Steric promotion of the intramolecular Pauson-Khand reaction of aryl enynes

Article abstract of DOI:10.1055/s-2007-984880

The intramolecular Pauson-Khand reaction of 1,8-enynes derived from salicylaldehyde derivatives has been investigated. Substrates derived from salicylaldehyde itself reacted poorly in this reaction, but related substrates containing ortho-tert-butyl substituents participated quite effectively and in many cases the cyclizations proceeded with high levels of diastereoselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984880

LETTER
2011
Steric Promotion of the Intramolecular Pauson–Khand Reaction of
Aryl Enynes
I
ntramolecular Pa
h
uson–Khand
r
Reactio
i
n
of
A
r
yl Enyne
t
ian E. Madu, Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas, Arlington, TX 76019, USA
Fax +1(817)2723808; E-mail: lovely@uta.edu
Received 11 May 2007
O
Abstract: The intramolecular Pauson–Khand reaction of 1,8-
enynes derived from salicylaldehyde derivatives has been investi-
gated. Substrates derived from salicylaldehyde itself reacted poorly
in this reaction, but related substrates containing ortho-tert-butyl
substituents participated quite effectively and in many cases the
cyclizations proceeded with high levels of diastereoselectivity.
Co2(CO)8, PhMe
then 70 °C, 80%
n = 3
O
O
( )
n
Key words: organometallic, substituent effects, cyclization, stereo-
1
2
selectivity, cobalt–alkyne complexes
Scheme 1
Our lab has been interested for several years in extending (Scheme 2). These enynes were converted into the corre-
the scope of the intramolecular Pauson–Khand (PK) reac- sponding Co2(CO)6 complex by treatment with Co2(CO)8
tion to permit the construction of a cyclopentenone annu- and then subjected to the PK reaction under both oxidative
lated to a medium-sized ring, with the expectation of [exposure to N-methylmorpholine N-oxide, (NMO)]10 and
using this strategy in natural product total synthesis en- thermal conditions (toluene, ~70 °C).11 As can be seen in
deavors.1–3 Our earliest efforts along these lines involved Scheme 2 only the phenyl-substituted enyne 7 undergoes
the use of phenylacetylene analogues derived from cyclization, providing the cycloadduct 10 in poor yield.
iodophenols.4–6 The basic idea was to use the aromatic Interestingly, it was found that the corresponding silyl
framework as a means to reduce the conformational mo- ether underwent the cycloaddition somewhat more effi-
bility of the enyne, and thus enhance the encounter rate of ciently, providing 11 in 50% yield.12 However, despite the
the alkene and the Co-complexed alkyne. While systems fact that this latter example did undergo cyclization, we
of this type provided 5,6-fused systems quite efficiently,7 required a more general solution to cyclizing this type of
extension to higher homologues was not successful. How- substrate.13 In our previous study we had found that the
ever, it was found that the introduction of a steric buttress- incorporation of buttressing elements (ortho-tert-butyl
ing element ortho to the olefin-containing side chain led groups) increased both the rates and efficiencies of
to both enhanced reaction rates and access to medium- intramolecular PK reactions, and so we decided to explore
sized rings.8 Perhaps the most interesting result obtained this tactic with these substrates.5b,c
in the course of this investigation was that these systems
2,4-Di-tert-butylsalicylaldehyde (12) was O-alkylated
with allyl bromide as before (Scheme 3), and then treated
with acetylenic Grignard reagents, affording the enynes
14–16 in good yield (ca 75%). Initial attempts to engage
cyclized to give bridged systems, a mode of cyclization
hitherto unobserved (e.g. 1 → 2, Scheme 1).9 This out-
come was rationalized in terms of both electronic and
steric factors that are thought to control the PK reaction in
these substrates in the PK reaction were complicated by
general. In order to further probe this mode of cyclization,
the formation of multiple products, and therefore to ease
we began an investigation of a set of related substrates, in
our initial evaluation of these reactions, we decided to re-
which an additional carbon atom was placed between the
move the propargylic hydroxyl group. This was accom-
aromatic and acetylenic moieties. We hoped to establish
plished readily by treatment of enynes 14–16 with Et3SiH
in the presence of TFA leading to the formation of 17–19
(Scheme 3). The resulting reduced products were subject-
ed to the PK reaction under both oxidative and thermal
whether this apparently minor modification was tolerated
in a general sense, and whether the unusual regiochemis-
try would be observed in this case.
Our initial investigations began with the elaboration of conditions (Scheme 4, Table 1). Under both sets of condi-
salicylaldehyde (3), by O-alkylation and subsequent re- tions similar results were obtained. The TMS- and Ph-
action with variously substituted acetylenic Grignard substituted derivatives 18 and 19 both underwent cycliza-
derivatives, which provided enynes 5–7 in good yields tion, providing the expected enones, 21 and 22, in yields
between 45–55% as the only isolable product. An X-ray
crystal structure of enone 22 was obtained (Figure 1), con-
SYNLETT 2007, No. 13, pp 2011–2016
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984880; Art ID: S03207ST
© Georg Thieme Verlag Stuttgart · New York
1
3
.0
8
.2
0
0
7
firming the formation of the anticipated tricyclic system.
Interestingly, the parent substrate 17 failed to undergo cy-
clization, providing only decomplexed enyne. We assume

2012
C. E. Madu, C. J. Lovely
LETTER
HO
R
CHO
O
CHO
OH
b
a
O
5: R = H, 80%
6: R = TMS, 85%
7: R = Ph, 86%
3
4, 90%
c or d
e, d
R
HO
O
R
TBSO
O
O
O
Figure 1 X-ray crystal structure of PK cycloadduct 22
R
H
TMS
Ph
[O] (%)
[O] (%)
11, 49% (two steps)
8
9
10
0
0
0
0
0
31
R
X
O
R
Table 1
Scheme 2 Reagents and conditions: (a) allyl bromide, DMF,
K2CO3; (b) BrMgC≡CR, THF, 0 °C; (c) Co2(CO)8, CH2Cl2, NMO; (d)
Co2(CO)8, toluene, 70 °C; (e) TBSCl, imidazole, DMF, 55 °C.
X = OH or H
O
O
20: R = H
21: R = TMS
22: R = Ph
14–19
that the substituted enyne complexes are somewhat more
stable under the PK reaction conditions, whereas the par-
ent substrate complex decomposes faster than it partici-
pates in cyclization. We were also able to engage both 15
and 16 in a one-pot, complexation, reduction and cycliza-
tion sequence, which provided the enones in comparable
yields (Table 1, conditions C), whereas the parent sub-
strate 14 again failed to provide cycloadduct.
Scheme 4
Table 1 PK Reaction of Reduced Enynes
Substrate
Conditionsa Product
Yield (%)
17, R = X = H
A
B
A
B
A
B
C
C
C
20
20
21
21
22
22
20
21
22
0
0
17, R = X = H
CHO
18, R = TMS, X = H
18, R = TMS, X = H
19, R = Ph, X = H
19, R = Ph, X = H
14, R = H, X = OH
15, R = TMS, X = OH
16, R = Ph, X = OH
56
45
43
46
0
CHO
Br
O
OH
K2CO3, DMF, r.t.
13, 93%
12
BrMg
THF, 0 °C
R
48
50
OH
O
a Conditions A: Co2(CO)8, toluene, 70 °C; conditions B: Co2(CO)8,
CH2Cl2, NMO; conditions C: (i) Co2(CO)8, CH2Cl2; (ii) NaBH4, TFA,
(iii) NMO.
R
R
Et3SiH
TFA, CH2Cl2
O
conditions. As alluded to above, each of these substrates
gave several products (Scheme 5, Table 2), including the
expected enones 22–25. In the case of the parent substrate
14, a total of four cycloadducts were obtained. Under ox-
idative conditions, the expected cycloadduct 23 was the
minor product, obtained in only 17% yield as a 1:1 mix-
ture of diastereomers, the major product was in fact the
1,4-diketone 26, which was isolated in 80% yield as a 6:1
mixture of diastereomers.5f Under thermal conditions the
combined yield was somewhat lower, but the same
products were obtained.14 The TMS- and Ph-substituted
14: R = H, 75%
15: R = TMS, 74%
16: R = Ph, 75%
17: R = H, 96%
18: R = TMS, 99%
19: R = Ph, 98%
Scheme 3
Given this preliminary success with 17–19, we returned
our attention to the propargyl alcohols 14–16 as sub-
strates, which, after conversion into the Co2(CO)6 com-
plex, were subjected to both oxidative and thermal
Synlett 2007, No. 13, 2011–2016 © Thieme Stuttgart · New York

LETTER
Intramolecular Pauson–Khand Reaction of Aryl Enynes
2013
derivatives 15 and 16 also provided multiple products
under oxidative conditions, both the expected cycloadduct
24 and 25, as an approximately 2:1 mixture of diastereo-
mers and the reduction products 21 and 22 were obtained.
Interestingly, under thermal conditions, none of the reduc-
tion product was formed, only the expected cycloadducts.
Furthermore, only one diastereomer was obtained from
these reactions. An X-ray crystal structure of the product
obtained from the Ph-substituted enyne indicated that it
was the exo alcohol (Figure 2).
R
HO
HO
O
R
Table 2
Figure 2 X-ray crystal structure of exo-25
O
O
LnCo
R
Co2(CO)6
23: R = H
24: R = TMS
25: R = Ph
HO
HO
14: R = H
15: R = TMS
16: R = Ph
O
H
R
O
H
O
O
O
29
O
28
26
H
OH
LnCo
Scheme 5
Table 2 Oxidative and Thermal PK Cyclizations of Enynes 12–14
LnCo
HO
R
O
O
Substrates
Condi- Product, Yield (%), Product,Yield (%),
tionsa
(Epimer ratio)
(Epimer ratio)
O
O
32
30
23
26
14, R = H
A
B
17 (1:1)
11 (2:1)
24
80 (6:1)
– CO2
?
50 (1:1)
H
LnCo
HO
H
LnCo
R
21
20
0
O
O
15, R = TMS
16, R = Ph
A
B
70 (2:1)
58 (1:0)
25
O
O
33
31
22
55
0
A
B
26 (2:1)
94 (1:0)
R
H
O
H
O
O
a Conditions: A: Co2(CO)8, CH2Cl2, NMO; Conditions B: Co2(CO)8,
toluene, 70 °C.
O
O
26
21–22
We assume that the diketone products 26 arise as a result
of the insertion of cobalt into the allylic C–H bond and the
formation of a p-allyl complex 30 (Scheme 6). Formation
of and elimination via the isomeric olefin provides the
enol 31, decomplexation of the cobalt cluster and tau-
tomerization then provides the diketone derivative 26. We
similarly assume that the reduction products arise from
ionization of the allylic hydroxyl group forming 32, in a
process reminiscent of Nicholas-type chemistry.15,16 Loss
of the oxygen, presumably as CO2, then provides the
Scheme 6
cobalt hydride species 33, which undergoes reductive
elimination and decomplexation to provide the reduction
products 21 and 22. While the formation of these products
can be rationalized, what is more difficult to understand is
the substrate dependence and the product variation as a
function of reaction conditions.17 Once the cobalt com-
plex is formed, the distal substituents exert little electronic
Synlett 2007, No. 13, 2011–2016 © Thieme Stuttgart · New York

2014
C. E. Madu, C. J. Lovely
LETTER
TBSO
In summary our investigation demonstrates that an aro-
matic ring alone does not sufficiently preorganize the
enyne substrate for cyclization leading to medium-sized
rings. However, the incorporation of conformational con-
straints induced by bulky ortho substituent enhances both
the efficiency and the yield of the enyne cyclization.21 The
PK cyclizations of the substrates reported in this Letter
occur with normal regiochemistry and where relevant,
proceed with reasonable to high levels of diastereoselec-
tivity. In several examples deoxygenation of the propar-
gylic hydroxyl moiety was observed, but this can be
generally attenuated by incorporation of a silyl protecting
group. It was also found that these reactions proceed with
the typical regioselectivity observed in intramolecular PK
reactions, presumably as a result of other orientations
requiring unfavorable geometric arrangement of the react-
ing functional groups. We are continuing to explore the
use of buttressing elements in the PK reaction and will
report on these in due course.22
OH
R
R
TBSCl, DMF
O
imidazole, 55 °C
O
34: R = H, 98%
35: R = TMS, 97%
36: R = Ph, 97%
14: R = H
15: R = TMS
17: R = Ph
Table 3
R
TBSO
O
34: R = H
35: R = TMS
36: R = Ph
O
Scheme 7
Table 3 PK Cyclization of Protected Substrate
Acknowledgment
Substrates
Condi- Product, Yield (%), Product, Yield
tionsa
(Epimer ratio)
(%)
20
0
We are grateful to the Robert A. Welch Foundation (Y-1362) for the
provision of financial support for this program and to the NSF
(CHE-9601771 and CHE-0234811) for partial support of the NMR
spectrometers used in the course of this investigation. We would
also like to express our thanks to Prof. Rasika Dias for obtaining and
solving the X-ray crystal structures reported in this paper.
37
34, R = H
A
B
52 (2:1)
80 (1:1)
38
0
21
0
References and Notes
35, R = TMS
36, R = Ph
A
B
61 (1:0)
0
(1) (a) Schore, N. E. Chem. Rev. 1988, 88, 1081. (b) Schore, N.
E. Org. React. (N. Y.) 1991, 40, 1. (c) Schore, N. E. In
Comprehensive Organometallic Chemistry II, Transition
Metal Alkyne Complexes: Pauson–Khand Reaction, Vol. 12;
Hegedus, L. S., Ed.; Pergamon: Oxford, 1995, 703.
(d) Geis, O.; Schmalz, H.-G. Angew. Chem. Int. Ed. 1998,
37, 911. (e) Ingate, S. T.; Marco-Contelles, J. Org. Prep.
Proced. Int. 1998, 30, 123. (f) Chung, Y. K. Coord. Chem.
Rev. 1999, 188, 297. (g) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263. (h) Gibson, S. E.; Stevanazzi,
A. Angew. Chem. Int. Ed. 2003, 42, 1800. (i) Blanco-
Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.; Dominguez, G.;
Perez-Castells, J. Chem. Soc. Rev. 2004, 33, 32. (j) Gibson,
S. E.; Mainolfi, N. Angew. Chem. Int. Ed. 2005, 44, 3022.
(k) Struebing, D.; Beller, M. Top. Organomet. Chem. 2006,
18, 165.
0
39
22
11
0
A
B
60 (5:1)
95 (10:1)
a Conditions: A: Co2(CO)8, CH2Cl2, NMO; Conditions B: Co2(CO)8,
toluene, 70 °C.
influence toward the propargylic center,18 although they
do provide a steric bias, which frequently leads to the exo-
type selectivity observed in PK reactions.5c,19
Given that under oxidative reaction conditions, and to a
limited extent thermal conditions, side reactions involving
the free hydroxyl group had been observed, we decided to
protect it as a silyl ether. This was readily accomplished
under standard conditions providing 34–36 (Scheme 7).
The resulting enynes were subjected to the PK reaction
under both oxidative and thermal conditions (Table 3). In
general terms, the cyclizations occurred uneventfully,
providing the expected PK products 37–3920 in good to
moderate yields and with good to excellent levels of dia-
stereoselectivity. Some reduction product 22 was still ob-
served under oxidative conditions with the Ph-substituted
derivative, but the level was substantially attenuated in
comparison to 14. Similarly, thermal conditions appear to
provide greater levels of diastereoselectivity.
(2) For an excellent discussion of abnormal cyclization
pathways and products, see: Bonaga, L. V. R.; Krafft, M. E.
Tetrahedron 2004, 60, 9795.
(3) For related work with allenynes, see: (a) Ahmar, M.;
Chabanis, O.; Gauthier, J.; Cazes, B. Tetrahedron Lett.
1997, 38, 5277. (b) Mukai, C.; Nomura, I.; Yamanishi, K.;
Hanaoka, M. Org. Lett. 2002, 4, 1755. (c) Brummond, K.
M.; Chen, H. F.; Fisher, K. D.; Kerekes, A. D.; Rickards, B.;
Sill, P. C.; Geib, S. J. Org. Lett. 2002, 4, 1931. (d) Mukai,
C.; Nomura, I.; Kitagaki, S. J. Org. Chem. 2003, 68, 1376.
(e) Mukai, C.; Inagaki, F.; Yoshida, T.; Yoshitani, K.; Hara,
Y.; Kitagaki, S. J. Org. Chem. 2005, 70, 7159. (f) Mukai,
C.; Hirose, T.; Teramoto, S.; Kitagaki, S. Tetrahedron 2006,
61, 10983.
(4) Krafft, M. E.; Fu, Z.; Bonaga, V. R. Tetrahedron Lett. 2001,
42, 1427.
Synlett 2007, No. 13, 2011–2016 © Thieme Stuttgart · New York

LETTER
Intramolecular Pauson–Khand Reaction of Aryl Enynes
2015
(5) (a) Blanco-Urgoiti, J.; Casarrubios, L.; Pérez-Castells, J.
Tetrahedron Lett. 1999, 40, 2817. (b) Pérez-Serrano, L.;
Blanco-Urgoiti, J.; Casarrubios, L.; Domínguez, G.; Pérez-
Castells, J. J. Org. Chem. 2000, 65, 3513. (c) Perez-
Serrano, L.; Gonzalez-Perez, P.; Casarrubios, L.;
Dominguez, G.; Perez-Castells, J. Synlett 2000, 1303.
(d) Blanco-Urgoiti, J.; Casarrubios, L.; Dominguez, G.;
Perez-Castells, J. Tetrahedron Lett. 2001, 42, 3315.
(e) Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.;
Perez-Castells, J. Chem. Commun. 2001, 2602. (f) Perez-
Serrano, L.; Dominguez, G.; Perez-Castells, J. J. Org. Chem.
2004, 69, 5413.
(6) (a) Lovely, C. J.; Seshadri, H. Synth. Commun. 2001, 31,
2479. (b) Lovely, C. J.; Seshadri, H.; Wayland, B. R.;
Cordes, A. W. Org. Lett. 2001, 3, 2607. (c) Madu, C. E.;
Seshadri, H.; Lovely, C. J. Tetrahedron 2007, 63, 5019.
(7) Congested systems arising from the cyclization of internal
alkynes and 2,2-disubstituted olefins were generally poor
substrates in this reaction. See ref. 6c for further discussion
of this issue.
(19) (a) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26,
4851. (b) Magnus, P.; Principe, L. M.; Slater, M. J. J. Org.
Chem. 1987, 52, 1483.
(20) The stereochemistry of the major cycloadducts was
determined either through NOE experiments, or in the case
of 39, by desilylation and comparison to exo-23, to which it
was identical.
(21) Selected experimental procedures and selected
characterization data. 4,6-Di-tert-butyl-2-(-3-phenyl-2-
propynyl)-2-propenyloxybenzene (19): Triethylsilane
(1.24 g, 10.7 mmol) was added at r.t. to a solution of 16
(2.0 g, 5.3 mmol) in CH2Cl2 (10 mL) under a N2 atmosphere.
Then trifluoroacetic acid (2.43 g, 21.3 mmol) was added and
stirred for 20 min. The reaction mixture was quenched with
aq NaHCO3 and extracted with CH2Cl2 (2 ꢀ 10 mL) to give
a yellow liquid. The crude product was purified by flash
chromatography (hexane–EtOAc, 95:5) to give 19 as a light
yellow liquid (1.87 g, 98%). 1H NMR (500 MHz, CDCl3):
d = 7.52 (d, J = 2.5 Hz, 1 H), 7.44 (m, 2 H), 7.30 (d, J = 2.5
Hz, 1 H), 7.29 (d, J = 3.0 Hz, 3 H), 6.11 (ddt, J = 4.6, 11.0,
17.0 Hz, 1 H), 5.55 (dq, J = 1.8, 17.4 Hz, 1 H), 5.32 (dq,
J = 1.8, 10.5 Hz, 1 H), 4.46 (dt, J = 1.8, 4.6 Hz, 2 H), 3.83
(d, J = 5.0 Hz, 2 H), 1.46 (s, 9 H), 1.38 (s, 9 H). 13C NMR
(125 MHz, CDCl3): d = 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): 2959, 2870,
1451, 1225, 991, 755 cm–1. HRMS (ESI): m/z [M + H]+ calcd
for C26H33O: 361.2526; found: 361.2538.
(8) (a) For a review of this area, see: Sammes, P. G.; Weller, D.
J. Synthesis 1995, 1205. (b) Also see: Jung, M. E.; Piizzi, G.
Chem. Rev. 2005, 105, 1735.
(9) For another example of this abnormal regiochemistry, see:
Comer, E.; Rohan, E.; Deng, L.; Porco, J. A. Jr. Org. Lett.
2007, 9, 2123.
(10) (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
Tetrahedron Lett. 1990, 31, 5289. (b) Jeong, N.; Chung, Y.
K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett 1991, 204.
(11) Belanger, D. B.; O’Mahony, D. J. R.; Livinghouse, T.
Tetrahedron Lett. 1998, 39, 7637.
(12) Our initial explanation of this change was that bulky silyl
ether led to an increase in the reactive conformer population,
resulting in enhanced cyclization yields. In other words, the
silyl ether was serving as a type of steric buttressing element.
However, our subsequent experience with related substrates
suggests that this may be only one aspect that contributes to
the increased yield. We subsequently observed that
substrates containing a free propargylic hydroxyl group
were prone to several types of side reactions, and its
protection may lead to a reduction of these types of
reactions.
General Procedure for the Oxidative PK Reaction
(Procedure A): Co2(CO)8 (1.1 equiv) was added to a stirred
solution of enyne in CH2Cl2 and under N2 at r.t. The reaction
mixture was stirred for 5 h at r.t. The reaction mixture was
cooled to 0 °C before NMO (12 equiv) was added in three
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 (ca 1:1) and washed with EtOAc. After rotary
evaporation, the crude product was purified by flash
chromatography (hexane–EtOAc mixtures).
General Procedure for the Thermal PK Reaction
(Procedure B): Co2(CO)8 (1.1 equiv) was added to a stirred
solution of enyne in toluene and under N2 and stirred for 5 h
at r.t. The reaction mixture was then heated at 70 °C under
N2 for overnight. Workup and purification was identical to
Procedure A.
(13) For a complementary approach to this type of ring system
through the Pauson–Khand reaction, see: Mohamed, A. B.;
Green, J. R.; Masuda, J. Synlett 2005, 1543.
6,8-Di-tert-butyl-1-phenyl-4,4a-dihydro-3H,10H-5-
oxabenzo[f]azulen-2-one (22): The PK cyclization was
carried out according to the general Procedures A and B. The
enyne 19 (130 mg, 0.36 mmol) was dissolved in the
appropriate solvent (10 mL). 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
chromatography (hexane–EtOAc, 9:1) to afford 22 (60 mg,
43% using Procedure A and 64 mg, 46% using Procedure B)
as a yellow solid; mp 160–162 °C. 1H NMR (500 MHz,
CDCl3): d = 7.46 (t, J = 7.8 Hz, 2 H), 7.40 (d, J = 2.8 Hz, 1
H), 7.34 (d, J = 2.8 Hz, 2 H), 7.30 (s, 1 H), 7.14 (s, 1 H), 4.67
(dd, J = 5.5, 11.5 Hz, 1 H), 3.91 (d, J = 12.8 Hz, 1 H), 3.76
(d, J = 12.8 Hz, 1 H), 3.54 (m, 1 H), 3.35 (t, J = 11.5 Hz, 1
H), 2.75 (dd, J = 7.1, 18.9 Hz, 1 H), 2.03 (dd, J = 2.8, 18.8
Hz, 1 H), 1.41 (s, 9 H), 1.35 (s, 9 H). 13C NMR (125 MHz,
CDCl3): d = 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): 2958, 1705, 1474, 758
cm–1. HRMS (ESI): m/z [M + Na]+ calcd for C27H32O2Na:
411.2295; found: 411.2266.
(14) Control experiments suggest the diastereomer ratios are
kinetically controlled, as the epimeric ketones do not appear
to interconvert upon heating in toluene, or on treatment with
Et3N, although at this point, we cannot rule out the
possibility of a Co-catalyzed epimerization.
(15) (a) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.
(b) Green, J. R. Curr. Org. Chem. 2001, 5, 809.
(c) Teobald, B. J. Tetrahedron 2002, 58, 4133.
(16) It is also conceivable that the ionization and reduction take
place prior to cyclization, and experiments to address this
possibility are currently underway.
(17) It is quite likely that the active complexes (number and type
of ligands) are not the same under oxidative and thermal
conditions, and thus the differences observed under these
two reaction conditions may not only be a result of the
temperature differences, but of the precise identity of the
active complex.
(18) (a) Thermodynamic study: Connor, R. E.; Nicholas, K. M.
J. Organomet. Chem. 1977, 125, C45. (b) Kinetic study:
Kuhn, O.; Rau, D.; Mayr, H. J. Am. Chem. Soc. 1998, 120,
900.
Synlett 2007, No. 13, 2011–2016 © Thieme Stuttgart · New York

2016
C. E. Madu, C. J. Lovely
LETTER
6,8-Di-tert-butyl-10-hydroxy-1-phenyl-4,4a-dihydro-
3H,10H-5-oxabenzo[f]azulen-2-one (25): The PK
H), 7.23 (m, 2 H), 7.14 (d, J = 2.8 Hz, 1 H), 5.49 (d, J = 9.2
Hz, 1 H), 4.61 (dd, J = 5.7, 11.5 Hz, 1 H), 4.09 (m, 1 H), 3.51
(t, J = 11.9 Hz, 1 H), 3.15 (d, J = 8.7 Hz, 1 H), 2.76 (dd, J =
6.9, 19.3 Hz, 1 H), 2.03 (dd, J = 2.8, 18.8 Hz, 1 H), 1.40 (s,
9 H), 1.32 (s, 9 H). 13C NMR (125 MHz, CDCl3): d = 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): 3435, 2959, 1702, 1598, 756 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C27H33O3: 405.2424;
found: 405.2425.
cyclization of the enyne 16 (250 mg, 0.67 mmol) in the
appropriate solvent (10 mL), 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. The crude product was purified by flash
chromatography (silica gel, hexane–EtOAc, 90:10) to afford
the reduced PK product 22 (142 mg, 55%) and the expected
PK product 25 (70 mg, 26%) as a 1:1 mixture of epimers
using Procedure A. Procedure B afforded only exo-25 (255
mg, 94%) as a light yellow solid; mp 171–173 °C. 1H NMR
(500 MHz, CDCl3): d = 7.46 (m, 3 H), 7.35 (d, J = 2.8 Hz, 1
(22) Some initial experiments with olefins with terminal
substitution have been successful, but internal substitution is
apparently not tolerated.
Synlett 2007, No. 13, 2011–2016 © Thieme Stuttgart · New York

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