Initiating radical cyclizations by H{radical dot} transfer from transition metals

Article abstract of DOI:10.1016/j.tet.2008.10.030

CpCr(CO)₃H and HV(CO)₄(P-P) (where P-P is a chelating diphosphine) can be used to initiate radical cyclizations by transferring H{radical dot} to activated terminal olefins. CpCr(CO)₃H can catalyze reductive cyclizations,

Full text of DOI:10.1016/j.tet.2008.10.030

Tetrahedron 64 (2008) 11822–11830
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ꢀ
Initiating radical cyclizations by H transfer from transition metals
y
*
John Hartung, Mary E. Pulling, Deborah M. Smith , David X. Yang, Jack R. Norton
Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
CpCr(CO)3H and HV(CO)4(P–P) (where P–P is a chelating diphosphine) can be used to initiate radical
cyclizations by transferring Hꢀ to activated terminal olefins. CpCr(CO)3H can catalyze reductive cycliza-
tions, with H2 as the ultimate reductant. Appropriate substrates can be assembled by the Morita–Baylis–
Hillman reaction of methyl acrylate with an aldehyde. Six- as well as five-membered rings can be formed,
and a tandem cyclization to decalin can be effected.
Received 2 October 2008
Accepted 10 October 2008
Available online 17 October 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Radical cyclization
Hydrogen atom transfer
Transition-metal hydrides
Acrylates
1. Introduction
-CO2
SnBu3
+
Bu3Sn
S
+
R
N
O
N
O
S
SnBu3
R
N
S
R
Methods involving carbon-centeredradicals are extensivelyused
in synthesis, particularly in cyclization reactions. Such radicals can
be generated in many ways, the most common being the abstraction
of Xꢀ byan organotin radical (Eq.1), whereX is Br, I, occasionally Cl, or
PhSe or PhS.1 The radical Rꢀ, often aftercyclization or rearrangement,
then abstracts Hꢀ from a tin hydride (typically Bu3SnH), regenerating
the tin radical (Eq. 2) and continuing the chain.
O
O
ð4Þ
Such methods are necessarily stoichiometric both in tin and in
another heavy element (Br, I, Se, S). In the laboratory, special care is
required to handle trialkyltin hydrides and the waste they generate,
and standard purification techniques often leave toxic levels of tin
compounds in the product.3 The industrial application of these
methods has been hindered by the need to remove such tin-con-
taining byproducts. In order to ameliorate this problem, methods
catalytic in tin have been developed,4–6 and tin hydride reagents
modified to make their removal easier.7–13 However, the need for
alternatives to tin remains as evidenced by reviews such as ‘Flight
from the Tyranny of Tin’.14–17 Substitutes such as N-ethyl-
piperidinium hypophosphite,18 (Me3Si)3SiH,19 Bu3GeH,20 HGaCl2,21
and HInCl222 contain a bond to hydrogen stronger than the 78 kcal/
mol one in Bu3SnH23 and are therefore likely to be less reactive at Hꢀ
transfer.
+
Bu3SnX
Bu3Sn
Bu3Sn
R
R
X
+
ð1Þ
ð2Þ
+
+
R'
Bu3SnH
R'
H
Related methods begin with the addition of a tin radical to the
C]S double bond in a xanthate (Eq. 3) or thiohydroxamate (Eq. 4)
ester.1,2 The resulting intermediates then give Rꢀ by
decarboxylation (Eq. 4).
b-scission and
RO
Bonds to hydrogen weaker than Sn–H are common in transition-
metal hydrides. Although an Os–H bond >82 kcal/mol has been
reported,24 most M–H bonds lie between 60 and 65 kcal/mol.25 We
have found V–H bonds (see below) as weak as 55 kcal/mol.26 These
weak bonds enable transition-metal hydrides to generate radicals
in ways not available to tin hydrides. In 1977 Sweany and Halpern
concluded, after observing CIDNP and an inverse H/D isotope effect,
that the hydrogenation of a-methylstyrene by HMn(CO)5 (Eqs. 5
and 6) begins with the reversible transfer of Hꢀ from Mn to the
olefin.27 (They presumed the new C–H bond to have a frequency of
RO
S
O
S
SnBu3
SnBu3
+
S
Bu3Sn
+
ð3Þ
R
SMe
SMe
MeS
* Corresponding author. Tel.: þ1 212 854 7644; fax: þ1 212 854 7660.
E-mail address: jrn11@columbia.edu (J.R. Norton).
Present address: Johnson & Johnson PRD, 3210 Merryfield Row, San Diego, CA
y
92121, USA.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.030

J. Hartung et al. / Tetrahedron 64 (2008) 11822–11830
11823
‘w3000 cmꢁ1’, and implied that the inverse isotope effect arose
from the equilibrium in Eq. 5. However, such C–H bonds are
Metalloradicals Mꢀ have proven to be effective catalysts for
chain transfer. The original catalysts were macrocyclic cobalt(II)
complexes,40 but their hydrides are unobservable during the
catalytic cycle, apparently because they are so efficient in trans-
ferring Hꢀ back to monomer (Eq. 9). We have found that Cr
metalloradicals are almost as effective while offering the advan-
tage that their hydrides are stable enough to be observed during
catalysis. For the polymerization of methyl methacrylate,
(C5Ph5)Cr(CO)3 is a good chain transfer catalyst, CpCr(CO)3 (in
equilibrium with its dimer) is a much better one,41 and the va-
nadium metalloradical V(CO)4(dppe)ꢀ shows respectable activity.42
This effectiveness implies that the corresponding hydrides
((C5Ph5)Cr(CO)3H, 1, and 2b) are efficient in transferring Hꢀ back to
methyl methacrylate.
weakened by an adjacent radical center,28 and
DH for Eq. 5 is en-
dothermic, þ8 to 10 kcal/mol,29,30 which raises the possibility31 that
the observed inverse effect has a kinetic origin.32).
Ph
Ph
H
HMn(CO)5
+
+
Mn(CO)5
+
ð5Þ
Me
Me
ꢀ
ꢀ
Ph
Ph
H
+
HMn(CO)5
Mn2(CO)10
CH3
ð6Þ
Me
Me
Some years ago we showed that CpCr(CO)3H (1) and related Cr
hydrides could serve as Hꢀ donors to methyl methacrylate and
styrene.29,30 However, these Cr–H bonds are 62–64 kcal/mol and
their Hꢀ transfer reactions were not fast. We considered where we
might find weaker M–H bonds, and noted (1) the unusually effi-
cient transfer of Hꢀ to a carbon radical from an anionic vanadium
hydride,33 (2) a number of papers in which vanadium hydrides
appeared to transfer Hꢀ onto various dienes,34,35 and (3) a calcula-
tion on the hypothetical VH5 that gave it the weakest M–H bond
of any of the hydride complexes considered.36 We therefore
The effectiveness with which M–H bond strengths can control
rates of Hꢀ transfer is illustrated by the recent work of O’Connor and
Friese on Bergman cycloaromatizations. They found that
CpW(CO)3H, with an M–H bond strength of 72 kcal/mol,25 does not
react with an enediyne but does transfer Hꢀ to the diradical formed
by its cyclization.43
Using Hꢀ transfer to selectively generate radicals requires that
we know the relative rates at which such transfers occur to various
olefins. There has been virtually no information on the rate con-
stants kH with which different double bonds accept Hꢀ. We have
therefore examined the reactivity of CpCr(CO)3H (1) toward the
nine olefins in Table 2, determining kH from either the rate of H/D
exchange or the rate of hydrogenation.26
prepared
a series of vanadium hydrides HV(CO)4(P–P) (P–
P]Ph2P(CH2)nPPh2, with n¼1 (dppm), n¼2 (dppe), n¼3 (dppp),
and n¼4 (dppb)) (2a–d),37,38 determined the strength of their V–H
bonds, and found that these bonds are indeed weak (Table 1).39
The stability of the resulting radical has a large effect on kH:
olefins bearing phenyl substituents (entries 1–3 and 8) accept Hꢀ
more readily than do olefins bearing CO2Me substituents (entries
4, 6, and 9), although the latter accept Hꢀ more readily than do
olefins bearing methyl substituents. Additional methyl or phenyl
Table 1
Bond dissociation energies of some chromium and vanadium hydrides
M–H
5-C5H5)Cr(CO)3H (1)
M–H BDE (kcal/mol)
(
h
62.2
57.9
57.5
56.0
54.9
HV(CO)4(dppm) (2a)
HV(CO)4(dppe) (2b)
HV(CO)4(dppp) (2c)
HV(CO)4(dppb) (2d)
substituents on the
a carbondwhich provide additional stabili-
zation for the radical being generateddincrease the rate further.
Table 2
Rate constants kH for Hꢀ transfer from CpCr(CO)3H to various olefins at 323 K
The V–H bonds in 2a–d transfer Hꢀ more rapidly than does the
Cr–H bond in 1, although the increase in rate is not as large as one
would expect from the decrease in M–H bond strength.
HV(CO)4(dppe) (2b) transfers Hꢀ to styrene about 10 times more
rapidly than does 1.39 Presumably, the steric bulk of the chelating
ligand undermines the effect of the weaker bond.
Such Hꢀ transfer reactions are familiar as part of the catalytic
cycle for chain transfer during radical polymerizations (Eq. 7). In
the first step of that cycle, Eq. 8, Hꢀ is removed from the chain-
carrying radical; its transfer to fresh monomer (Eq. 9) begins a new
chain.40 The competition between Eq. 8 and propagation (Eq. 7)
reduces the chain length and molecular weight of the polymer.
Entry
Olefin
Ph
kH (ꢂ10ꢁ3) (Mꢁ1 sꢁ1
)
Relative rate
1
0.59 (2)
1
Ph
Ph
2
460 (60)
780
Ph
Ph
3
4
79 (3)
134
ꢃ3.2ꢂ10ꢁ4
ꢃ5ꢂ10ꢁ4
CO2Me
H
H
kprop
+
Me
ð7Þ
ð8Þ
ð9Þ
ꢃ1.1ꢂ10ꢁ4
ꢃ2ꢂ10ꢁ4
z0.02
CO2Me
5
6
CO2Me
CO2Me
P
P
P
5
(0.8–1.6)ꢂ10ꢁ2
CO2Me
H
ktr
+
ꢃ3.2ꢂ10ꢁ3
ꢃ0.005
M
+
M
H
7
8
CO2Me
CO2Me
4
P
Ph
15.8 (6)
27
H
9
14 (3)
24
kH
+
+
M •
Me
Me
M
H
CO2Me
CO2Me
CO2Me

11824
J. Hartung et al. / Tetrahedron 64 (2008) 11822–11830
ka= 14 x 10-3 M-1s-1
k
b = 0.59 x 10-3 M-1s-1
R
a
R
Me
R
R
favored
R
R
Ph
Ph
Ph
MeO2C
MeO2C
MeO2C
b
Ph
Ph
Ph
4a, b
3a R = H
3b R = CO2Me
5a, b
Scheme 1. Hꢀ transfer to dienes 3a and 3b.
Me
MeO2C
R
R
Me
Ph
kH[M-H]
ktr[M•]
R
R
kcyc
Ph
Ph
MeO2C
MeO2C
H2[M-H]
R
Ph
H
R
Ph
Ph
tr2[M•]
Me
3a R = H
3b R = CO2Me
4a, b
6a, b
R
k
k
Me
R
R
R
Ph
Ph
MeO2C
MeO2C
Ph
Ph
8a, b
7a, b
Scheme 2. Pathways available to radicals 4a and 4b.
A methyl substituent on the
b
carbon (the one receiving the Hꢀ)
reduces the rate substantially, presumably as a result of steric
hindrance to the transfer. The results in Table 2 have enabled us
to design substrates that can be cyclized by transition-metal
hydrides.
Me
MeO2C
Ph
Ph
CpCr(CO)3H, 7 mol%
H2, 3 atm
50°C, C6D6, 4 d
MeO2C
Ph
Ph
3a
6a, 72%
2. Results and discussion
ð11Þ
According to Table 2, the ‘a’ double bond in 3 (Scheme 1) should
be kinetically favored (25 times faster) for Hꢀ transfer, yielding
radical 4 rather than radical 5.
Me
Me
MeO2C
MeO2C
+
+
Several reactions, all shown in Scheme 2, are available to 4. Such
radicals are known to cyclize rapidly, with rate constants
Ph
Ph
Ph
Ph
(kcyc)>105 sꢁ1 44
However, they can also undergo back transfer
.
(ktr[Mꢀ]), hydrogenation (kH2[M–H]), and isomerization by Hꢀ ab-
straction from the adjacent carbon (ktr2[Mꢀ]).
7a, 21%
8a, 7%
Back transfer and isomerization require Mꢀ, and can be avoided
if we convert Mꢀ back to M–Hda transformation that has the
advantage of making the overall reaction catalytic. If Mꢀ is
When we increase kcyc, by placing two substituents on the
g
carbon (3b, Eq. 12) to take advantage of the Thorpe–Ingold effect,47
the reaction becomes fast and quantitative.46
ꢀ
CpCr(CO)3 , we can convert it back to CpCr(CO)3H (1) with modest
hydrogen pressures (3 atm H2, Eq. 10). (This transformation was
reported by Fischer and co-workers in 1955, but under a pressure
of 150 atm at 70 ꢄC!45) Unfortunately, we have as yet been unable
to regenerate the vanadium hydrides 2 from the corresponding
vanadoradicals, so they can only be used as stoichiometric
reagents.
R
MeO2C Me
R
Ph
CpCr(CO)3H, 7 mol%
MeO2C
Ph
Ph
R
R
H2, 3 atm
50°C, C6D6, 1.5 d
ð12Þ
Ph
3b, R = CO2Me
6b, >95%
H2
3 atm
Stoichiometric useof the vanadiumhydrides2 gavesimilar results
with 3a and 3b, but more quickly even at lower temperatures.39 For
example, treatment of 3a with 2b yielded 6a in 77% yield in 24 h,
while treatment of 3b with 2a–d gave 6b quantitatively in 6–24 h.
There have been previous reports on the use of organometallic
complexes to effect the cyclization of 1,6-dienes. Cp*2YH (gener-
ated in situ) under H2 reductively cyclizes some terminal dienes,48
Ni and Pd allyls cyclize other dienes to unsaturated products,49 and
Ru and Rh catalysts cyclize heterocycle-substituted dienes.50 Rh(I)
catalysts under H2 effect the reductive cyclization of diynes and
enynes.51 In none of these cases has evidence been reported for
a radical mechanism.
2 CpCr(CO)3
2 CpCr(CO)3H
ð10Þ
With 1 under 3 atm of H2, we can carry out (Eq. 11) the
catalytic and tin-free cyclization of 3a to 6a, although we also
observe some hydrogenation (to 7a) and isomerization (to
8a).46 The reaction is slow but conversion is complete. The
transfer of Hꢀ to the cyclized radical gives the observed product
6a as two diastereomers (only the major one is shown). An
increase in the H2 pressure favors (as we would expect) 7a over
8a, while a decrease in the pressure has the opposite effect (see
Section 4.2).

J. Hartung et al. / Tetrahedron 64 (2008) 11822–11830
11825
R
9a R = Me
R
9b R = Ph
N
Me
R
Me
M–H
R
Me
N
N
+
N
R
11a
12
R
13
If M–H = CpCr(CO)3H
Ph
If M–H comes from Co/Ti
R
11a R = Me
11b R = Ph
N
Ph
R
N
10a R = Me
10b R = Ph
N
11b
14
Scheme 3. Treatment of 9a and 9b with B12/Ti(III) (van der Donk) versus treatment with chromium hydride 1.
2.1. Substrates that generate pyrrole-stabilized radicals
Our cyclization reaction has proven tolerant of the additional
substituent. Treatment of diene 15 with catalytic amount
a
Van der Donk and co-workers have reported the cyclization of
9a and 9b (Scheme 3), with Vitamin B12 as a catalyst and Ti(III)
citrate as the ultimate reductant.52,53 The substrates 9 closely re-
(7 mol %) of Cp(CO)3CrH in C6D6 under 3 atm H2 generated the
substituted cyclopentanol 16 after 3 days at 50 ꢄC. Alternatively,
treatment of 15 with a stoichiometric amount of the vanadium hy-
dride 2b gave 16 in 77% yield after 3 h at room temperature, a yield
similar to that obtained (see above) with 2b and substrates 3a and
semble a
-methylstyrene, and should be attractive recipients for Hꢀ
transfer from transition metals (recall Eq. 5). It seems likely that the
reported reaction involves Hꢀ transfer from a transient cobalt hy-
dride with a very weak Co–H bond. We have treated 9a and 9b
with 1 under H2, but obtained only the hydrogenated products 13
and 14.
These results (from treating 9a and 9b with 1/H2) imply that the
radicals 10a and 10b cyclize moreslowly than radicals 4a and 4b. The
cyclizations of 10a and 10b are plainly slower than that of 4a (which
gave only 21% hydrogenation with 1 in Eq. 11) and that of 4b (which
gave a quantitative yield of the cyclization product 6b with 1 in Eq.
12). The cause of this slow cyclization is probably the planar pyrrole
ring, which places 120ꢄ angles in the ‘5-hexenyl’ radical of 10 and
makes it difficult to form products 11 and 12 by a 5-exo-trig
pathway.47
3b. Apparently, a
which is not surprising in view of a literature report58 that
-methoxy substituent slows down the cyclization of a 6,6-Ph2-5-
b-hydroxy substituent has little influence on kcyc,
a
b
hexenyl radical by only a factor of two.
By NMR, we were able to observe four diastereomers of the
cyclopentanol 16. Jones oxidation deleted the alcohol stereocenter
and gave a separable mixture of two diastereomers, 17a and 17b, in
a 3:2 ratio (Scheme 4).
We have also changed the substituents on the trisubstituted
double bond of 15 in an effort to encourage cyclization to a six-
membered ring (‘6-endo-trig’). Cyclization of 5-hexenyl radicals is
normally slower to six-membered rings than to five-membered
ones,59 but can be encouraged by removing the two phenyl sub-
stituents from 3/15 and placing a methyl substituent on C-5 of the
radical.60,61 We have therefore prepared 18 and treated it with the
vanadium hydride 2b (Eq. 14).
2.2. Substrates from the Morita–Baylis–Hillman reaction
Additional a-substituted acrylates related to our original sub-
CH2
strates 3 are readily assembled by the Morita–Baylis–Hillman re-
action,54,55 but necessarily bear an additional hydroxyl group. For
example, diene 15 is available in 98% yield (Eq. 13) by treatment of
the known aldehyde56 5,5-diphenylpent-4-enal with methyl acry-
late and quinuclidine57 at room temperature.
HV(CO)4dppe
MeO2C
ð14Þ
CH3
CO2Me
HO
C6D6
OH
18
19
After 6 h, the acrylate methylene signal (1H NMR) of 18 was
gone, and the resulting mixture contained a single diastereomer of
the 6-endo-trig cyclization product 19 (15%) along with material
containing unreacted trisubstituted olefin (51%). The exo double
bond of 19 echoes one obtained by Breslow and co-workers (ap-
parently via a radical) after treating geranyl acetate with DBPO,
CuCl, and Cu(O2CPh)2.62 The regeneration of unsaturation in 19
Ph
Ph
Ph
Ph
quinuclidine
MeOH
CO2Me
ð13Þ
MeO2C
OHC
OH
15
Ph
Ph
Ph
Ph
Ph
a
b
Ph
MeO2C
Ph
CO2Me
16, 70%
HO
O
O
OH
15
Ph
CO2Me
CO2Me
17a
17b
Scheme 4. Synthesis of cyclopentanones 17a and 17b. (a) HV(CO)4(dppe), C6D6, 3 h; (b) CrO3, aq H2SO4, acetone.

11826
J. Hartung et al. / Tetrahedron 64 (2008) 11822–11830
suggests that it may be possible to make our cyclization reactions
catalytic in hydride even without hydrogen.
We then considered as a substrate 21, an elaboration of 18 with an
additional double bond to trap the radical formed by the initial cycli-
zation. Triene 21 contains many features of polyolefins that have given
terpene natural product substructures by radical mechanisms.63–69
Cr–H
Cp(CO3)CrH
H2
O
O
O
50 °C, C6D6
35
36
Scheme 8. Hydrogenation of 35.
37, 92%
MeO2C
The synthesis of 21 (Scheme 5) began with the addition of
isopropenyl magnesium bromide to the known69 lactol 22. The
primary alcohol of the resulting diol was protected as the silyl
ether before treatment with triethyl orthoacetate at reflux in the
presence of a catalytic amount of propionic acid. The Johnson–
Claisen product 24 was reduced to the aldehyde 25, and the latter
treated with methyl acrylate to give the alcohol 26 in a Morita–
Baylis–Hillman reaction. Alcohol 26 was protected as the methoxy
methyl ether, desilylated, and oxidized to the aldehyde 28. Wittig
olefination was then effected with E selectivity by treatment with
methyl (triphenylphosphoranylidene)acetate, giving the cycliza-
tion substrate 21.
MOMO
CO2Me
21
OTBDPS
OH
b
a
O
HO
OTBDPS
O
OEt
24
22
23
c
O
The treatment of 21 with a catalytic amount of CpCr(CO)3H
under H2 for 6 days gave the cyclization product 32 in 23% isolated
yield, presumably by the mechanism in Scheme 6. Alternatively,
treatment of 21 with a stoichiometric amount of the vanadium hy-
dride 2b gave 32 in 35% yield overnight at room temperature.
According to Scheme 6, the initial Hꢀ transfer will occur to the
OTBDPS
CO2Me
OTBDPS
f
d
MOMO
RO
e
CO2Me
O
H
28
25
26 R = H
27 R = MOM
a-substituted acrylate, giving radical 29. The 6-endo-trig cyclization
g
of 29 gives tertiary radical 30, which forms decalin 32 by intra-
molecular addition to its E double bond.
MeO2C
The resulting 32 was a mixture of one major diastereomer and
two minor ones, in the ratio 62:24:14. Deprotection, followed by
oxidation of the resulting alcohol 33 (Scheme 7), gave a 3:1 mixture
of two diastereomeric decalones 34. From this result we infer that,
while 32 contains material with different configurations at the
hydroxyl-bearing stereocenter, the resulting 34 consists of two
diastereomers with different configurations elsewhere.
A minor product of the reaction contained an exo ]CH2, sug-
gesting that Mꢀ abstracted some Hꢀ from the first cyclized radical 30
in competition with the second cyclization (to 31).
MOMO
CO2Me
21
Scheme 5. Synthesis of cyclization precursor 21. (a) (1) Isopropenylmagnesium bro-
mide, THF; (2) TBDPSCl, TEA, DMAP, CH2Cl2, 97% over two steps; (b) triethyl ortho-
acetate, propionic acid, reflux, 96%; (c) DIBAL, CH2Cl2, ꢁ78 ꢄC, 88%; (d) methyl acrylate,
quinuclidine, methanol, 81%; (e) MOMCl, DIPEA, TBAI, CH2Cl2, 70%; (f) (1) TBAF, AcOH
(aq), THF, 78%; (2) Dess–Martin periodinane, NaHCO3, CH2Cl2, 50%; (g) methyl (tri-
phenylphosphoranylidene)acetate, CH2Cl2, 76%.
2.3. Can a,b-unsaturated ketones serve as substrates?
MeO2C
MeO2C
MeO2C
Acyl substituents stabilize radicals more effectively than car-
boalkoxy ones,70 suggesting that an
-unsaturated ketone can
M–H
a,b
also serve as an Hꢀ acceptor. We therefore prepared 35 and placed it
under 3 atm H2 with a catalytic amount of the Cr hydride 1. How-
ever, the result was exclusively hydrogenationda 92% yield of the
isopropyl ketone 36 (Scheme 8).
MOMO
M–H
MOMO
MOMO
CO2Me
Me CO2Me
30
CO2Me
29
21
Presumably, the radical 36 is formed but does not cyclize before
it receives a second Hꢀ. The low kcyc of 36 probably arises from its
stability.70
CO2Me
M–H
CO2Me
3. Conclusion
MOMO
Me
MOMO
Me
CO2Me
CO2Me
CpCr(CO)3H (1) and HV(CO)4(P–P) (2) can be used to initiate
radical cyclizations by transferring Hꢀ to activated terminal olefins.
However, the resulting radical must cyclize quickly; competing
31
32
Scheme 6. Proposed mechanism for the formation of 32.
reactions include transfer of
a
second Hꢀ (resulting in
CO2Me
CO2Me
CO2Me
MeO2C
a
c
b
MOMO
MOMO
HO
O
CO2Me
34
Me CO2Me
32, 23%
Me
CO2Me
Me
CO2Me
21
33
Scheme 7. Synthesis of decalones 34 from acyclic precursor 21. (a) Cp(CO)3CrH, 7 mol %, C6D6, 50 ꢄC; (b) HCl, MeOH, 65 ꢄC; (c) CrO3, aq H2SO4, acetone.

J. Hartung et al. / Tetrahedron 64 (2008) 11822–11830
11827
hydrogenation) and removal of an Hꢀ (resulting in isomerization).
Cp(CO)3CrH (1) is relatively slow at Hꢀ transfer, but can be regen-
erated with H2 gas, enabling it to carry out reductive cyclization
catalytically; vanadium hydrides HV(CO)4(P–P) (2) are faster but
operate stoichiometrically. Substrates (1,6-dienes) can be prepared
by the Morita–Baylis–Hillman reaction of methyl acrylate with
appropriate unsaturated aldehydes. Six- as well as five-membered
rings can be formed, and a tandem cyclization to a decalin can be
effected.
material was consumed (6 days), the reaction mixture was filtered
through a silica plug and concentrated in vacuo to yield hydroge-
nated product 12 (100%, determined by NMR). 1H NMR (400 MHz,
CDCl3):
d 6.56–6.55 (1H, m), 6.08–6.09 (1H, m), 5.91–5.90 (1H, m),
5.31–5.28 (1H, m), 4.43 (2H, d, J¼6.8 Hz), 2.93–2.87 (1H, m), 1.75
(6H, s), 1.24 (6H, d, J¼6.8 Hz); HRMS (FABþ) calcd for C12H19N [M]þ:
177.1517, found 177.1514, C12H19N.
4.4. 1-(3,3-Diphenylpropyl)-2-isopropyl-1H-pyrrole (13)
4. Experimental section
The above procedure was followed with 9b (77.9 mg,
0.26 mmol), CpCr(CO)3H in C6D6 (0.038 M, 0.46 mL), and hexame-
thylcyclotrisiloxane (0.074 M, 0.21 mL) in C6D6 (1.94 mL total vol-
ume) to yield hydrogenated product 13 in 4 days (100%, determined
4.1. Materials and methods
All reactions were carried out under an atmosphere of argon in
glassware that had been flame-dried under vacuum and backfilled
with Argon. High pressure reactions were carried out in a Fisher &
Porter bottle equipped with a pressure gauge, gas inlet, and pres-
sure release valve. Unless otherwise noted, all reagents were
commercially obtained and, where appropriate, purified prior to
use. Deuterated benzene (C6D6) was purified by vacuum transfer
from sodium–benzophenone ketyl. THF, Et2O, toluene, and CH2Cl2
were dried by filtration through alumina. CpCr(CO)3H71 (1) and
HV(CO)4(P–P)72,73 (2a–d) were stored and manipulated in an inert
argon atmosphere dry box (O2 <1 ppm). CpCr(CO)3H was sublimed
prior to use. Reaction mixtures involving 1 and 2a–d were prepared
in the drybox. 1H NMR and 13C NMR spectra were recorded at
ambient temperature at 400 or 300 MHz and 100 or 75 MHz, re-
spectively, using a Bruker DRX400 or DRX 300 spectrometer. The
data are reported as follows: chemical shift in parts per million
by NMR). 1H NMR (400 MHz, CDCl3):
d 7.32–7.18 (10H, m), 6.52–
6.51 (1H, m), 6.09–6.08 (1H, m), 5.89–5.87 (1H, m), 3.89 (1H, t,
J¼15.6 Hz), 3.78–3.75 (2H, m), 2.68–2.58 (1H, m), 2.50 (2H, q,
J¼8 Hz), 1.14 (6H, d, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
d 144.3,
140.1, 129.1, 128.1, 126.9, 119.7, 107.3, 103.2, 48.9, 44.9, 37.7, 30.1,
25.7, 23.7; HRMS (FABþ) calcd for C22H25N [M]þ: 303.1987, found
303.1997, C22H25N.
4.5. Methyl 3-hydroxy-2-methylene-7,7-diphenylhept-6-
enoate (15)
Methyl acrylate (0.46 mL, 5.11 mmol), methanol (0.13 mL,
3.08 mmol), and quinuclidine (0.12 g,1.08 mmol) were added to the
known56 5,5-diphenylpent-4-enal (1.00 g, 4.24 mmol) at room
temperature. The mixture was stirred for 3 days, at which point TLC
indicated completion. Solvent was evaporated under reduced
pressure, and the crude product was subjected to flash chroma-
tography to give acrylate 15 (1.35 g, 4.18 mmol, 98%). 1H NMR
from internal tetramethylsilane on the
d scale, integration, multi-
plicity (br¼broad, s¼singlet, d¼doublet, t¼triplet, q¼quartet,
qn¼quintet, m¼multiplet), and coupling constants (Hz). High-
resolution mass spectra were acquired on a JOEL JMS-HX110 HF
mass spectrometers, and were obtained by peak matching.
(400 MHz, CDCl3):
J¼7.2 Hz), 5.71 (1H, s), 4.40–4.35 (1H, m), 3.74 (3H, s), 2.32–2.15
(2H, m), 1.87–1.70 (2H, m); 13C NMR (100 MHz, CDCl3):
167.0,
d 7.37–7.15 (10H, m), 6.16 (1H, s), 6.08 (1H, t,
d
142.7,142.4,142.2,140.1,129.9,128.9, 128.3, 128.2,127.3,127.1,127.0,
125.2, 71.1, 51.9, 36.4, 26.2; HRMS (FABþ) calcd for C21H23O3
[MþH]þ: 323.1642, found 323.1661, C21H23O3.
4.2. Methyl 2-benzhydryl-1-methylcyclopentane-
carboxylate (6a)
A stock solution of CpCr(CO)3H in C6D6 (0.05 M, 0.18 mL) was
stirred under H2 pressure as specified in the table below. After
30 min, a solution of diene substrate 3a (40 mg, 0.13 mmol) and
4.5.1. Methyl 2-benzhydryl-5-hydroxy-1-methylcy-
clopentanecarboxylate (16)
To diene 15 (10 mg, 0.031 mmol) and hexamethyltrissiloxane
hexamethylcyclotrisiloxane (0.074 M, 80
mL) in C6D6 (0.83 mL) was
(0.074 M, 23 mL) in C6D6 (1.16 mL) was added (dppe)(CO)4VH
added (1.0 mL total volume). The reaction mixture was again
pressurized with H2 according to the table below and stirred at
50 ꢄC. After NMR analysis indicated that the reaction was complete,
yields of 6a (as a pair of diastereomers) and byproducts 7a (hy-
drogenation) and 8a (isomerization) were determined from in-
tegration versus the hexamethylcyclotrisiloxane standard.
(35 mg, 0.062 mmol). The reaction mixture was set at room tem-
perature until completion (3 h) to give cyclopentanol 16 as a mix-
ture of diastereomers (70%, determined by NMR). Isolated product
from preparative runs with 7 mol% CpCr(CO)3H was characterized.
HRMS (FABþ) calcd for C21H25O3 [MþH]þ: 325.1798, found
325.1796, C21H25O3.
4.5.2. Methyl 2-benzhydryl-1-methyl-5-oxocyclopentane-
carboxylate (17)
H2 pressure (psi)
Time (days)
SM (3a) (%)
6a (%)
7a (%)
8a (%)
Jones reagent was added dropwise to a mixture of cyclopentanol
diastereomers 16 (67 mg, 0.21 mmol) dissolved in acetone
(1.75 mL) until the orange color remained. 2-Propanol was added
until the solution turned green. Water was added and the reaction
mixture was extracted with ether. The collected organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated to
give a separable mixture of cyclopentanone diastereomers 17a
(24 mg, 0.074 mmol), 17b (15 mg, 0.046 mmol, 57% combined
8
30
80
7
4
1.5
5
d
55
62
55
20
26
31
20
12
9
5
4.3. 2-Isopropyl-1-(3-methylbut-2-enyl)-1H-pyrrole (12)
A stock solution of CpCr(CO)3H in C6D6 (0.038 M, 0.51 mL) was
stirred under 80 psi of H2 for 30 min. A solution of diene 9a (50 mg,
0.29 mmol) and hexamethylcyclotrisiloxane (0.074 M, 0.21 mL) in
C6D6 (1.7 mL) was added to the reaction mixture (2.2 mL total
volume). The reaction mixture was pressurized to 80 psi of H2 and
stirred at 50 ꢄC. After NMR analysis indicated that the starting
yield). 1H NMR (400 MHz, CDCl3)
d major product: 7.37–7.16 (10H,
m), 3.76–3.73 (2H, m), 3.34 (3H, s), 2.39–2.35 (2H, m), 1.91–1.84
(1H, m), 1.54–1.52 (1H, m), 1.18 (3H, s); minor product: 7.37–7.16
(10H, m), 3.90 (1H, d, J¼15.2 Hz), 3.72 (3H, s), 3.03–2.93 (1H, m),
2.60–2.50 (1H, m), 2.33–2.20 (1H, m), 1.92–1.85 (2H, m), 0.871 (3H,
s). Proposed stereochemistry confirmed by 2D NOESY.

11828
J. Hartung et al. / Tetrahedron 64 (2008) 11822–11830
4.6. (E)-Methyl 3-hydroxy-6-methyl-2-methyleneoct-6-
enoate (18)
was brought to reflux and monitored by TLC. After 1.5 h, the
reaction mixture was cooled to room temperature, and placed
under vacuum to remove excess triethyl orthoacetate. Silica gel
chromatography of the crude mixture gave the ester 24 (2.00 g,
Methyl acrylate (0.26 mL, 2.89 mmol), methanol (73 mL, 1.80
mmol), and quinuclidine (67 mg, 0.60 mmol) were added to the
known74,75 (E)-4-methylhex-4-enal (0.27 g, 2.4 mmol). The mix-
ture was stirred for 2 days until completion based on TLC at which
point the solvents were evaporated. Flash chromatography gave the
desired acrylate 18 (0.372 g, 1.87 mmol, 78%). 1H NMR (400 MHz,
4.40 mmol, 96%). 1H NMR (400 MHz, CDCl3):
d 7.71–7.69 (4H,
m), 7.44–7.38 (6H, m), 5.17 (1H, t, J¼7.2 Hz), 4.14 (2H, q,
J¼7.2 Hz), 3.68 (2H, t, J¼6.4 Hz), 2.44–2.40 (2H, m), 2.36–2.30
(2H, m), 1.99 (2H, q, J¼7.2 Hz), 1.61 (3H, s), 2.36–2.30 (2H, m),
1.47–1.40 (2H, m), 1.26 (2H, t, J¼7.2 Hz), 1.08 (9H, s); 13C NMR
CDCl3):
d
6.19 (1H, s), 5.78 (1H, s), 5.24–5.21 (1H, m), 4.35 (1H, br),
(100 MHz, CDCl3) d 173.3, 135.4, 133.9, 133.2, 129.3, 127.4, 125.2,
3.74 (3H, s), 2.76 (1H, br), 2.10–1.98 (2H, m), 1.79–1.62 (2H, m), 1.57
63.6, 60.0, 34.5, 33.1, 32.0, 27.4, 26.7, 25.7, 19.0, 15.7, 14.1; HRMS
(FABþ) calcd for C28H41O3Si [MþH]þ: 453.2819, found 453.2819,
C28H41O3Si.
(3H, s), 1.53 (3H, d, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3):
d 167.0,
142.7, 135.2, 125.0, 119.0, 71.2, 51.9, 35.9, 34.5, 15.6, 13.4; HRMS
(FABþ) calcd for C11H19O [MþH]þ: 199.1329, found 199.1328,
C11H19O3.
4.8.4. (E)-9-(tert-Butyldiphenylsilyloxy)-4-methylnon-4-enal (25)
To a solution of ester 24 (1.25 g, 2.77 mmol) in CH2Cl2 (4.5 mL)
at ꢁ78 ꢄC was added DIBAL (1.0 M in CH2Cl2, 2.77 mL) dropwise.
When the reaction reached completion as indicated by TLC,
4.7. Methyl 6-hydroxy-1,2-dimethyl-3-methylenecyclo-
hexanecarboxylate (19)
EtOAc (10 mL) was added dropwise, followed by saturated
To diene 18 (4.3 mg, 0.023 mmol) and hexamethyltrissiloxane
(0.074 M, 18 mL) in C6D6 (1 mL) was added (dppe)(CO)4VH (28 mg,
Rochelle’s solution (4.7 mL). The mixture was stirred vigorously
overnight until two clear phases separated. The aqueous layer
was then extracted with CH2Cl2 and the collected organic layers
were washed with brine, dried over MgSO4, filtered, and con-
centrated. Silica gel purification gave the desired aldehyde 25
0.050 mmol). The reaction mixture was set at room temperature
until completion (6 h) to give cyclohexanol 19 (15%, determined by
NMR). Isolated product from preparative runs with 7 mol %
CpCr(CO)3H was characterized. 1H NMR (400 MHz, CDCl3)
d
4.89
(1.00 g, 2.45 mmol, 88%). 1H NMR (400 MHz, CDCl3):
d 9.75 (1H,
(1H, s), 4.67 (1H, s), 4.23–4.15 (1H, m), 3.75 (3H, s), 2.51 (1H, q,
J¼7.8 Hz), 2.39–2.32 (1H, m), 2.20–2.10 (1H, m), 1.90–1.82 (1H, m),
0.96 (1H, s), 0.91 (3H, d, J¼6.6 Hz); LRMS (APCIþ) found [MþH]þ:
199.1.
s), 7.68–7.65 (4H, m), 7.42–7.35 (6H, m), 5.14 (1H, t, J¼7.2 Hz),
3.65 (2H, t, J¼6.4 Hz), 2.50 (2H, t, J¼7.6 Hz), 2.31 (2H, t, J¼7.6 Hz),
1.97 (2H, q, J¼6.8 Hz), 1.54 (3H, s), 1.59–1.54 (2H, m), 1.44–1.38
(2H, m), 1.05 (9H, s).
4.8. Synthesis of tandem cyclization substrate
4.8.5. (E)-Methyl 11-(tert-butyldiphenylsilyloxy)-3-hydroxy-6-
methyl-2-methyleneundec-6-enoate (26)
4.8.1. 6-Methylhept-6-ene-1,5-diol
To the neat aldehyde 25 (260 mg, 0.64 mmol) were added
A solution of tetrahydro-2H-pyran-2-ol69 (0.81 g, 7.97 mmol) in
THF (11 mL) was added dropwise to a solution of isopropenyl-
magnesium bromide in THF (0.50 M, 28.7 mL, 14.3 mmol) at 0 ꢄC.
After 20 min, more Grignard reagent was added (0.2 equiv) and the
reaction was slowly warmed to room temperature. Upon comple-
tion as indicated by TLC, the reaction mixture was poured into
a saturated NH4Cl solution and extracted several times with ether.
The combined organic fractions were washed with brine, dried over
MgSO4, filtered, and concentrated. The crude diol was used in the
methyl acrylate (69 mL, 0.76 mmol), methanol (22 mL, 0.48 mmol),
and quinuclidine (18 mg, 0.16 mmol) at room temperature. The
mixture was stirred for 2 days until completion as indicated by TLC.
The flask was placed under vacuum to remove excess solvent and
purified by flash chromatography to yield the Baylis–Hillman ad-
duct 26 (0.26 g, 0.52 mmol, 81%). 1H NMR (400 MHz, CDCl3):
d 7.68–
7.66 (4H, m), 7.42–7.36 (6H, m), 6.24 (1H, s), 5.81 (1H, s), 5.17 (1H, t,
J¼6.8 Hz), 4.41–4.36 (1H, m), 3.78 (3H, s), 3.66 (2H, t, J¼6.4 Hz),
2.18–2.04 (2H, m),1.98 (2H, q, J¼7.2 Hz),1.83–1.68 (2H, m),1.59 (3H,
s), 1.59–1.53 (2H, m), 1.44–1.37 (2H, m), 1.05 (9H, s); 13C NMR
subsequent step. 1H NMR (400 MHz, CDCl3):
d 4.93 (1H, s), 4.83 (1H,
s), 4.06 (1H, t, J¼6.4 Hz), 3.65 (2H, t, J¼6.4 Hz),1.71 (3H, s),1.63–1.54
(100 MHz, CDCl3): d 164.5, 142.5, 135.7, 134.6, 134.3, 129.6, 127.7,
(6H, m).
125.5, 125.2, 71.6, 64.0, 52.0, 36.1, 34.6, 32.4, 27.8, 27.0, 26.1, 19.4,
16.1; HRMS (FABþ) calcd for C30H43O4Si [MþH]þ: 495.2925, found
495.2932, C30H43O4Si.
4.8.2. 7-(tert-Butyldiphenylsilyloxy)-2-methylhept-1-en-3-ol (23)
To a solution of the crude diol from above (1.37 g, 9.51 mmol) in
CH2Cl2 (10 mL) were added tert-butylchlorodiphenylsilane
(12.2 mL, 47 mmol), Et3N (6.6 mL, 47 mmol), and DMAP (60 mg,
0.50 mmol) at room temperature. The reaction mixture was stirred
and monitored by TLC until completion (3 h). The reaction mixture
was then diluted, saturated NH4Cl solution was added, and the
organic layer was separated. The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated.
Silica gel purification of the crude product gave the silyl ether 23
(2.97 g, 7.77 mmol, 97% over two steps). 1H NMR (400 MHz, CDCl3):
4.8.6. (E)-Methyl 11-(tert-butyldiphenylsilyloxy)-3-
(methoxymethoxy)-6-methyl-2-methyleneundec-6-enoate (27)
To a solution of alcohol 26 (0.50 g, 1.01 mmol) in CH2Cl2
(2 mL) were added chloromethyl methyl ether (155 mL,
2.02 mmol), diisopropylethylamine (0.485 mL, 2.53 mmol), and
[Bu4N]þIꢁ (0.186 g, 0.5 mmol) at 0 ꢄC. The reaction mixture was
stirred at 0 ꢄC for 1 h and then stirred overnight at room tem-
perature. Upon completion, the mixture was diluted with CH2Cl2
and washed with 5% NaHCO3 solution. The combined organic
fractions were washed with brine, dried over MgSO4, filtered,
and concentrated. The crude product was purified by flash
chromatography to give the methoxymethyl ether 27 (0.38 g,
d
7.68–7.65 (4H, m), 7.42–7.35 (6H, m), 4.93 (1H, s), 4.83 (1H, s), 4.04
(1H, t, J¼6.4 Hz), 3.67 (2H, t, J¼6.4 Hz), 1.71 (3H, s), 1.63–1.51 (6H,
m), 1.05 (9H, s).
0.70 mmol, 70%). 1H NMR (400 MHz, CDCl3):
d 7.68–7.65 (4H, m),
4.8.3. (E)-Ethyl 9-(tert-butyldiphenylsilyloxy)-4-methylnon-4-
enoate (24)
Five drops of propionic acid were added to a mixture of the
silyl ether 23 (1.24 g, 3.24 mmol) and triethyl orthoacetate
(3.5 mL, 19.1 mmol) at room temperature. The reaction mixture
7.42–7.35 (6H, m), 6.31 (1H, s), 5.85 (1H, s), 5.14 (1H, t, J¼6 Hz),
4.61–4.55 (2H, m), 4.49–4.44 (1H, m), 3.76 (3H, s), 3.65 (2H, t,
J¼6.3 Hz), 3.38 (3H, s), 2.14–2.03 (2H, m), 1.97 (2H, q, J¼6.9 Hz),
1.86–1.64 (2H, m), 1.57 (3H, s), 1.57–1.52 (2H, m), 1.44–1.37 (2H,
m), 1.04 (9H, s).

J. Hartung et al. / Tetrahedron 64 (2008) 11822–11830
11829
4.8.7. (E)-Methyl 11-hydroxy-3-(methoxymethoxy)-6-methyl-2-
methyleneundec-6-enoate
J¼3.2, 14.8 Hz), 1.16 (3H, s), 0.83 (3H, s); minor product: 4.57 (1H,
dd, J¼6.8, 52.4 Hz), 3.89 (1H, dd, J¼4.4, 11.6 Hz), 3.72 (3H, s), 3.67
(3H, s), 3.29 (3H, s), 2.31 (1H, dd, J¼8.4, 15.4 Hz), 1.16 (3H, s), 1.14
(3H, s).
A premixed solution of acetic acid (0.2 mL) and [Bu4N]þFꢁ
(1.0 M in THF, 3.48 mL) was added to 27 (0.38 g, 0.70 mmol) at 0 ꢄC,
and the solution allowed to stir overnight at room temperature.
Upon completion, water was added and the aqueous layer was
extracted with CH2Cl2. The collected organic fractions were washed
with 5% NaHCO3 solution, dried over MgSO4, filtered, and concen-
trated. Flash chromatography gave the free alcohol (0.16 g,
4.8.11. Methyl 2-hydroxy-5-(2-methoxy-2-oxoethyl)-1,4a-
dimethyldecahydronaphthalene-1-carboxylate (33)
One drop of concentrated HCl was added to decalin 32 (5.4 mg,
0.015 mmol) in MeOH (0.15 mL), and the vessel was heated to 65 ꢄC
until completion as indicated by TLC. The solvent was evaporated
and the crude alcohol 33 was used in the subsequent step. 1H NMR
0.54 mmol, 78%). 1H NMR (400 MHz, CDCl3):
d 6.30 (1H, s), 5.85 (1H,
s), 5.13 (1H, t, J¼7.2 Hz), 4.60–4.55 (2H, m), 4.48–4.45 (1H, m), 3.76
(3H, s), 3.38 (3H, s), 3.63 (2H, t, J¼6.6 Hz), 2.17–2.02 (4H, m), 1.90–
1.54 (4H, m), 1.44–1.37 (2H, m), 1.60 (3H, s).
(400 MHz, CDCl3)
d
major product: 3.99 (1H, dd, J¼4, 11.8 Hz), 3.70
(3H, s), 3.65 (3H, s), 2.43 (1H, dd, J¼3.2, 14.8 Hz), 1.14 (3H, s), 0.82
(3H, s); minor product: 3.92 (1H, dd, J¼5.2, 11 Hz), 3.7 (3H, s), 3.67
(3H, s), 2.32 (1H, dd, J¼8.4, 15.4 Hz), 1.12 (3H, s), 1.1 (3H, s).
4.8.8. (E)-Methyl 3-(methoxymethoxy)-6-methyl-2-methylene-11-
oxoundec-6-enoate (28)
To a solution of alcohol from above (0.16 g, 0.54 mmol) in CH2Cl2
(3.6 mL) were added NaHCO3 (68 mg, 0.81 mmol) and Dess–Martin
periodinane (0.46 g, 1.08 mmol) at room temperature. The reaction
mixture was stirred vigorously for 1.5 h and then water was added.
The organic layer was separated and the aqueous layer was
extracted with ether. The combined organic layers were separately
washed with brine, dried over MgSO4, filtered, and concentrated.
Flash chromatography gave the desired aldehyde 28 (80 mg,
0.27 mmol, 50%), along with some unreacted alcohol (19 mg). 1H
4.8.12. Methyl 5-(2-methoxy-2-oxoethyl)-1,4a-dimethyl-2-
oxodecahydronaphthalene-1-carboxylate (34)
Jones reagent was added dropwise to the crude alcohol 33
(2.1 mg) from above dissolved in acetone (0.15 mL) until the orange
color remained. 2-Propanol was added until the solution turned
green. Water was added and the reaction mixture was extracted
with ether. The collected organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated to give decalone 34
(1.3 mg, 4.1
m
mol, 70% over two steps) after preparative TLC (silica,
major product: 3.72 (3H, s),
NMR (400 MHz, CDCl3):
d
9.76 (1H, s), 6.30 (1H, s), 5.85 (1H, s), 5.13
500 d
m
m). 1H NMR (400 MHz, CDCl3)
(1H, t, J¼7.6 Hz), 4.60–4.55 (2H, m), 4.48–4.45 (1H, m), 3.76 (3H, s),
3.38 (3H, s), 2.42 (2H, t, J¼7.2 Hz), 2.18–2.11 (2H, m), 2.04 (2H, q,
J¼7.6 Hz), 1.85–1.76 (2H, m), 1.70–1.64 (2H, m), 1.59 (3H, s); 13C
3.67 (3H, s), 2.69–2.32 (4H, m), 2.03–1.65 (5H, m), 1.48–1.39 (4H,
m), 1.35 (3H, s), 0.99 (3H, s); minor product: 3.73 (3H, s), 3.68 (3H,
s), 2.69–2.32 (4H, m), 2.03–1.65 (5H, m),1.48–1.39 (4H, m),1.32 (3H,
s), 1.28 (3H, s); HRMS (FABþ) calcd for C17H27O5 [MþH]þ: 311.1853,
found 311.1871, C17H27O5.
NMR (100 MHz, CDCl3):
d 203.0, 166.7, 141.4, 135.9, 125.6, 123.7,
95.2, 74.6, 56.0, 52.0, 43.5, 35.8, 34.4, 27.6, 22.5, 16.2; HRMS (FABþ)
calcd for C16H26O5Na [MþNa]þ: 321.1672, found 321.1694,
C16H26O5Na.
4.9. (E)-N-Methoxy-N-4-dimethylhex-4-enamide
4.8.9. (2E,7E)-Dimethyl 11-(methoxymethoxy)-8-methyl-12-
methylenetrideca-2,7-dienedioate (21)
To a thin slurry of N,O-dimethylhydroxylamine hydrochloride
(1.03 g, 10.58 mmol) in CH2Cl2 (90 mL) was added dimethylalumi-
num chloride (1.0 M in CH2Cl2, 10.6 mL) at 0 ꢄC. The mixture was
stirred for 1 h while warming to room temperature. Known67 (E)-
ethyl 4-methylhex-4-enoate (0.55 g, 3.53 mmol) was added drop-
wise. After 30 min, 35 mL of phosphate buffer (pH 8) was added
and the aqueous layer was extracted with CH2Cl2. The collected
organic fractions were washed with brine, dried over MgSO4, fil-
tered, and concentrated. The crude product was used in the sub-
To aldehyde 28 (80 mg, 0.27 mmol) in CH2Cl2 (0.9 mL) was
added methyl (triphenylphosphoranylidene)acetate (90 mg, 0.27
mmol) at room temperature. The mixture was stirred overnight
until completion was indicated by TLC. Solvent was evaporated at
reduced pressure and the crude mixture was purified by pre-
parative TLC (silica, 1 mm) to give the desired acrylate 21 (73 mg,
0.21 mmol, 76%). 1H NMR (400 MHz, CDCl3):
d 7.00–6.93 (1H, m),
6.30 (1H, s), 5.85 (1H, s), 5.81 (1H, d, J¼14 Hz), 5.13 (1H, t, J¼6.8 Hz),
4.60–4.55 (2H, m), 4.48–4.45 (1H, m), 3.76 (3H, s), 3.72 (3H, s), 3.38
(3H, s), 2.19 (2H, q, J¼7.6 Hz), 2.01 (2H, q, J¼8 Hz),1.85–1.76 (2H, m),
1.70–1.62 (2H, m), 1.59 (3H, s), 1.50 (2H, qn, J¼7.2 Hz); 13C NMR
sequent step. 1H NMR (400 MHz, CDCl3):
d
5.23 (1H, q, J¼5.6 Hz),
3.66 (3H, s), 3.15 (3H, s), 2.49 (1H, t, J¼7.6 Hz), 2.27 (2H, t, J¼8.4 Hz),
1.60 (3H, s), 1.55 (1H, d, J¼6.8 Hz).
(75 MHz, CDCl3)
d
167.4, 166.6, 149.7, 141.5, 135.4, 125.5, 124.1, 121.1,
4.10. (E)-2,6-Dimethylocta-1,6-dien-3-one (35)
95.2, 74.6, 56.0, 51.9, 51.5, 35.7, 34.4, 31.8, 28.2, 27.4, 16.2; HRMS
(FABþ) calcd for C19H30O6Na [MþNa]þ: 377.1935, found 377.1941,
C19H30O6Na.
To a solution of crude Weinreb amide 10 from above in THF
(18 mL) was added isopropenylmagnesium bromide (0.5 M in THF,
14 mL) dropwise at ꢁ78 ꢄC. The reaction mixture was stirred at 0 ꢄC
until completion as indicated by TLC. Saturated NH4Cl solution was
added and the mixture was extracted with ether. The combined
organic fractions were washed with brine, dried over MgSO4, fil-
tered, and concentrated. Flash chromatography gave enone 35
(0.52 g, 3.41 mmol, 96% over two steps). 1H NMR (400 MHz, CDCl3):
4.8.10. Methyl 5-(2-methoxy-2-oxoethyl)-2-(methoxymethoxy)-
1,4a-dimethyldecahydronaphthalene-1-carboxylate (32)
A solution of CpCr(CO)3H (0.04 M in C6D6, 0.14 mL) was added to
acrylate 21 (23 mg, 0.065 mmol) in C6D6 (0.41 mL) in a Fisher &
Porter high pressure apparatus. The apparatus was charged with
30 psi H2 and placed in a heat bath at 50 ꢄC. The reaction mixture
was stirred until completion as indicated by NMR (6 days). The
solvent was evaporated and the crude product was subjected to
flash chromatography to give decalin 32 (5.4 mg, 0.015 mmol, 23%).
Alternatively, acrylate 21 (3.7 mg, 0.014 mmol) was mixed with
(dppe)(CO)4VH (12 mg, 0.028 mmol) in C6D6 (0.6 mL) overnight to
give decalin 32 (35%, determined by NMR). 1H NMR (400 MHz,
d
5.93 (1H, s), 5.73 (1H, s), 5.23–5.17 (1H, m), 2.75 (2H, t, J¼7.6 Hz),
2.26 (2H, t, J¼7.6 Hz), 1.85 (3H, s), 1.59 (3H, s), 1.54 (3H, d, J¼6.8 Hz);
13C NMR (100 MHz, CDCl3):
d 202.0, 144.6, 134.7, 124.4, 119.0, 36.4,
34.4, 17.8, 15.8, 13.4; LRMS (APCIþ) found [MþH]þ: 152.9.
4.11. (E)-2,6-Dimethyloct-6-en-3-one (37)
CDCl3)
d
major product: 4.57 (1H, dd, J¼6.8, 52.4 Hz), 3.95 (1H, dd,
A solution of CpCr(CO)3H (0.04 M in C6D6, 0.625 mL) was added
to diene 35 (55 mg, 0.36 mmol) in C6D6 in a Fisher & Porter high
J¼4.4, 12 Hz), 3.68 (3H, s), 3.66 (3H, s), 3.28 (3H, s), 2.43 (1H, dd,

11830
J. Hartung et al. / Tetrahedron 64 (2008) 11822–11830
30. The range has been estimated from
D
H for transfer from HMn(CO)5 to styrene
pressure apparatus. The apparatus was charged with 30 psi H2 and
placed in a heat bath at 50 ꢄC. The reaction mixture was stirred until
completion as indicated by NMR. The solvent was evaporated and
the crude product was subjected to flash chromatography to give
ketone 36 (51 mg, 0.33 mmol, 92%). 1H NMR (300 MHz, CDCl3)
itself, which is þ10 kcal/mol. Tang, L. H.; Papish, E. T.; Abramo, G. P.; Norton, J.
R.; Baik, M. H.; Friesner, R. A.; Rappe, A. J. Am. Chem. Soc. 2006, 128, 11314.
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d
5.23–5.17 (1H, m), 2.64–2.50 (3H, m), 2.22 (1H, t, J¼8.1 Hz), 1.59
33. Kinney, R. J.; Jones, W. D.; Bergman, R. G. J. Am. Chem. Soc. 1978, 100, 635–637.
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(3H, s), 1.55 (3H, d, J¼6.6 Hz), 1.08 (3H, d, J¼6.9 Hz); 13C NMR
(75 MHz, CDCl3):
d 214.7, 134.7, 119.0, 41.0, 39.2, 33.6, 18.4, 15.9,
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Acknowledgements
This work was supported by US Department of Energy Grant DE-
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