+
371.2581 found 371.2587.
The solvent was removed by rotary evaporation, dissolved
in pentane, washed with 10% aq KOH (30 mL), dried
(Na2SO4), and concentrated. The residue was dissolved in
1:1 MeOH/THF (15 mL) and K2CO3 (0.42 g, 3.0 mmol)
was added to it, followed by stirring overnight. The reaction
mixture was concentrated, dissolved in EtOAc, filtered
through a plug of silica gel, and the filtrate was concentrated.
The residue was purified by flash chromatography (hexane)
to provide 33 (0.36 g, 83%) as a pale yellow liquid. 1H NMR
(500 MHz): d¼7.33 (d, J¼2.6 Hz, 1H), 7.32 (d, J¼2.6 Hz,
1H), 5.89 (ddt, J¼17.0, 10.1, 6.6 Hz, 1H), 5.06–5.10 (m,
1H), 4.98–5.00 (m, 1H), 4.24 (t, J¼6.8 Hz, 2H), 3.28 (s,
1H), 2.27 (app. dt, J¼7.3, 6.6 Hz, 2H), 1.97 (m, 2H), 1.38
(s, 9H), 1.28 (s, 9H); 13C NMR (125 MHz): d¼158.2,
145.1, 142.0, 138.4, 129.5, 125.5, 115.4, 114.8, 82.1, 81.2,
72.6, 35.3, 34.5, 31.4, 30.8, 30.3, 29.5; IR (neat, cmꢁ1):
3301, 2857, 2103, 1641, 1122, 730; EIMS (m/z): 298
(M+), 282 (100%), 214, 57. Anal. Calcd for C21H30O: C,
84.51; H, 10.13. Found: C, 84.58; H, 10.51.
4.1.19. 6,8-Di-tert-butyl-1-isopropyl-3a-methyl-3a,4-di-
hydro-3H-cyclopenta[c]chromen-2-one (28). Cyclization
following the general procedures B utilizing 26 (110 mg,
0.34 mmol), toluene (5 mL), and Co2(CO)8 (130 mg,
0.37 mmol) followed by flash chromatography (hexane/
EtOAc, 90:10) to afford 28 (100 mg, 84%) as a solid. Mp
1
147–149 ꢀC; H NMR (300 MHz): d¼7.40 (d, J¼2.3 Hz,
1H), 7.34 (d, J¼2.3 Hz, 1H), 4.31 (d, J¼10.5 Hz, 1H),
3.90 (d, J¼10.5 Hz, 1H), 3.14 (m, 1H), 2.28 (d,
J¼17.9 Hz, 1H), 2.04 (d, J¼17.9 Hz, 1H), 1.40 (s, 9H),
1.38 (d, J¼6.8 Hz, 3H), 1.32 (s, 9H), 1.26 (d, J¼6.8 Hz,
3H), 1.19 (s, 3H); 13C NMR (75 MHz): d¼206.2, 164.9,
19.7; 150.9, 142.0, 138.8, 137.3, 126.9, 123.0, 117.1, 74.9,
46.2, 35.8, 35.3, 34.4, 31.5, 29.6, 25.9, 22.9, 20.6; IR
(neat, cmꢁ1): 3375, 2962, 1698, 1611, 1474, 1386, 1363,
1307, 1231, 1166, 1129, 1021; HRMS: calcd for C24H35O2
(M+H)+ 355.2632, found 355.2635.
4.2. Oxidative cyclization of 31
4.1.20. 4,6-Di-tert-butyl-2-trimethylsilylethynyl-(3-but-
enyloxy)benzene (30). DEAD (3.46 g, 19.9 mmol) in THF
(20 mL) was added dropwise to a solution of 10 (2.0 g,
6.62 mmol), 3-buten-1-ol (0.96 g, 13.3 mmol), and PPh3
(5.22 g, 19.9 mmol) in THF (50 mL) and stirred at 0 ꢀC
for 6 h. The solvent was removed by rotary evaporation
and the crude product was purified by flash chromatography
(hexane) to give 30 as a clear liquid (2.35 g, 99%). 1H NMR
(300 MHz): d¼7.31 (d, J¼1.2 Hz, 2H), 5.92 (m, 1H), 5.15
(dd, J¼17.2, 2.1 Hz, 1H), 5.09 (dd, J¼17.2, 2.1 Hz, 1H),
4.29 (app. t, J¼6.9 Hz, 2H), 2.61 (dd, J¼7.2, 6.9 Hz, 2H),
1.38 (s, 9H), 1.29 (s, 9H), 0.27 (s, 9H); 13C NMR
(75 MHz): d¼157.8, 145.0, 141.9, 134.9, 135.4, 129.4,
125.3, 116.8, 116.4, 103.5, 98.3, 71.8, 35.3. 34.7, 34.5,
31.5, 30.8, 0.1; IR (neat, cmꢁ1): 3106, 2959, 2151, 1437,
1235, 1123, 960, 912; HRMS: calcd for C23H37OSi
(M+H)+ 357.2608, found 357.2613.
Cyclization of 31 (113 mg, 0.40 mmol) utilizing general
procedure A provided after purification by flash chromato-
graphy (hexane/EtOAc/Et3N, 87.4:12.5:0.1) 35 (47 mg,
36%) and 34 (22 mg, 18%), both as colorless solids.
4.2.1. Epoxy ketone 35. Mp 216–219 ꢀC; 1H NMR
(500 MHz): d¼7.39 (d, J¼2.4 Hz, 1H), 7.35 (d, J¼2.4 Hz,
1H), 4.45 (app. d, J¼13.9 Hz, 1H), 4.04 (s, 1H), 3.40 (app.
t, J¼13.0 Hz, 1H), 2.93–2.95 (m, 1H), 2.76 (dd, J¼6.3,
18.1 Hz, 1H), 2.53–2.50 (m, 1H), 1.98 (app. d, J¼18.1 Hz,
1H), 1.94 (app. d, J¼15.6 Hz, 1H), 1.32 (s, 9H), 1.31 (s,
9H); 13C NMR (125 MHz): d¼207.0, 157.7, 145.5, 141.3,
125.4, 125.0, 70.1, 67.5, 56.8, 36.6, 35.2, 34.7, 32.4,
31.5, 30.7; IR (KBr, cmꢁ1): 2954, 1744, 1435, 1113,
737, 647; EIMS (m/z): 328 (M+), 299 (100%). Anal.
Calcd for C21H28O3: C, 76.59; H, 8.59. Found: C, 76.92;
H, 8.79.
4.1.21. 4,6-Di-tert-butyl-2-ethynyl-(3-butenyloxy)benz-
ene (31). K2CO3 (1.13 g, 8.2 mmol) was added to a solution
of 30 (1.41 g, 4.1 mmol) in MeOH/THF (10 mL, 1:1). The
mixture was stirred at room temperature for 4 h. The reaction
mixture was concentrated under reduced pressure and fil-
tered through a plug of silica gel (EtOAc). The residue
was purified by flash chromatography (silica gel, 83:17
n-hexane/ether) to furnish 31 (0.75 g, 80%) as a colorless
1
4.2.2. Ketone 34. Mp 236–238 ꢀC; H NMR (500 MHz):
d¼8.25 (s, 1H), 7.26 (s, 1H), 7.24 (s, 1H), 4.11 (app. d,
J¼13.9 Hz, 1H), 3.41 (br s, 1H), 3.33 (app. t, J¼13.0 Hz,
1H), 2.77 (dd, J¼5.0, 17.8 Hz, 1H), 2.64 (app. t, J¼13.6,
1H), 2.28 (app. d, J¼17.8 Hz, 1H), 2.04 (app. d,
J¼15.4 Hz, 1H), 1.35 (s, 9H), 1.31 (s, 9H); 13C NMR
(125 MHz): d¼208.2, 176.0, 158.1, 145.4, 141.3, 125.5,
125.1, 125.0, 67.5, 56.8, 36.6, 35.2, 34.7, 32.4, 31.6, 30.7;
IR (KBr, cmꢁ1): 2955, 1701, 1637, 1477, 1112, 836, 737,
747; EIMS (m/z): 312 (M+), 297 (100%).
1
liquid. H NMR (500 MHz): d¼7.34 (d, J¼2.4 Hz, 1H),
7.33 (d, J¼2.4 Hz, 1H), 5.98 (ddt, J¼17.0, 10.3, 6.8 Hz,
1H), 5.16–5.20 (m, 1H), 5.09–5.11 (m, 1H), 4.30 (app. t,
J¼7.0 Hz, 2H), 3.30 (s, 1H), 2.62–2.67 (m, 2H), 1.39 (s,
9H), 1.29 (s, 9H); 13C NMR (125 MHz): d¼158.1, 145.1,
142.0, 134.9, 129.5, 125.5, 116.8, 115.4, 82.1, 81.3, 72.2,
35.3, 34.8, 34.5, 31.5, 30.8; IR (neat, cmꢁ1): 3304, 2959,
2107, 1656, 1122, 727; EIMS: 57, 171, 215 (100%), 269,
284 (M+). Anal. Calcd for C20H28O: C, 84.45; H, 9.92.
Found: C, 84.48; H, 10.03.
4.3. Thermal cyclization of 3-butenyloxy-4,6-di-tert-
butylethynylbenzene (31)
Cyclization followed the general procedure utilizing 31
(200 mg, 0.70 mmol), toluene (5 mL), and Co2(CO)8
(270 mg, 0.78 mmol), and refluxed to afford the epoxide
35 (40 mg, 17%) and Michael product 36 (30 mg, 13%) as
a colorless solid after purification by flash chromatography
(hexane/EtOAc, 87:13).
4.1.22. 4,6-Di-tert-2-ethynyl-(4-pentenyloxy)benzene (33).
DEAD (0.78 g, 4.5 mmol) in THF (15 mL) was added drop-
wise to a solution of 10 (0.44 g, 1.5 mmol), 4-penten-1-ol
(0.25 g, 3.0 mmol), and PPh3 (1.18 g, 3.0 mmol) in THF
(50 mL). The reaction mixture was stirred at 0 ꢀC for 2 h.
4.3.1. 4060-Di-tert-butyl-14-hydroxy-8-oxa-tricyclo-
[9.2.1.0]-tetradeca-2,4,6-triene-13-one (36). Mp 192–194 ꢀC;

5028
C. E. Madu et al. / Tetrahedron 63 (2007) 5019–5029
1H NMR (500 MHz): d¼7.23 (d, J¼2.3 Hz, 1H), 7.07
(d, J¼2.3 Hz, 1H), 4.18 (d, J¼11.9 Hz, 1H), 3.51 (t,
J¼10.5 Hz, 1H), 3.27 (s, 1H), 3.06 (dd, J¼8.7, 18.3 Hz, 1H),
2.66 (s, 1H), 1.31 (s, 9H), 1.33 (s, 9H), 1.72 (d, J¼14.7 Hz,
1H), 1.96 (s, 1H), 2.38 (m, 1H), 2.16 (d, J¼18.3 Hz, 1H);
13C NMR (125 MHz): d¼219.2, 145.5, 142.0, 129.0, 123.4,
71.1, 63.0, 43.0, 41.2, 35.5, 35.2, 34.5, 31.6, 31.2; IR (Neat,
cmꢁ1): 3396, 2957, 1734; ESI-MS: 353 [M+Na]+, 365. Anal.
Calcd for C21H30O3: C, 76.33; H, 9.15. Found: C, 76.17;
H, 9.31.
1.76 (qd, J¼10.2, 3.0 Hz, 1H), 1.39 (s, 9H), 1.30 (s, 9H),
ꢁ0.03 (s, 9H); 13C NMR (75 MHz): d¼212.5, 189.4,
154.6, 144.7, 141.5, 132.6, 125.5, 125.2, 125.2, 72.7, 43.8,
43.7, 35.2, 31.6, 34.7, 31.6, 30.4, ꢁ0.7; IR (neat, cmꢁ1):
2954, 1692, 1587, 1560, 1432, 1360, 1248, 1224, 1123,
1068, 1025, 936; HRMS: calcd for C24H36O2SiNa
(M+Na)+ 407.2377, found 407.2397.
4.5.2. (7,6-Di-tert-butyl-4-methylene-3,4-dihydro-2H-
benzo[b]oxepin-5-ylidenemethyl)trimethylsilane (49).
Mp 105–107 ꢀC. 1H NMR (500 MHz): d¼7.23 (d,
J¼1.8 Hz, 1H), 7.19 (d, J¼1.8 Hz, 1H), 5.77 (s, 1H), 4.94
(d, J¼6.4 Hz, 2H), 4.16 (t, J¼5.1 Hz, 2H), 2.76 (t,
J¼5.1 Hz, 2H), 1.37 (s, 9H), 1.32 (s, 9H), 0.50 (s, 9H);
13C NMR (125 MHz): d¼159.1, 153.5, 148.9, 144.4,
139.7, 134.9, 130.5, 123.5, 123.4, 111.8, 70.4, 39.8, 35.3,
34.6, 31.7, 30.6, 0.6; IR (neat, cmꢁ1): 2955, 1639, 1571,
1468, 1433, 1361, 1245, 1166; HRMS: calcd for
C23H36OSi 356.2530, found 356.2533.
4.4. Oxidative cyclization of 3-butenyloxy-4,6-di-tert-
butylethynylbenzene (31) under oxygen atmosphere
The enyne 31 (300 mg, 1.06 mmol) was dissolved in CH2Cl2
(10 mL) and Co2(CO)8 (400 mg, 1.16 mmol) was added
under N2 and stirred for 2 h. The reaction mixture was
then purged with O2 and then NMO (1.24 g, 10.6 mmol)
was added in three portions at 0 ꢀC and the reaction was
left to stir to room temperature under an oxygen atmosphere.
The reaction was worked up as indicated in the general
procedure. The crude product was purified by flash chroma-
tography (hexane/EtOAc, 90:10) to afford only the epoxide
35 (220 mg, 63%).
Acknowledgements
This work has been supported by The Robert A. Welch
Foundation (Y-1362) and the University of Texas at Arling-
ton. The NSF (CHE-9601771 and CHE-0234811) is thanked
for providing partial support for the purchase of the NMR
spectrometers used in this study.
4.4.1. 4060-Di-tert-butyl-8-oxa-tricyclo[10.2.1.0]penta-
deca-1(14),2,4,6-tetraene-14-one (37). Cyclization em-
ploying the oxidative method utilizing the enyne 33
(121 mg, 0.41 mmol), CH2Cl2 (20 mL), Co2(CO)8 (278 mg,
0.81 mmol), and NMO (569 mg, 4.86 mmol) or the thermal
method, utilizing the enyne (130 mg, 0.44 mmol) in toluene
(10 mL) and Co2(CO)8 (164 mg, 0.48 mmol), and then
heated at 70 ꢀC provided 37 in 41 mg, 31% and 120 mg,
86%, respectively, as a colorless solid after flash chromato-
References and notes
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1
graphy (hexane/EtOAc, 90:10). Mp 191–192 ꢀC; H NMR
(300 MHz): d¼7.28 (d, J¼2.5 Hz, 1H), 7.52 (s, 1H), 7.07
(d, J¼2.5 Hz, 1H), 4.37 (app. t, J¼10.3 Hz, 1H), 3.34–
3.35 (m, 1H), 3.20–3.22 (m, 1H), 2.67 (dd, J¼5.8,
18.0 Hz, 1H), 2.27 (app. d, J¼18.0 Hz, 1H), 1.93–2.04 (m,
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145.3, 141.5, 141.1, 127.8, 123.9, 123.6, 76.3, 40.5, 39.3,
35.0, 34.6, 33.7, 31.6, 31.2, 25.6; IR (KBr, cmꢁ1): 2956,
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4.5. Thermal cyclization of 30
Cyclization followed the general procedure utilizing 30
(0.20 g, 0.56 mmol), toluene (10 mL), and Co2(CO)8
(0.21 g, 0.62 mmol), and refluxed under N2 to afford the
expected PK product 48 (30 mg, 14%) and the diene 49
(150 mg, 75%) as a yellow solid after flash chromatography
(hexane/EtOAc, 87:13). When the above reaction was car-
ried out under CO (1 atm, balloon) afforded 48 (47 mg,
22%).
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