Stereochemical requirements of oxidative cyclizations in extended iterative organoiron-mediated routes to alkaloids

Article abstract of DOI:10.1021/jo301617f

Oxidative cyclization by reaction of benzylic and phenolic OH groups on tricarbonyl(?⁴-cyclohexa-1,3-diene)iron(0) complexes has been achieved with the hypervalent iodine oxidant PIFA which was shown to be compatible with the tricarbonyliron complex. The reaction proceeds with substrates with the nucleophilic substituent on the opposite face of the ligand to the iron. IBX gives efficient oxidation of the benzyl alcohol to the aldehyde in the presence of the Fe(CO)₃ group. Reduction of 1-arylcyclohexadienyliron(1+) complexes with sodium borohydride to access the endo series also gave a novel rearranged 2-aryl reduction product with a 5-endo OMe group. The cis relative stereochemistry of the oxidative cyclization product, the exo delivery of hydride to the 1-arylcyclohexadienyliron(1+) complex, and the 2-aryl-5-endo-methoxy relative stereochemistry of the rearranged product were proved by X-ray crystallography.

Full text of DOI:10.1021/jo301617f

Article
pubs.acs.org/joc
Stereochemical Requirements of Oxidative Cyclizations in Extended
Iterative Organoiron-Mediated Routes to Alkaloids
G. Richard Stephenson,*,† Caroline Roe,† and Christopher E. Anson‡
†School of Chemistry, University of East Anglia, Norwich NR4 7TJ, U.K.
‡Institut fur Anorganische Chemie, Karlsruhe Institute of Technology, Karlsruhe, Engesserstrasse Geb. 30.45, D-76128 Karlsruhe,
̈
Germany
S
* Supporting Information
ABSTRACT: Oxidative cyclization by reaction of benzylic and phenolic OH
groups on tricarbonyl(η4-cyclohexa-1,3-diene)iron(0) complexes has been
achieved with the hypervalent iodine oxidant PIFA which was shown to be
compatible with the tricarbonyliron complex. The reaction proceeds with
substrates with the nucleophilic substituent on the opposite face of the ligand to
the iron. IBX gives efficient oxidation of the benzyl alcohol to the aldehyde in the
presence of the Fe(CO)3 group. Reduction of 1-arylcyclohexadienyliron(1+)
complexes with sodium borohydride to access the endo series also gave a novel
rearranged 2-aryl reduction product with a 5-endo OMe group. The cis relative
stereochemistry of the oxidative cyclization product, the exo delivery of hydride to
the 1-arylcyclohexadienyliron(1+) complex, and the 2-aryl-5-endo-methoxy relative
stereochemistry of the rearranged product were proved by X-ray crystallography.
INTRODUCTION
■
We have established the strategic utility of our 1,1 iterative
strategy1 to introduce the quaternary center at the heart of the
carbon skeleton of the Amaryllidaceae alkaloids.2 This
procedure makes use of a sequence of two nucleophile
additions to chiral electrophilic cyclohexadienyliron complexes
and has been exemplified by syntheses of O-methyljouberti-
amine1a and mesembrine3 and formal total syntheses1b of
lycoramine and maritidine (for examples of these approaches to
maritidine 2 and mesembrine 3, see Figure 1). The
complementary 1,2 iterative sequence is illustrated by our
work toward hippeastrine.4 These procedures are referred to as
iterative because the same hapticity in the metal complex is
employed in each of the electrophilic intermediates.5 Each
nucleophile addition step is linked to the next by a reactivation
step which increases the hapticity from ηn to ηn+1. The metal
provides activation and stereocontrol in each iteration, and its
value in the synthesis is increased each time the series of
iterations is lengthened.
Figure 1. 1,1-Iterative strategies for the quaternary centers in
maritidine and mesembrine.
With tricarbonyliron complexes, intramolecular oxidative
cyclization followed by acid catalyzed ring-opening is an
attractive reactivation step.6−8 The cyclization produces an η4
diene complex with an allylic leaving group, which is converted
into the η5 electrophile by the ring-opening step. We describe
here an investigation of the scope and stereochemical
requirements of the oxidative cyclization in arylcyclohexadiene
complexes, with the aim of developing procedures that would
adapt our synthesis3 of mesembrine to give rapid access to the
medically important Amaryllidaceae alkaloid galanthamine 49
and shorten our synthetic route1b to maritidine (Figure 2).
RESULTS AND DISCUSSION
■
Two different classes of oxygen-centered nucleophiles [a benzyl
alcohol (in 1) and a phenolic OH (in 5) (Figure 2)] with
substantially different oxidation potentials and nucleophilicities
have been compared in this study. Either a widely applicable
Received: August 20, 2012
Published: October 15, 2012
© 2012 American Chemical Society
9684
dx.doi.org/10.1021/jo301617f | J. Org. Chem. 2012, 77, 9684−9692

The Journal of Organic Chemistry
Article
present in 1 (Figure 2) and was easily made in the racemic
series in two steps starting from “Birch’s salt”11 ( )-712 using a
diaryl cuprate reagent 6 generated from the aryllithium reagent
used in our earlier studies of the preparation of 1-
arylcyclohexadienyliron complexes. The aryllithium and copper
iodide produced the diaryl cuprate species 6 which on addition
of 2-methoxy salt 7 gave the exo adduct 8, which was taken on
to the benzyl alcohol in the presence of a small quantity of
methyl 3,4-dimethoxybenzyl ether, which was produced when
the excess diaryl cuprate was quenched with water. The alcohol
9 was obtained from 8 by a simple solvolysis procedure13 in
48% yield after purification by chromatography.
The majority of oxidative conditions used in this study
formed either the aldehyde 11 or the required cyclization
product 10, but the ferrocenium ion procedure, which had
proved very effective in the examples examined by Knolker,12
̈
failed to produce an isolable product or, when used in the
presence of sodium carbonate to control the build-up of acid,
proved unreactive (Table 1). The hypervalent iodine reagents
Table 1. Different Conditions Used in the Oxidative
Cyclization in Scheme 1
entry
reaction conditions
IBX, DMSO, rt, 2 h
product and yield
1
2
3
4
5
6
7
8
9
67% of aldehyde 11
formed aldehyde 11
a
a
MnO2, toluene, 120 °C, 3.5 h
5% FeCl3 on silica, 1 h under vac
Cp2FePF6, CH2Cl2, rt, 4 h
a
Figure 2. Use of oxidative cyclization to extend the iterative strategy
for regiodiverse structural targets such as maritidine and galanthamine.
trace of product 10
no product isolated
no reaction
Cp2FePF6, Na2CO3, CH2Cl2, rt, 12 h
DDQ, CH2Cl2, rt, 1.5 h
oxidative cyclization method or two efficient but more
specialized procedures are needed. Known oxidants from
earlier reports6−8 of oxidative cyclizations of dieneiron
complexes and new reagents have been examined in this
work. In particular, the hypervalent iodine reagent phenyliodine
bis(trifluoroacetate) (PIFA), which has been used by Ley’s
group10 to synthesize oxomaritidine, seemed an attractive
option since it is known to be compatible with other organic
functionality in the alkaloid target molecules. In order to
quickly test a range of oxidizing conditions, a model compound
9 (Scheme 1) was chosen. The substrate 9 contains the (η4-
cyclohexadiene)iron(0) complex and benzyl alcohol structures
formed aldehyde 11
a
PIFA, CH2Cl2, −40 °C, 10 min
PIFA, MeCN, −40 °C to rt, 12 h
PIFA, CF3CH2OH, −40 °C, 10 min
trace of product 10
no reaction
42% of product 10
a
Evidence from thin-layer chromatography.
behaved differently, with IBX showing selectivity for the
aldehyde 11 and PIFA producing 10. The best results with
PIFA were obtained using 2,2,2-trifluoroethanol as the solvent,
and only traces of the cyclized product were obtained in
1
dichloromethane and none at all in acetonitrile. The H NMR
spectrum of the cyclized product 10 was easily distinguished
from the starting material 9 by the loss of the signals for the
methylene group of the cyclohexadiene at 2.39 and 1.68 ppm
and the appearance of a doublet of doublets at 4.56 ppm for
new H-4a of the 4a,10b-dihydro-3,8,9-trimethoxy-6H-dibenzo-
[b,d]pyran ring system. The cis coupling constant for J4a,10b is
9.3 Hz, which is comparable to the 9 Hz cis coupling observed
after a similar oxidative cyclization by Pearson.7 The benzyl
methylene group of 9 changes from a singlet at 4.63 ppm to
two doublets at 4.47 and 4.30 ppm for H-6 in 10. The H-5
signal moves further upfield from ∼3.5 ppm in 9 to 3.12 ppm in
10, and similarly in the 13C NMR the 5-C signal moves further
upfield from 38.2 ppm in 9 to 35.4 ppm in 10. The product 10
was crystallized, and the cis ring fusion was confirmed by X-ray
crystallography.14
Scheme 1. Study of the Oxidation of the Benzyl Alcohol 9
In the phenolic series (Scheme 2, Table 2), the starting point
was the SEM-protected aryllithium reagent used in our
lycoramine formal total synthesis.1b The corresponding diaryl
cuprate reagent 12 was generated at −78 °C and reacted with
the salt 7 to give 13 in 30% yield. The SEM group was removed
without difficulty with sulfuric acid in methanol/THF to give
the desired phenol 14 in 86% yield. In practice it was more
efficient (46% overall) to combine the two reactions into a
9685
dx.doi.org/10.1021/jo301617f | J. Org. Chem. 2012, 77, 9684−9692

The Journal of Organic Chemistry
Article
nucleophile additions has been completed, the arene
substituent, which was introduced first, has been displaced to
the endo face of the ligand by the introduction of the CH2CN
side chain. The arenes are on the same side of the ring as the
metal complex in the two real examples and on the opposite
side in the model. The proposed mechanisms both involve
intramolecular nucleophile addition to the iron-bound multi-
hapto ligand, and an exo stereochemistry for this process would
be preferred. Rather than risk wasting precious material from
the two synthetic routes, it was decided to examine this
stereochemical issue with a second model compound. It was
expected that the required endo arene complexes could be
prepared by borohydride reduction of the 1-aryl-4-methoxy-
cyclohexadienyl electrophiles which were available in much
larger amounts because they are at a far earlier stage in the
routes to lycoramine and maritidine. In practice, although
eventually successful, this reduction step produced unexpected
results which raise interesting mechanistic issues.16
Scheme 2. Study of the Oxidation of the
Cyclohexadienylphenol 14
Table 2. Different Conditions Used in the Oxidative
Reduction of the methyl ether derivative 16a of 1 with
sodium borohydride in acetonitrile at 0 °C was examined first
(Scheme 3). Three products were formed, of which two were
Cyclization in Scheme 2
entry
reaction conditions
product and yield
1
2
3
4
5
6
7
MnO2, toluene, 130 °C, 20 min
MnO2, benzene, 100 °C, 2 h
10% FeCl3 on silica, 1 h
no product
a
trace of product 15
4% of product 15
no product
Scheme 3. Study of the Reduction of 1-
Arylcyclohexadienyliron Complexes (a: R = Me; b: R =
SitBuPh2; c: R = SiiPr3)
CAN, MeOH, rt, 12 h
DDQ, CH2Cl2, rt, 1 h
no reaction
PIFA, CH2Cl2, −40 °C, 10 min
PIFA, CF3CH2OH, −40 °C, 20 min
no product
b
15% of product 15
a
b
Evidence from thin-layer chromatography. See text.
single procedure, treating the crude product from the
organocuprate addition with acid for 10 min at room
temperature before working up the reaction. The hypervalent
iodine reagent PIFA again required the use of 2,2,2-
trifluoroethanol as the solvent, and the reaction was rather
less efficient than for substrate 9. In the case of 14, the product
was hard to separate from the byproduct of the reaction and
residues from PIFA itself. The 1H NMR of the cyclized product
15 differs from the starting material 14 because of the loss of
the C(6) methylene peaks at 2.40 and 1.76 ppm and the
appearance of the doublet of doublets at 5.31 ppm. This same
product (15) was obtained pure but in low yield by oxidation of
14 using FeCl3 on silica. PIFA is capable of promoting the
required cyclization under mild conditions and would be
suitable for further development as an alternative reagent for
the oxidative cyclization of tricarbonyl(η4-diene)iron(0) com-
plexes with pendant nucleophilic substituents. A supported
analogue15 of the PIFA reagent, if attachment was made at the
phenyl group, would be useful to simplify the separation of
byproduct from 15.
inseparable but appeared from their NMR spectrum to be the
expected products of i and ω hydride addition to the dienyl
ligand. These products corresponded to a 47% yield from 16a.
The 1H NMR spectra of structures of this type are characteristic
around δ = 5−6 ppm, as the 2-methoxy-5-arylcyclohexadiene
complex 18a has a single “inner” hydrogen at C(3) of the diene
and the 1-methoxy-4-arylcyclohexadiene regioisomer 17a has
two. The hydrogen at 5.26 ppm in 18a showed the typical clear
doublet of doublets from coupling to the two hydrogens at
C(1) and C(4). In 17a, the two hydrogens at δ = 5.51 and δ =
5.33 are close together in the spectrum and the coupling
between them is difficult to identify. The third product 19a was
obtained pure in 13% yield and was similar to 18a as it had a
single hydrogen (H-3) in the range δ = 5−6 ppm, coupled in
the normal fashion to H-4, but the OMe signal did not appear
in the expected position for a C(2) methoxy group. The
possibility that the ipso hydride reduction lacked stereo-
selectivity was also ruled out because the product 19a was
different to the exo adduct 8 prepared earlier as a precursor to
9. An attempt to isomerize 19a into one of the other three
The key intermediates 1 and 5 from our synthetic studies1b
were also examined with PIFA in 2,2,2-trifluoroethanol at −40
°C, conditions that had been suitable to allow oxidative
cyclization to occur in the model study. Neither case was
successful. The intermediate 5 for lycoramine proved more
sensitive than the model compound, and after only 10 min,
TLC analysis showed that complete decomposition had
occurred. With the benzyl alcohol 1, no trace of product was
observed even after 40 min. The FeCl3 oxidation was also
examined, but similarly without success.
There is an important difference between the models and
these two “real” systems. Because 1 and 5 are further advanced
in the synthetic route and the 1,1 iterative sequence of two
9686
dx.doi.org/10.1021/jo301617f | J. Org. Chem. 2012, 77, 9684−9692

The Journal of Organic Chemistry
Article
1
known products caused instead the loss of MeOH to form the
trisubstituted biaryl 20. Both OMe groups were removed in this
process, suggesting that the methoxy group on the cyclo-
hexadiene ligand was allylic or rearranged to an allylic position.
The solvolysis of the benzylic OMe is comparable to the
process that formed 9 and is consistent with our earlier
studies.13 The product 19a was crystallized and identified by X-
ray crystallography14 as the 2-aryl-5-endo-methoxy 1,3-diene
complex.
Table 4. Comparison of H Chemical Shifts for 5-H in
Epimeric 2-Methoxy-5-arylcyclohexadieneiron Complexes
entry
substituent
exo 5-H (ppm)
endo 5-H (ppm)
1
2
3
4
5
aldehyde
4.17 (11)
3.46 (8)
CH2OMe
CH2OTBDPS
CH2OTIPS
CH2OH
2.69 (18b)
2.82 (18c)
3.02 (21)
3.48 (9)
Two silyl-protected benzyl ethers 16b and 16c were available
from the maritidine project1b and were similarly reduced with
sodium borohydride in acetonitrile (Scheme 3, Table 3). Again
structures prepared in this study is certain. The novel reduction
to give the 5-endo methoxy complexes forms the expected
stereoisomer for a product of exo delivery of hydride from the
borohydride reducing agent, but the regioisomer formed cannot
be accounted for directly by acid catalyzed rearrangement of
one of the other reduction products, since this process would
deliver hydride on the endo face. Equilibration of exo and endo
methoxy products would also be required and although endo
delivery of methoxy groups is known17 under thermodynamic
control, exo endo mixtures would be expected. In none of the
examples reported here were any traces of the 5-exo methoxy
diastereoisomer identified, and the relative stereochemistry of
19b is clear from the crystallographic results. Furthermore, a
characteristic NOESY cross-peak between 3-H of the
rearranged 2-aryldiene ligand and one of the hydrogens on
the aromatic ring (see the Supporting Information) confirms
the structure of all three products 19a−c.
Table 3. Regioisomer Ratios from the Reduction of the
Ethers 16a−c
entry
starting material
product ratio 17/18/19
yield (%)
1
2
3
16a (R = Me)
45:33:22
18:50:32
9:25:66
60
40
32
16b (R = SitBuPh2)
16c (R = SiiPr3)
the unexpected rearranged 2-aryl products 19b,c were obtained
in 13−21% yield. As might be expected with a more bulky
benzyl ether, the ω hydride addition was enhanced when the
silyl group was TBDPS (substrate 16b). Fortunately, however,
the minor product was crystalline and was isolated by fractional
crystallization. The resulting crystals were of X-ray quality and
established the relative stereochemistry, which had been in
doubt because hydride addition at substituted positions on
cyclohexadienyliron complexes is known sometimes to proceed
on the endo face. The X-ray structure (see the Supporting
Information) shows that the product 18b was the required endo
aryl stereoisomer. Removal of the silyl group, however, to form
the diastereoisomer of 9, could not be achieved with TBAF,
even in refluxing THF. The problem was finally solved in the
TIPS ether series which again gave the 5-endo aryl product 18c
which although formed in low yield (the major product was the
novel rearranged 2-aryl-5-endo methoxy isomer) was obtained
pure by crystallization and was successfully converted into 21,
the diastereoisomer of 9. Fortunately, the desilylation step this
time was efficient (75% yield) and proceeded at room
temperature. A sufficient amount of the product 21 was
obtained to test the stereochemical requirements of the
oxidative cyclization. The PIFA oxidation was performed in
exactly the same way that afforded 42% yield of 10 from the exo
isomer 9. In the endo series with 21, however, no traces of a
cyclization product could be identified. It is concluded that the
oxidative cyclization of oxygen atoms present as ortho
substituents on aryl cyclohexadiene derivatives proceeds only
in the exo stereoisomer series.
CONCLUSION
■
The oxidative cyclization of benzylic and phenolic OH groups
in the 5-arylcyclohexadieneiron(0) series appears to require the
exo relative stereochemistry between the arene and the
tricarbonyliron groups, which is consistent with the possibility
of an intramolecular nucleophilic addition to the iron-bound
ligand. Reduction of 1-aryl-4-methoxycyclohexadienyliron(1+)
complexes with sodium borohydride gives 5-endo products
from hydride addition to the exo face, by the ipso (i) pathway
relative to the arene, together with the 1,4-disubstituted
product from ω addition, and a novel 2-aryl-5-endo-methoxy
rearranged product. The hypervalent iodine oxidants PIFA and
IBX are compatible with the presence of the tricarbonyliron
complex, but show different chemoselectivities. IBX is selective
for oxidation of the benzyl alcohol to the aldehyde and PIFA
oxidizes the tricarbonyliron group to effect the oxidative
cyclization. The Fe(CO)3 group, however, can be retained in
the product. Iron(III) chloride was also shown to cause
oxidative cyclization in the 5-exo-aryl series, but is less effective
than PIFA. 2,2,2-Trifluoroethanol is the solvent of choice for
PIFA-promoted oxidative cyclizations of tricarbonyl(η4-diene)-
iron(0) complexes with pendant nucleophilic heteroatom side-
chain groups.
The diastereoisomers described in this work have character-
1
istic H NMR signals for the epimeric H-5 protons. The H-5
EXPERIMENTAL SECTION
General Methods. Features. See the Supporting Information.
HRMS measurements were performed on a high-resolution double-
focusing (BE) mass spectrometer.
opposite to the tricarbonyliron group (i.e., endo arene; exo H)
consistently appears downfield from the alternative stereo-
isomer with the hydrogen on the same side of the ligand as the
metal (i.e., exo arene; endo H). In the benzyl alcohol series
where both diastereoisomers are available, the difference is clear
(Table 4, entry 5). The relative stereochemistry listed in entry 3
was proved by crystallography. In the other diastereoisomer
series, the relative stereochemistry is known from the delivery
of the aryl substituent from the organocuprate reagent in the
arylation of the 2-methoxycyclohexadienyliron starting material
7. Thus the assignment of relative stereochemistry in all the
■
( )-Tricarbonyl[(1,2,3,4-η)-5α-(4′,5′-dimethoxy-2′-methoxyme-
thylphenyl)-2-methoxy-1,3-cyclohexadiene]iron(0) (8). 4,5-Dime-
thoxy-2-methoxymethylbromobenzene18 (1.48 g, 5.69 mmol) was
dissolved in dry THF (80 mL) at −78 °C. n-Butyllithium (2.3 M in
hexanes; 2.47 mL, 5.69 mmol) was added. After 1 h at −78 °C,
copper(I) iodide (541 mg, 2.84 mmol) was added. After 1.5 h at −78
°C, the reaction mixture turned black and cyclohexadienyliron salt 711
(1.60 g, 4.06 mmol) was added, and after a further 1 h at −78 °C, the
9687
dx.doi.org/10.1021/jo301617f | J. Org. Chem. 2012, 77, 9684−9692

The Journal of Organic Chemistry
Article
reaction mixture was allowed to warm to rt overnight. The solvent was
removed under reduced pressure. Water (100 mL) was added, and the
reaction mixture was extracted into Et2O (1 × 100 mL, 3 × 50 mL).
The combined organic extracts were washed with brine (50 mL), dried
(MgSO4), filtered, and evaporated under reduced pressure to give the
crude product (1.84 g) as an orange oil. The crude oil was purified by
column chromatography over silica gel (eluting with a gradient of 2:1
to 1:1 hexanes − Et2O) to give ( )-tricarbonyl[(1,2,3,4-η)-5α-(4′,5′-
dimethoxy-2′-methoxymethylphenyl)-2-methoxy-1,3-cyclohexadiene]-
iron(0) 8 as a brown oil (1.04 g, 56%): Rf = 0.22 (1:1 Et2O −
hexanes); IR νmax/cm−1 (CDCl3) 3008 (ArH), 2955 and 2936 (CH),
IR νmax/cm−1 (CDCl3) 3010 (ArH), 2938 and 2839 (CH), 2050 and
1980 (CO), 1512 (CC); 1H NMR (400 MHz, CDCl3) δ 6.69 (s,
1 H, 10-H), 6.52 (s, 1 H, 7-H), 5.01 (dd, J = 6.3, 2.2 Hz, 1 H, 2-H),
4.56 (dd, J = 9.3, 3.7 Hz, 1 H, 4a-H), 4.47 (d, J = 14.0 Hz, 1 H, 6-H),
4.30 (d, J = 14.0 Hz, 1H, 6-H), 3.87 (s, 3H, 9-OMe), 3.84 (s, 3H, 8-
OMe), 3.64 (s, 3H, 3-OMe), 3.33 (dd, J = 3.7, 2.2 Hz, 1H, 4-H), 3.12
(dd, J = 9.3, 3.9 Hz, 1 H, 10b-H), 2.88 (dd, J = 6.3, 3.9 Hz, 1 H, 1-H);
13C NMR (75 MHz, CDCl3) δ = 210.7 (Fe-CO), 148.5 (8-C or 9-C),
147.1 (8-C or 9-C), 141.1 (3-C), 131.7 (10a-C), 126.8 (6a-C), 111.2
(10-C), 108.0 (7-C), 75.0 (2-C), 65.8 (4a-C), 62.7 (6-C), 56.0 (9-
OMe), 55.9 (8-OMe), 54.7 (3-OMe), 52.0 (4-C), 51.7 (1-C), 35.4
(10b-C); MS (EI) m/z 414 (2) [M]+, 386 (5) [M − 2CO]+, 358 (18)
[M − 3CO]+, 300 (46), 42 (100); HRMS (EI) m/z calcd for
C19H18O756Fe 414.0396, found 414.0397 [M]+.
( )-Tricarbonyl[(1,2,3,4-η)-5α-(2′-formyl-4′,5′-dimethoxyphenyl)-
2-methoxy-1,3-cyclohexadiene]iron(0) (11). Alcohol 9 (12 mg, 28.8
μmol) was dissolved in DMSO (0.2 mL). 2-Iodoxybenzoic acid (16
mg, 57.1 μmol) dissolved in DMSO (0.4 mL) was added to the
reaction mixture, which turned pink. After 2 h, 5% aqueous sodium
bicarbonate (0.5 mL) was added to the reaction mixture, which was
then extracted with Et2O (3 × 1 mL). The combined organics were
evaporated under reduced pressure to give crude product (13 mg) as a
yellow oil. The crude product was purified by column chromatography
over silica gel (eluting with 2:1 hexanes−EtOAc) to ( )-tricarbonyl-
[(1,2,3,4-η)-5α-(2′-formyl-4′,5′-dimethoxyphenyl)-2-methoxy-1,3-
cyclohexadiene]iron(0) 11 as a pale yellow oil (8 mg, 67%): Rf = 0.48
(1:1 hexanes−EtOAc); IR νmax/cm−1 (CDCl3) 3011 (ArH), 2964,
2936, and 2856 (CH), 2048 and 1977 (CO), 1673 (CO), 1599
and 1510 (CC), 1098 (CO); 1H NMR (400 MHz, CDCl3) δ 10.19
(s, 1 H, formyl CH), 7.28 (s, 1 H, 3′-H), 6.76 (s, 1 H, 6′-H), 5.22 (dd,
J = 6.4, 1.7 Hz, 1 H, 3-H), 4.17 (ddd, J = 11.0, 3.5, 3.0 Hz, 1 H, 5-H),
3.96 (s, 3 H, 5′-OMe), 3.90 (s, 3 H, 4′-OMe), 3.71 (s, 3 H, 2-OMe),
3.48 (dd, J = 3.7, 1.7 Hz, 1 H, 1-H), 2.72 (dd, J = 6.4, 3.5 Hz, 1 H, 4-
H), 2.48 (ddd, J = 15.0, 11.0, 3.7 Hz, 1 H, 6β-H), 1.73 (dd, J = 15.0,
3.0 Hz, 1H, 6α-H); 13C NMR (101 MHz, CDCl3) δ 189.4 (formyl
CH), 153.8 (5′-C), 147.5 (4′-C), 144.2 (1′-C), 140.3 (2-C), 126.4 (2′-
C), 111.1 (3′-C), 108.7 (6′-C), 66.1 (3-C), 56.0 (4′-OMe and 5′-
OMe), 54.5 (2-OMe), 54.4 (4-C), 53.0 (1-C), 36.7 (5-C), 34.6 (6-C);
MS (CI) m/z 432 (18) [M + NH4]+, 415 (100) [M + H]+, 275 (70)
[M − Fe(CO)3]+, 259 (52); HRMS (CI) m/z calcd for C19H19O756Fe
415.0475, found 415.0480 [M + H]+.
1
2044 and 1972 (CO), 1515 (CC), 1106 (CO); H NMR (400
MHz, CDCl3) δ 6.75 (s, 1 H, 6′-H), 6.66 (s, 1 H, 3′-H), 5.19 (dd, J =
6.4, 2.2 Hz, 1 H, 3-H), 4.33 (s, 2H, methoxymethyl OCH2), 3.87 (s, 3
H, 5′-OMe), 3.85 (s, 3 H, 4′-OMe), 3.70 (s, 3 H, 2-OMe), 3.50−3.42
(m, 2 H, 1-H and 5-H), 3.39 (s, 3 H, methoxymethyl OMe), 2.74 (dd,
J = 6.4, 3.6 Hz, 1 H, 4-H), 2.37 (ddd, J = 14.9, 11.0, 3.6 Hz, 1 H, 6β-
H), 1.66 (dd, J = 14.9, 2.5 Hz, 1 H, 6α-H); 13C NMR (101 MHz,
CDCl3) δ = 212.7 (Fe-CO), 148.7 (4′-C or 5′-C), 146.9 (4′-C or 5′-
C), 140.2 (2-C), 137.7 (1′-C), 127.6 (2′-C), 112.5 (6′-C), 109.5 (3′-
C), 72.6 (methoxymethyl OCH2), 66.5 (3-C), 58.1 (methoxymethyl
OMe), 56.0 (5′-OMe), 55.9 (4′-OMe), 55.8 (4-C), 54.4 (2-OMe),
53.4 (1-C), 38.5 (5-C), 34.3 (6-C); MS (EI) m/z 430 (2) [M]+, 402
(99) [M − CO]+, 374 (100) [M − 2CO]+, 346 (58) [M − 3CO]+,
223 (86); HRMS (EI) m/z calcd for C20H22O756Fe 430.0709, found
430.0707 [M]+. A trace of methyl 3,4-dimethoxybenzyl ether derived
from the excess nucleophile was visible in the NMR spectrum. The
compound was used at this state of purity for the next step to form 9
because chromatographic purification was easier at that stage.
( )-Tricarbonyl[(1,2,3,4-η)-5α-(4′,5′-dimethoxy-2′-hydroxyme-
thylphenyl)-2-methoxy-1,3-cyclohexadiene]iron(0) (9). Compound
8 (60 mg, 131 μmol) was dissolved in THF (4 mL). Aqueous HCl (2
M, 4 mL) was added to the reaction mixture, which was then heated at
reflux overnight. After cooling, water (5 mL) was added and the
mixture was extracted into Et2O (3 × 5 mL). The combined organics
were washed with brine (5 mL), dried (K2CO3), filtered and
evaporated under reduced pressure to give crude product (49 mg)
as a yellow oil. The crude oil was purified by column chromatography
over silica gel (eluting with a gradient from 2:1 to 1:1 hexanes−
EtOAc) to give ( )-tricarbonyl[(1,2,3,4-η)-5α-(4′,5′-dimethoxy-2′-
hydroxymethylphenyl)-2-methoxy-1,3-cyclohexadiene]iron(0) 9 as a
brown oil (26 mg, 48%): Rf = 0.3 (1:1 hexanes−EtOAc); IR νmax/cm−1
(CDCl3) 3482 (OH), 3006 (ArH), 2955 and 2937 (CH), 2042 and
1964 (CO), 1516 (CC), 1099 (CO); 1H NMR (400 MHz,
CDCl3) δ 6.80 (s, 1H, 6′-H), 6.68 (s, 1 H, 3′-H), 5.19 (dd, J = 6.2, 1.5
Hz, 1 H, 3-H), 4.63 (s, 2 H, hydroxymethyl OCH2), 3.88 (s, 3 H, 5′-
OMe), 3.85 (s, 3 H, 4′-OMe), 3.71 (s, 3 H, 2-OMe), 3.51−3.45 (m, 2
H, 1-H and 5-H), 2.73 (dd, J = 6.2, 3.2 Hz, 1 H, 4-H), 2.39 (ddd, J =
14.7, 11.0, 3.2 Hz, 1 H, 6β-H), 1.68 (d, J = 14.7 Hz, 1 H, 6α-H), 1.60
(br s, 1H, OH); 13C NMR (101 MHz, CDCl3): δ = 211.2 (Fe-CO),
148.6 (4′-C or 5′-C), 147.0 (4′-C or 5′-C), 140.2 (2-C), 137.2 (1′-C),
130.1 (2′-C), 111.7 (6′-C), 109.6 (3′-C), 66.2 (3-C), 62.7
(hydroxymethyl OCH2), 55.9 (5′-OMe), 55.8 (4′-OMe), 55.6 (4-
C), 54.4 (2-OMe), 53.3 (1-C), 38.2 (5-C), 34.5 (6-C); MS (EI) m/z
416 (2) [M]+, 388 (4) [M − CO]+, 360 (60) [M − 2CO]+, 332 (45)
[M − 3CO]+, 209 (100); HRMS (EI) m/z calcd for C19H20O756Fe
416.0553, found 416.0550 [M]+.
( )-Tricarbonyl[(1,2,3,4-η)-(4a,10b-dihydro-3,8,9-trimethoxy-6H-
dibenzo[b,d]pyran)]iron(0) (10). Alcohol 9 (60 mg, 144 μmol) was
dissolved in F3CCH2OH (2 mL) and cooled to −40 °C.
Phenyliodine(III) bis(trifluoroacetate) (62 mg, 144 μmol) was
added to the reaction mixture which turned brown. After 25 min of
stirring at −40 °C, more phenyliodine(III) bis(trifluoroacetate) (62
mg, 144 μmol) was added. After 1 h, the solvent was removed under
reduced pressure. The crude product was purified by column
chromatography over silica gel (eluting with a gradient of 2:1 to 1:1
hexanes−Et2O) to give ( )-tricarbonyl[(1,2,3,4-η)-(4a,10b-dihydro-
3,8,9-trimethoxy-6H-dibenzo[b,d]pyran)]iron(0) 10 (25 mg, 42%),
which was crystallized from Et2O−hexanes as colorless needles (8 mg)
for X-ray analysis: mp 142−144 °C; Rf = 0.46 (1:1 hexanes−EtOAc);
( )-Tricarbonyl[(1,2,3,4-η)-2-methoxy-5α-(3′-methoxy-2′-(2″-
trimethylsilanylethoxymethoxy)phenyl)-1,3-cyclohexadiene]iron(0)
(13). 3-Methoxy-2-(2′-trimethylsilanylethoxymethoxy)bromobenzene7
(888 mg, 2.67 mmol) was dissolved in dry THF (25 mL) at −78 °C.
n-Butyllithium (1.89 M in hexanes; 1.41 mL, 2.67 mmol) was added.
After 1 h at −78 °C, copper(I) iodide (254 mg, 1.33 mmol) was
added. After 1 h at −78 °C, the reaction mixture had turned dark gray
and cyclohexadienyliron salt 711 (525 mg, 1.33 mmol) was added, and
after a further 2 h at −78 °C, the reaction mixture was allowed to
warm to rt overnight. Water (15 mL) was added, and the mixture was
extracted into Et2O (4 × 20 mL). The combined organics were
washed with brine (20 mL), dried (MgSO4), filtered, and evaporated
under reduced pressure to give the crude product (972 mg) as a brown
oil. The crude oil was purified by column chromatography over silica
gel twice (eluting in the first column with 8:1 hexanes−Et2O, and the
second with CH2Cl2) to give ( )-tricarbonyl[(1,2,3,4-η)-2-methoxy-
5α-(3′-methoxy-2′-(2″-trimethylsilanylethoxymethoxy)phenyl)-1,3-
cyclohexadiene]iron(0) 13 as a yellow oil (201 mg, 30%): Rf = 0.38
(4:1 hexanes−Et2O); IR νmax/cm−1 (CDCl3) 3009 (ArH), 2957 and
1
2898 (CH), 2043 and 1972 (CO), 1583 (CC); H NMR (300
MHz, CDCl3) δ 6.99 (t, J = 8.0 Hz, 1 H, 5′-H), 6.72 (d, J = 8.0 Hz, 2
H, 4′-H and d, J = 8.0 Hz, 6′-H), 5.16 (dd, J = 6.5, 2.3 Hz, 1 H, 3-H),
5.09 (s, 2 H, O−CH2-O), 3.99−3.78 (m, 2 H, O−CH2), 3.80 (s, 3 H,
3′-OMe), 3.83−3.74 (m, 1 H, 5-H), 3.70 (s, 3 H, 2-OMe), 3.48 (dt, J
= 3.7, 2.3 Hz, 1 H, 1-H), 2.83 (1H, dd, J = 6.5, 3.5 Hz, 4-H), 2.39
(ddd, J = 14.9, 11.2, 3.7 Hz, 1 H, 6β-H), 1.68 (ddd, J = 14.9, 3.3, 2.3
Hz, 1 H, 6α-H), 1.03 (t, J = 8.5 Hz, 2 H, SiCH2), 0.05 (s, 9 H, SiMe3);
13C NMR (75 MHz, CDCl3) δ 211.5 (Fe-CO), 152.0 (2′-C), 144.1
(3′-C), 140.8 (2-C or 1′-C), 140.3 (2-C or 1′-C), 124.2 (5′-C), 118.7
9688
dx.doi.org/10.1021/jo301617f | J. Org. Chem. 2012, 77, 9684−9692

The Journal of Organic Chemistry
Article
(6′-C), 109.9 (4′-C), 97.4 (OCH2O), 67.4 (OCH2), 66.6 (3-C), 55.7
(4-C), 55.6 (3′-OMe), 54.3 (2-OMe), 53.7 (1-C), 35.7 (5-C), 34.0 (6-
C), 18.1 (SiCH2), −1.6 (SiMe3); MS (CI) m/z 520 (1) [M + NH4]+,
445 (1), 249 (4), 118 (14), 90 (100); HRMS (CI) m/z calcd for
C23H34O7N28Si56Fe 520.1448, found 520.1440 [M + NH4]+.
Hz, 1 H, 4-H), 2.97 (dd, J = 6.5, 4.3 Hz, 1 H, 1-H); 13C NMR (101
MHz, CDCl3) δ 147.2 (5a-C or 6-C), 144.4 (5a-C or 6-C), 140.1 (3-
C), 131.6 (9a-C), 120.8 (8-C), 115.7 (7-C), 111.0 (9-C), 86.9 (4a-C),
67.7 (2-C), 55.8 (6-OMe), 54.8 (3-OMe), 53.2 (4-C), 49.4 (1-C), 45.6
(9b-C); MS (EI) m/z 370 (8) [M]+, 342 (30) [M − CO]+, 286 (100)
[M − 3CO]+, 178 (32), 84 (46); HRMS (EI) m/z calcd for
C17H15O656Fe 371.0213, found 371.0211 [M + H]+.
Method ii. The phenol 14 (80 mg, 215 μmol) was dissolved and
sonicated in F3CCH2OH (4 mL) and cooled to −40 °C.
Phenyliodine(III) bis(trifluoroacetate) (111 mg, 258 μmol) in
F3CCH2OH (3 mL) was added to the reaction mixture, and the
mixture turned brown. After 20 min, the solvent was removed under
reduced pressure. The crude product was partially purified by multiple
column chromatography over silica gel (eluting the first column with a
gradient of 1:1 to 3:1 CH2Cl2−hexanes and the second column with
4:1 hexanes−Et2O) to give ( )-tricarbonyl[(1,2,3,4-η)-(3,6-dime-
thoxy-4a,9b-dihydrodibenzofuran)]iron(0) 15 (12 mg, 15%), data
for which matched the spectral data from method i except for some
inseparable impurities.
( )-Tricarbonyl[(1,2,3,4-η)-5α-(2′-hydroxy-3′-methoxyphenyl)-2-
methoxy-1,3-cyclohexadiene]iron(0) (14). Method i. Compound 13
(200 mg, 398 μmol) was dissolved in THF (10 mL) and CH3OH (10
mL). Concentrated H2SO4 (0.3 mL) in CH3OH (5 mL) was added to
the reaction mixture. After 10 min, aqueous Na2CO3 (15 mL) was
added. Solvent was evaporated from the reaction mixture under
reduced pressure, and the residue was extracted into EtOAc (3 × 25
mL). The combined organics were washed with brine (20 mL), dried
(MgSO4), filtered and evaporated under reduced pressure to give
crude product (157 mg) as a pale yellow oil. The crude oil was purified
by column chromatography over silica gel (eluting with 4:1 hexanes/
Et2O) to give ( )-tricarbonyl[(1,2,3,4-η)-5α-(2′-hydroxy-3′-methox-
yphenyl)-2-methoxy-1,3-cyclohexadiene]iron(0) 14 as a pale yellow oil
(128 mg, 86%): Rf = 0.22 (4:1 hexanes−Et2O); IR νmax/cm−1 (film)
3530 (OH), 2932 and 2844 (CH), 2034, 1960, and 1939 (CO),
( )-Tricarbonyl[(1,2,3,4-η)-2-(4′,5′-dimethoxy-2′-methoxyme-
thylphenyl)-5β-methoxy-1,3-cyclohexadiene]iron(0) (19a). ( )-Tri-
carbonyl-[(1,2,3,4,5-η)-1-(4′,5′-dimethoxy-2′-methoxymethylphenyl)-
4-methyoxycyclohexadienyl]iron(1+) tetrafluoroborate(1−) 16a1b
(700 mg, 1.36 mmol) was dissolved in dry CH3CN (10 mL) at 0
°C. Sodium borohydride (2.0 equiv, 103 mg, 2.71 mmol) was added.
After 3 h at 0 °C, more sodium borohydride (1.2 equiv, 61 mg, 1.61
mmol) was added, and after 10 min, the solvent was removed under
reduced pressure. Water (20 mL) was added, and the reaction mixture
was extracted with Et2O (4 × 20 mL). The combined organic extracts
were dried (MgSO4), filtered, and evaporated under reduced pressure
to give the crude product (663 mg) as a yellow oil. Column
chromatography (silica gel eluted with 3:2 hexanes−CH2Cl2)
affordedan inseparable mixture of dienes 17a and 18a in a ratio of
1
1614 and 1591 (CC); H NMR (400 MHz, CDCl3) δ 6.82−6.68
(m, 3 H, 4′-H, 5′-H and 6′-H), 5.71 (s, 1 H, OH), 5.18 (dd, J = 6.5,
2.3 Hz, 1 H, 3-H), 3.87 (s, 3 H, 3′-OMe), 3.69 (s, 3 H, 2-OMe), 3.61
(dt, J = 11.1, 3.5 Hz, 1 H, 5-H), 3.46 (dt, J = 3.7, 2.3 Hz, 1 H, 1-H),
2.79 (dd, J = 6.5, 3.5 Hz, 1 H, 4-H), 2.40 (ddd, J = 14.9, 11.1, 3.7 Hz, 1
H, 6β-H), 1.76 (ddd, J = 14.9, 3.5, 2.3 Hz, 1 H, 6α-H); 13C NMR (101
MHz, CDCl3) δ 211.3 (Fe-CO), 146.1 (2′-C or 3′-C), 142.8 (2′-C or
3′-C), 140.1 (2-C), 132.1 (1′-C), 119.3 (5′-C or 6′-C), 119.1 (5′-C or
6′-C), 108.2 (4′-C), 66.6 (3-C), 56.0 (3′-OMe), 54.6 (4-C), 54.3 (2-
OMe), 53.6 (1-C), 36.1 (5-C), 33.0 (6-C); MS (CI) m/z 373 (100)
[M + H]+, 305 (28), 235 (27), 233 (81); HRMS (CI) m/z calcd for
C17H17O656Fe 373.0369, found 373.0373 [M + H]+.
Method ii. 3-Methoxy-2-(2′-trimethylsilanylethoxymethoxy)-
bromobenzene7 (955 mg, 2.86 mmol) was dissolved in dry THF
(20 mL) at −78 °C. n-Butyllithium (1.89 M in hexanes; 1.52 mL, 2.86
mmol) was added. After 1 h at −78 °C, copper(I) iodide (273 mg,
1.43 mmol) was added. After 1 h at −78 °C, the reaction mixture had
turned black and cyclohexadienyliron salt 711 (564 mg, 1.43 mmol)
was added, and after a further 4 h at −78 °C, the reaction mixture was
allowed to warm to rt. CH3OH (15 mL) followed by concentrated
H2SO4 (0.5 mL) was added, causing the mixture to change from black
to green. After 10 min, concentrated sulfuric acid (0.5 mL) was added.
After 10 min, the mixture was reduced in volume by evaporation under
reduced pressure. Water (20 mL) was added, and the mixture was
extracted into EtOAc (4 × 50 mL). The combined organics were
washed with brine (25 mL), dried (MgSO4), filtered, and evaporated
under reduced pressure to give crude product (869 mg) as a brown oil.
The crude oil was purified by column chromatography over silica gel
twice (eluting with 4:1 hexanes/Et2O in the first column and 1:1
hexanes−CH2Cl2 in the second column) to give ( )-tricarbonyl-
[(1,2,3,4-η)-5α-(2′-hydroxy-3′-methoxyphenyl)-2-methoxy-1,3-
cyclohexadiene]iron(0) 14 (247 mg, 46%) as a pale yellow oil with
identical spectral data to those produced using method i.
1
1.3:1 and a combined yield of 47%. The H NMR spectrum of this
mixture confirmed their presence with a doublet of doublets at 5.26
ppm for diene 18a and two doublets at 5.51 and 5.33 ppm for diene
17a. An additional product from the first chromatographic separation
was further purified by column chromatography over silica gel (eluting
with a gradient of 4:1 hexanes−EtOAc to EtOAc) and then was
crystallized from Et2O−hexanes to give ( )-tricarbonyl[(1,2,3,4-η)-2-
(4′,5′-dimethoxy-2′-methoxymethylphenyl)-5β-methoxy-1,3-
cyclohexadiene]iron(0) 19a as yellow plates for X-ray analysis (77 mg,
13%): mp 117−119 °C; Rf = 0.25 (2:1 hexanes/EtOAc). IR νmax/cm−1
(film) 2936 and 2827 (C−H), 2037 and 1966 (CO), 1603 and
1
1518 (CC); H NMR (300 MHz, CDCl3) δ 6.95 (s, 1 H, 6′-H),
6.90 (s, 1 H, 3′-H), 5.41 (d, J = 6.8 Hz, 1 H, 3-H), 4.48 (s, 2 H,
methoxymethyl OCH2), 3.91 (s, 3 H, 4′-OMe), 3.87 (s, 3 H, 5′-OMe),
3.45−3.38 (m, 2 H, 1-H, 5-H), 3.41 (s, 3 H, methoxymethyl OMe),
3.31 (s, 3 H, 5β-OMe), 3.26 (dd, J = 6.8, 2.3 Hz, 1 H, 4-H), 2.16 (ddd,
J = 15.0, 6.7, 2.1 Hz, 1 H, 6β-H), 1.76 (ddd, J = 15.0, 3.3, 2.4 Hz, 1 H,
6α-H); 13C NMR (75 MHz, CDCl3) δ 211.0 (Fe-CO), 149.1 (4′-C or
5′-C), 148.3 (4′-C or 5′-C), 130.0 (1′-C or 2′-C), 129.2 (1′-C or 2′-
C), 114.0 (6′-C), 112.3 (3′-C), 106.5 (2-C), 86.3 (3-C), 75.4 (1-C),
72.4 (methoxymethyl OCH2), 62.1 (5-C), 61.2 (4-C), 58.2 (5β-OMe),
55.9 (4′-OMe and 5′-OMe), 55.2 (methoxymethyl OMe), 34.6 (6-C);
MS (CI) m/z 448 (1) [M+ + NH4]+, 399 (22), 246 (34), 227 (100);
HRMS (CI) m/z calcd for C20H26O7N54Fe 446.1100, found 446.1096
[M + NH4]+.
(
)-Tricarbonyl[(1,2,3,4-η)-(3,6-dimethoxy-4a,9b-
dihydrodibenzofuran)]iron(0) (15). Method i. Iron(III) chloride on
silica (10%, 3.08 g) was dried under pressure (0.03 mmHg) at 70 °C
for 6 h and then added to the phenol 14 (140 mg, 376 μmol) in dry
THF (2 mL) and evaporated under reduced pressure on a rotary
evaporator for 1 h at 30 °C. The crude product was partially purified
by column chromatography over basic alumina (eluting with Et2O) to
give a colorless solid (13 mg), which was crystallized from Et2O/
hexanes to give ( )-tricarbonyl[(1,2,3,4-η)-(3,6-dimethoxy-4a,9b-
dihydrodibenzofuran)]iron(0) 15 as cream plates (5 mg, 4%): mp
206−208 °C (decomposes); Rf = 0.24 (1:1 CH2Cl2 − hexanes). IR
νmax/cm−1 (CDCl3) 3064 and 3012 (ArH), 2929 and 2843 (CH),
2052 and 1965 (CO); 1H NMR (400 MHz, CDCl3) δ 6.77 (dd, J =
(4,5-Dimethoxybiphenyl-2-yl)methanol (20). Compound 19a (39
mg, 90.7 μmol) was dissolved in THF (2 mL). Aqueous HCl (2 M, 2
mL) was added, and the reaction mixture was heated at reflux for 5 h.
After cooling, water (2 mL) was added and the mixture was extracted
into Et2O (4 × 2 mL). The combined organics were dried (MgSO4),
filtered, and evaporated under reduced pressure to give crude product
(30 mg) as a yellow oil. The crude oil was purified by column
chromatography over silica gel (eluting with a gradient from 2:1 to 1:1
hexanes−EtOAc) to give (4,5-dimethoxybiphenyl-2-yl)methanol 20 as
a yellow oil (8 mg, 36%): Rf 0.26 (1:1 hexanes/EtOAc); IR νmax/cm−1
(CDCl3) 3484 (OH), 3058 and 3003 (ArH), 2960, 2937, and 2848
(CH), 1608 and 1517 (CC); 1H NMR (300 MHz, CDCl3) δ 7.46−
3
8.0, 7.3 Hz, 1 H, 8-H), 6.70 (dd, J = 8.0, J7,9 0.9 Hz, 1 H, 9-H), 6.66
(dd, J = 7.3, 0.9 Hz, 1 H, 7-H), 5.31 (dd, J = 10.4, 4.2 Hz, 1 H, 4a-H),
5.17 (dd, J = 6.5, 2.3 Hz, 1 H, 2-H), 3.83 (s, 3 H, 6-OMe), 3.80 (dd, J
= 10.4, 4.3 Hz, 1 H, 9b-H), 3.61 (s, 3 H, 3-OMe), 3.60 (dd, J = 4.2, 2.3
9689
dx.doi.org/10.1021/jo301617f | J. Org. Chem. 2012, 77, 9684−9692

The Journal of Organic Chemistry
Article
7.32 (m, 5 H, 8-H, 9-H, 10-H, 11-H and 12-H), 7.08 (s, 1 H, 3-H),
6.80 (s, 1 H, 6-H), 4.56 (s, 2 H, hydroxymethyl OCH2), 3.95 (s, 3 H,
4-OMe), 3.89 (s, 3 H, 5-OMe), 1.58 (s, 1 H, OH); 13C NMR (75
MHz, CDCl3) δ 148.6 (4-C or 5-C), 148.3 (4-C or 5-C), 140.7 (1′-C),
134.1 (1-C), 130.5 (2-C), 129.4 (3′-C and 5′-C), 128.3 (2′-C and 6′-
C), 127.2 (4′-C), 113.3 (3-C), 111.8 (6-C), 62.9 (hydroxymethyl
OCH2), 56.0 (4-OMe and 5-OMe); MS (EI) m/z 244 (100) [M]+,
226 (10) [M − H2O]+, 215 (17), 141 (20), 115 (16), 77 (12)
[C6H5]+; HRMS (EI) m/z calcd for C15H16O3 244.1094, found
244.1092 [M]+.
C), 86.2 (3-C), 75.4 (1-C), 63.7 (silyloxymethyl OCH), 62.2 (5-C),
61.0 (4-C), 56.0 (5′-OMe), 55.8 (4′-OMe), 55.1 (5β-OMe), 34.2 (6-
C), 26.8 (tert-Bu Mes), 19.3 (tert-Bu C); MS (CI) m/z 672 (1) [M +
NH4]+, 623 (4), 227 (100); HRMS (CI) m/z calcd for
C35H42O728SiN56Fe 672.2074, found 672.2082 [M + NH4]+.
( )-Tricarbonyl[(1,2,3,4-η)-5β-(4′,5′-dimethoxy-2′-triisopropylsi-
lanyloxymethylphenyl)-2-methoxy-1,3-cyclohexadiene]iron(0)
(18c) and ( )-Tricarbonyl[(1,2,3,4-η)-2-(4′,5′-dimethoxy-2′-triiso-
propylsilanyloxymethylphenyl)-5β-methoxy-1,3-cyclohexadiene]-
iron(0) (19c). ( )-Tricarbonyl[(1,2,3,4,5-η)-1-(4′,5′-dimethoxy-2′-trii-
sopropylsilanyloxymethylphenyl)-4-methyoxycyclohexadienyl]iron-
(1+) tetrafluoroborate(1−) 16c1b (150 mg, 228 μmol) was dissolved
in dry CH3CN (5 mL) at 0 °C. Sodium borohydride (17 mg, 456
μmol) was added. After 2 h at 0 °C, the solvent was removed under
reduced pressure. Water (10 mL) was added, and the reaction mixture
was extracted with Et2O (4 × 10 mL). The combined organic extracts
were dried (MgSO4), filtered, and evaporated under reduced pressure
to give the crude product (142 mg) as a pale yellow solid. Column
chromatography (silica gel eluted with 3:2 hexanes − CH2Cl2)
afforded inseparable mixture of dienes 17c and 18c in a ratio of 1:2.7.
The 1H NMR spectrum of the mixture of 17c and 18c confirmed their
presence with a doublet of doublets at 5.25 ppm for diene 18c and two
doublets at 5.47 and 5.32 ppm for diene 17c. The crude product was
further purified by column chromatography over silica gel (eluting
with a gradient of 3:2 hexanes−CH2Cl2 to 1:4 hexanes−CH2Cl2) and
then was crystallized from Et2O − hexanes to give ( )-tricarbonyl-
[(1,2,3,4-η)-5β-(4′,5′-dimethoxy-2′-triisopropylsilanyloxymethyl-phe-
nyl)-2-methoxy-1,3-cyclohexadiene]iron(0) 18c as pale cream flakes-
(10 mg, 8%): mp 132−134 °C dec; Rf = 0.21 (1:1 hexanes/CH2Cl2).
IR νmax/cm−1 (CDCl3) 2943 and 2867 (CH), 2045 and 1970 (CO),
1510 (CC), 1116 (CO); 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1
H, 3′-H), 7.09 (s, 1 H, 6′-H), 5.25 (d, J = 6.3 Hz, 1 H, 3-H), 4.74 (d, J
= 13.0 Hz, 1 H, silyloxymethyl OCH), 4.62 (d, J = 13.0 Hz, 1 H,
silyloxymethyl OCH), 3.94 (s, 3 H, 5′-OMe), 3.86 (s, 3 H, 4′-OMe),
3.68 (s, 3 H, 2-OMe), 3.55 (m, 1 H, 1-H), 2.82 (dd, J = 7.6, 5.7 Hz, 1
H, 5-H), 2.72 (d, J = 6.3 Hz, 1 H, 4-H), 2.35 (ddd, J = 14.4, 7.6, 2.0
Hz, 1 H, 6β-H), 1.60 (dd, J = 14.4, 5.7 Hz, 1 H, 6α-H), 1.21−1.05 (m,
3 H, CH-Si), 1.08 (d, J = 6.6 Hz, 18 H, i-Pr Me groups); 13C NMR
(101 MHz, CDCl3) δ 147.2 (4′-C or 5′-C), 146.8 (4′-C or 5′-C),
140.4 (2-C), 133.4 (1′-C or 2′-C), 131.0 (1′-C or 2′-C), 109.9 (3′-C),
109.6 (6′-C), 65.6 (3-C), 62.2 (silyloxymethyl OCH2C), 55.8 (5′-
OMe), 55.7 (4′-OMe and 1-C), 55.5 (4-C), 54.5 (2-OMe), 37.1 (6-
C), 32.9 (5-C), 18.1 (i-Pr Me groups), 12.0 (CH-Si); MS (FAB) m/z
572 (1) [M]+, 544 (2) [M − CO]+, 516 (16) [M − 2CO]+, 488 (100)
[M − 3CO]+, 343 (17), 315 (18), 259 (18), 226 (16), 173 (13);
HRMS (FAB) m/z calcd for C26H40O528Si56Fe 516.1989, found
516.1987 M − 2CO]+.
The column chromatography also yielded ( )-tricarbonyl[(1,2,3,4-
η)-2-(4′,5′-dimethoxy-2′-triisopropylsilanyloxymethylphenyl)-5β-me-
thoxy-1,3-cyclohexadiene]iron(0) (19c) as a pale yellow oil (27 mg,
21%): Rf = 0.16 (1:1 hexanes−CH2Cl2); IR νmax/cm−1 (CDCl3) 2944
and 2867 (CH), 2051 and 1988 (CO), 1608 and 1514 (CC),
1100 (CO); 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1 H, 3′-H), 6.90
(s, 1 H, 6′-H), 5.36 (d, J = 6.6 Hz, 1 H, 3-H), 4.97 (d, J = 13.0 Hz, 1
H, silyloxymethyl OCH), 4.81 (d, J = 13.0 Hz, 1 H, silyloxymethyl
OCH), 3.90 (s, 3 H, 4′-OMe), 3.87 (s, 3 H, 5′-OMe), 3.40 (d, J = 6.1
Hz, 1 H, 1-H), 3.30 (m, 1 H, 5-H), 3.26 (d, J = 6.6 Hz, 1 H, 4-H), 3.22
(s, 3 H, 5β-OMe), 2.12 (dd, J = 14.9, 6.1 Hz, 1 H, 6β-H), 1.74 (d, J =
14.9 Hz, 1 H, 6α-H), 1.21−1.08 (m, 3H, 15-H, 18-H, 21-H), 1.09 (d,
3J 6.4 Hz, 18H, 16-H3, 17-H3, 19-H3, 20-H3, 22-H3, 23-H3); 13C NMR
(101 MHz, CDCl3) δ 210.7 (Fe-CO), 149.0 (4′-C or 5′-C), 147.2 (4′-
C or 5′-C), 133.7 (1′-C or 2′-C), 126.6 (1′-C or 2′-C), 113.5 (6′-C),
109.6 (3′-C), 106.5 (2-C), 82.3 (3-C), 75.4 (1-C), 62.9 (silylox-
ymethyl OCH), 62.1 (5-C), 60.9 (4-C), 56.0 (5′-OMe), 55.8 (4′-
OMe), 55.3 (5β-OMe), 34.5 (6-C), 18.0 (iso-Pr Mes), 12.0 (CH-Si);
MS (CI) 590 (99) [M + NH4]+, 573 (100) [M + H]+, 544 (93);
HRMS (CI) m/z calcd for C28H40O728Si54Fe 570.1934, found
570.1936 [M]+.
( )-Tricarbonyl[(1,2,3,4-η)-5β-(2′-(tert-butyldiphenylsilanyloxy-
methyl)-4′,5′-dimethoxyphenyl)-2-methoxy-1,3-cyclohexadiene]-
iron(0) (18b) and ( )-Tricarbonyl[(1,2,3,4-η)-2-(2′-(tert-butyldiphe-
nylsilanyloxymethyl)-4′,5′-dimethoxyphenyl)-5β-methoxy-1,3-
cyclohexadiene]iron(0) (19b). ( )-Tricarbonyl[(1,2,3,4,5-η)-1-(4′,5′-
dimethoxy-2′-(tert-butyl-diphenylsilanyloxymethylphenyl)-4-
methyoxycyclohexadienyl]iron(1+) tetrafluoroborate(1−) 16b1b
(1200 mg, 270 μmol) was dissolved in dry CH3CN (9 mL) at 0 °C.
Sodium borohydride (41 mg, 1.08 mmol) was added. After 2 h at 0 °C,
the solvent was removed under reduced pressure. Water (10 mL) was
added, and the reaction mixture was extracted with Et2O (3 × 15 mL).
The combined organic extracts were dried (MgSO4), filtered, and
evaporated under reduced pressure to give the crude product (149
mg) as a pale yellow oil. Column chromatography (silica gel eluted
with 3:2 hexanes−CH2Cl2) afforded inseparable dienes 17b and 18b
1
in a ratio of 1:2.8. The H NMR spectrum of the mixture of 17b and
18b confirmed their presence with a doublet of doublets at 5.13 ppm
for diene 18b and two doublets at 5.31 and 5.18 ppm for diene 17b.
The crude product was further purified by column chromatography
over silica gel (eluting with a gradient of 3:2 hexanes−CH2Cl2 to
CH2Cl2) and then was crystallized from Et2O−hexanes to give
( )-tricarbonyl[(1,2,3,4-η)-5β-(2′-(tert-butyldiphenylsilanyloxymeth-
yl)-4′,5′-dimethoxyphenyl)-2-methoxy-1,3-cyclohexadiene]iron(0)
18b as a yellow needles for X-ray analysis (35 mg, 20%): mp 97−99
°C; Rf = 0.24 (1:1 hexanes−CH2Cl2); IR νmax/cm−1 (CDCl3) 3002
(Ar−H), 2934 and 2857 (C−H), 2043 and 1967 (CO), 1609, 1589,
and 1513 (CC), 1111 (C−O); 1H NMR (300 MHz, CDCl3) δ 7.67
(dt, J = 8.0, 8 Hz, 4 H, 2Ph o-Hs), 7.48−7.34 (m, 6 H, 3Ph m-Hs, p-
Hs), 7.07 (s, 1 H, 6′-H), 7.04 (s, 1 H, 3′-H), 5.13 (dd, J = 6.7, 1.8 Hz,
1 H, 3-H), 4.67 (d, J = 12.9 Hz, 1 H, silyloxymethyl OCH), 4.57 (d, J
= 12.9 Hz, 1 H, silyloxymethyl OCH), 3.95 (s, 3 H, 5′-OMe), 3.83 (s,
3 H, 4′-OMe), 3.63 (s, 3 H, 2-OMe), 3.47 (m, 1 H, 1-H), 2.69 (dd, J =
7.7, 6.4 Hz, 1 H, 5-H), 2.61 (d, J = 6.7 Hz, 1 H, 4-H), 2.11 (ddd, J =
14.8, 7.7, 3.0 Hz, 1 H, 6β-H), 1.50 (ddd, J = 14.8, 6.4, 2.6 Hz, 1 H, 6α-
H), 1.07 (s, 9 H, tert-butyl); 13C NMR (75 MHz, CDCl3) δ 211.5 (Fe-
CO), 147.8 (4′-C or 5′-C), 146.9 (4′-C or 5′-C), 140.4 (2-C), 135.7
(2Ph o-Cs), 134.3 (1′-C8-C or 2′-C), 133.6 (2Phs C-Si), 130.5 (1′-C
or 2′-C), 129.8 (2Phs p-Cs), 127.8 (2 Phs m-Cs), 111.0 (3′-C), 109.8
(6′-C), 65.5 (3-C), 63.0 (silyloxymethyl OCH), 55.7 (1-C, 4-C, 4′-
OMe and 5′-OMe), 54.3 (2-OMe), 37.1 (6-C), 32.8 (5-C), 26.7 (t-Bu
Mes), 19.2 (t-Bu C); MS (ES) m/z 672 (2) [M + NH4]+, 591 (2), 315
(65), 64 (100); HRMS (ES) m/z calcd for C35H42O7SiNFe 672.2074,
found 672.2067 [M + NH4]+. The column chromatography also
yielded ( )-tricarbonyl[(1,2,3,4-η)-2-(2′-(tert-butyldiphenylsilanyloxy-
methyl)-4′,5′-dimethoxyphenyl)-5β-methoxy-1,3-cyclohexadiene]iron-
(0) 19b as a yellow oil (23 mg, 13%): Rf = 0.2 (1:1 hexanes/CH2Cl2);
IR νmax/cm−1 (CDCl3) 3072 (Ar−H), 2960, 2933, and 2857 (C−H),
2050, 1987, and 1968 (CO), 1608 and 1515 (CC), 1100 (C−O);
1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 8.0, 1.4 Hz, 2H, 2Phs o-
Cs), 7.63 (dd, J = 8.0, 1.4 Hz, 2Phs o-Cs), 7.48−7.33 (m, 6H, 2Phs m-
Cs and p-Cs), 7.01 (s, 1 H, 3′-H), 6.88 (s, 1 H, 6′-H), 5.27 (dd, J =
6.7, 1.8 Hz, 1 H, 3-H), 4.81 (d, J = 12.8 Hz, 1 H, silyloxymethyl
OCH), 4.71 (d, J = 12.8 Hz, 1 H, silyloxymethyl OCH), 3.88 (s, 3 H,
5′-OMe), 3.85 (s, 3 H, 4′-OMe), 3.23 (s, 3 H, 5β-OMe), 3.17−3.10
(m, 3 H, 1-H, 4-H and 5-H), 1.61 (dd, J = 15.1, 6.4 Hz, 1 H, 6β-H),
1.47 (d, J = 15.1 Hz, 1 H, 6α-H), 1.08 (s, 9 H, tert-Bu); 13C NMR
(101 MHz, CDCl3): δ = 210.7 (Fe-CO), 148.9 (4′-C or 5′-C), 147.5
(4′-C or 5′-C), 135.6 (2Ph o-Cs), 133.3 (1′-C or 2′-C), 133.0 (1′-C or
2′-C), 129.9 (2Ph p-Cs), 129.8 (2Ph p-Cs), 127.8 (2Ph m-Cs), 127.7
(2Ph m-Cs), 127.3 (2 Ph C−Si), 113.5 (6′-C), 110.4 (3′-C), 106.2 (2-
( )-Tricarbonyl[(1,2,3,4-η)-5β-(4′,5′-dimethoxy-2′-hydroxyme-
thylphenyl)-2-methoxy-1,3-cyclohexadiene]iron(0) (21). TBAF (1 M
9690
dx.doi.org/10.1021/jo301617f | J. Org. Chem. 2012, 77, 9684−9692

The Journal of Organic Chemistry
Article
in THF) (0.02 mL, 18.9 μmol) was added to compound 18c (9 mg,
15.7 μmol) dissolved in THF (0.5 mL), and the mixture was stirred at
rt for 20 min. Water (0.5 mL) was added to the reaction mixture, and
it was extracted with Et2O (3 × 0.5 mL). The combined organic layers
were evaporated under reduced pressure to give the crude product
(5.2 mg). The crude oil was purified by column chromatography over
silica gel (eluting with a gradient from 2:1 to 1:3 hexanes/EtOAc) to
give ( )-tricarbonyl[(1,2,3,4-η)-5β-(4′,5′-dimethoxy-2′-hydroxyme-
thylphenyl)-2-methoxy-1,3-cyclohexadiene]iron(0) 21 as a pale yellow
2012, 10, 4844−4846. (j) Lee, D. W.; Panley, R. K.; Lindeman, S.;
Donaldson, W. A. Org. Biomol. Chem. 2011, 9, 7742−7747. (k) Pandey,
R. K.; Wang, L.; Wallock, N. J.; Lindeman, S.; Donaldson, W. A. J. Org.
Chem. 2008, 73, 7236−7245. (l) Pearson, A. J.; Sun, H. J. Org. Chem.
2008, 73, 760−763. (m) Siddiquee, T. A.; Lukesh, J. M.; Lindeman, S.;
Donaldson, W. A. J. Org. Chem. 2007, 72, 9802−9803. (n) Pearson, A.
J.; Sun, H.; Wang, X. J. Org. Chem. 2007, 72, 2547−2557. (o) Pandey,
R. K.; Lindeman, S.; Donaldson, W. A. Eur. J. Org. Chem. 2007, 3829−
3831. (p) Wallock, N. J.; Bennett, D. W.; Siddiquee, T. A.; Haworth,
D. T.; Donaldson, W. A. Synthesis 2006, 3639−3646. (q) Chaudhury,
S.; Donaldson, W. A. J. Am. Chem. Soc. 2006, 128, 5984−5985.
(r) Pearson, A. J.; Wang, X. Tetrahedron Lett. 2005, 46, 4809−4811.
(s) Walock, N. J.; Donaldson, W. A. Org. Lett. 2005, 7, 2047−2049.
(t) Pearson, A. J.; Wang, X. Tetrahedron Lett. 2005, 46, 3123−3126.
(u) Pearson, A. J.; Ghidu, V. P. J. Org. Chem. 2004, 69, 8975−8978.
(v) Wallock, N. J.; Donaldson, W. A. J. Org. Chem. 2004, 69, 2997−
3007. (w) Pearson, A. J.; Wang, X.; Dorange, I. B. Org. Lett. 2004, 6,
2535−2538. (x) Pearson, A. J.; Wang, X. J. Am. Chem. Soc. 2003, 125,
13326−13327. (y) Pearson, A. J.; Wang, X. J. Am. Chem. Soc. 2003,
125, 638−639. (z) Frank-Neumann, M.; Geoffroy, P.; Hanss, D.
Tetrahedron Lett. 2002, 43, 2277−2280.
1
oil (5.0 mg, 75%): Rf = 0.13 (1:1 hexanes−EtOAc); H IR νmax/cm−1
(CDCl3) 3439 (OH), 3008 (ArH), 2963, 2937, and 2854 (CH), 2044
and 1966 (CO), 1609 and 1516 (CC), 1103 (CO); NMR (400
MHz, CDCl3) δ 7.14 (s, 1 H, 6′-H), 6.87 (s, 1 H, 3′-H), 5.27 (dd, J =
6.7, 2.0 Hz, 1 H, 3-H), 4.61 (d, J = 12.2 Hz, 1 H, hydroxymethyl
OCH), 4.52 (d, J = 12.2 Hz, 1 H, hydroxymethyl OCH), 3.95 (s, 3 H,
5′-OMe), 3.87 (s, 3 H, 4′-OMe), 3.67 (s, 3 H, 2-OMe), 3.57 (ddd, J =
3.1, 2.7, 2.0 Hz, 1 H, 1-H), 3.02 (dd, J = 7.9, 6.6 Hz, 1 H, 5-H), 2.70
(d, J = 6.7 Hz, 1 H, 4-H), 2.42 (ddd, J = 14.8, 7.9, 3.1 Hz, 1 H, 6β-H),
1.66 (ddd, J = 14.8, 6.6, 2.7 Hz, 1 H, 6α-H), 1.58 (s, 1H, OH); 13C
NMR (101 MHz, CDCl3) δ 211.5 (Fe-CO), 148.3 (4′-C or 5′-C),
146.8 (4′-C or 5′-C), 140.5 (2-C), 135.7 (1′-C or 2′-C), 130.1 (1′-C
or 2′-C), 111.9 (3′-C), 110.0 (6′-C), 65.5 (3-C), 62.8 (hydroxymethyl
OCH), 55.9 (4′-OMe), 55.8 (5′-OMe), 55.7 (1-C), 55.7 (4-C), 54.5
(2-OMe), 38.2 (6-C), 33.1 (5-C); MS (CI) m/z 417 (15) [M + H]+,
399 (7) [M − OH]+, 371 (18) [M − OH − CO]+, 343 (17) [M+ −
OH − 2CO], 280 (100), 261 (88); HRMS (CI) m/z calcd for
C19H21O756Fe 417.0631, found 417.0633 [M + H]+.
(2) Hoshino, O. The Amaryllidaceae alkaloids. In Alkaloids;
Academic Press: London, 1998; Vol. 51, Chapter 4, pp 382−387.
(3) Roe, C.; Sandoe, E. J.; Stephenson, G. R.; Anson, C. E.
Tetrahedron Lett. 2008, 49, 650−653.
(4) (a) Balfe, A. M.; Hughes, D. L.; Kelsey, R. D.; Stephenson, G. R.
Tetrahedron Lett. 2010, 51, 6806−6809. (b) Astley, S. T.; Stephenson,
G. R. Synlett 1992, 507−509.
ASSOCIATED CONTENT
* Supporting Information
(5) In an iterative sequence, nucleophile addition reduces hapticity
by 1 and reactivation returns the hapticity to the original value; in the
alternative, a linear sequence, nucleophile addition similarly reduces
hapticity by 1 but reactivation leaves the hapticity unchanged, so the
extent of the haptyl section of the ligand gets smaller as each
nuclephile is used. For the definition of these approaches for the
application of stoichiometric metal complexes, see ref 1b. The choice
of starting hapticity is also a crucial part of the planning process; see:
Alexander, R. P.; Morley, C.; Stephenson, G. R. J. Chem. Soc., Perkin
Trans. 1 1988, 2069−2074.
■
S
Spectroscopic data for all new compounds and X-ray data for
compounds 10, 18b, and 19a (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: g.r.stephenson@uea.ac.uk.
■
(6) (a) Martin, R.; Jager, A.; Knolker, H.-J. Synlett 2011, 2663−2666.
̈
̈
Notes
(b) Gruner, K. K.; Hopfmann, T.; Matsumoto, K.; Jager, A.; Katsuki,
̈
The authors declare no competing financial interest.
T.; Knolker, H.-J. Org. Biomol. Chem. 2011, 9, 2057−2061.
(c) Donaldson, W. A.; Chaudhury, S. Eur. J. Org. Chem. 2009,
̈
ACKNOWLEDGMENTS
■
3831−3843. (d) Knott, K. E.; Aushill, S.; Jager, A.; Knolker, H.-J.
̈
̈
We thank the EPSRC for financial support and the EPSRC
Mass Spectrometry Centre (Swansea University) for CI, FAB,
and high-resolution mass spectrometric measurements.
Chem. Commun. 2009, 1467−1469. (e) Knolker, H.-J.; Filali, S. Synlett
̈
2003, 1752−1754. (f) Knolker, E.; Baum, E.; Hopfmann, T.
̈
Tetrahedron 1999, 55, 10391−10412. (g) Donaldson, W. A. Cur.
Org. Chem. 2000, 4, 837−868. (h) Donaldson, W. A. Aldrichimica Acta
1997, 30, 17−24. (i) Knolker, H. J.; Frohner, W. Tetrahedron Lett.
̈
̈
DEDICATION
■
1996, 37, 9183−9186. (j) Pearson, A. J.; Cole, S. L.; Yoon, J.
Organometallics 1986, 5, 2075−2081. (k) Pearson, A. J.; Chandler, M.
Tetrahedron Lett. 1980, 3933−3936. (l) Birch, A. J.; Chamberlain, K.
B.; Thompson, D. J. J. Chem. Soc., Perkin Trans. 1 1973, 1900−1903.
(m) Birch, A. J.; Liepa, A. J.; Stephenson, G. R. J. Chem. Soc., Perkin
Trans. 1: 1982, 713−717. For a review of η4 Fe(CO)3 complexes in
This paper is dedicated to Professor Philip J. Parsons,
Chemistry Department, Imperial College London, to mark
his 60th birthday.
REFERENCES
■
synthesis that surveys oxidative cyclization methods, see: (n) Knolker,
̈
(1) All four possible patterns of iterative reactions (1,1, 1,2, 1,3, and
1,4) are accessible with the η5-cyclohexadienyliron series of electro-
philes: (a) Stephenson, G. R.; Finch, H.; Owen, D. A.; Swanson, S.
Tetrahedron 1993, 49, 5649−5662. (b) Stephenson, G. R.; Roe, C.;
Sandoe, E. J. Eur. J. Org. Chem. 2011, 1664−1681. For related
methodologies, see: (c) Pearson, A. J.; Fang, X. J. Org. Chem. 1997, 62,
5284−5292. (d) Gone, J. R.; Wallaock, N. J.; Lindeman, S.;
Donaldson, W. A. Tetrahedron Lett. 2009, 50, 1023−1025. (e) Li, S.;
Donaldson, W. A. Synthesis 2003, 2064−2068. (f) Pearson, A. J.; Lai,
Y. S.; Sriniavasan, K. Aust. J. Chem. 1992, 45, 109−119. (g) Pearson, A.
J.; Burello, M. P. Organometallics 1992, 11, 448−456. (h) Pearson, A.
J.; Lai, Y. S.; Lu, W.; Pinkerton, A. A. J. Org. Chem. 1989, 54, 3882−
3889. For other multiple bond-formation strategies utilizing
tricarbonyliron complexes, see (i) El-Mansey, M. F.; Sar, A.;
Chaudhury, S.; Wallock, N. J.; Donaldson, W. A. Org. Biomol. Chem.
H.-J. Chem. Soc. Rev. 1999, 28, 151−157. See also (o) Knolker, H.-J.
̈
Top. Curr. Chem. 2012, 309, 203−254. (p) Forke, R.; Gruner, K. K.;
Knott, K. E.; Aushill, S.; Agarwal, S.; Martin, R.; Bohl, M.; Richter, S.;
̈
Tsiavaliaris, G.; Fedorov, R.; Manstein, D. J.; Gutzeit, H. O.; Knolker,
̈
H.-J. Pure Appl. Chem. 2010, 82, 1975−1991. (q) Knolker, H.-J. Curr.
̈
Org. Chem. 2005, 9, 1601−1614.
(7) Pearson, A. J. Chem. Commun. 1980, 488−489.
(8) Ong, C. W.; Pearson, A. J. Tetrahedron Lett. 1980, 2349−2350.
(9) Galanthamine is approved for the treatment of early and
moderate stages of Alzheimer’s disease; see: (a) Jones, M.; Pulman, J.;
Walker, T. Chem. Ind. (London) 2011, 18−20. See also: (b) Popa, R.
V.; Pereira, E. F. R.; Lopes, C.; Maelicke, A.; Albuquerque, E. X. J. Mol.
Neurosci. 2006, 30, 227−232. (c) Lilienfield, S. CNS Drug Rev. 2002, 8,
159−176. (d) Weinstock, M. CNS Drugs 1999, 11, 307−323. For
9691
dx.doi.org/10.1021/jo301617f | J. Org. Chem. 2012, 77, 9684−9692

The Journal of Organic Chemistry
Article
examples of recent syntheses of galanthamine, see: (e) Chen, P.; Bao,
X.; Zhang, L.-F.; Ding, M.; Han, X.-J.; Li, J.; Zhang, G.-B.; Tu, Y.-Q.;
Fan, C.-A. Angew. Chem., Int. Ed. 2011, 50, 8161−8166. (f) Kato, T.;
Tanimoto, H.; Yamada, H.; Chida, N. Heterocycles 2010, 82, 563−579.
(g) Banwell, M. G.; Ma, X.; Karunaratne, O. P.; Willis, A. C. Aust. J.
Chem. 2010, 63, 1437−1447. (h) Chang, J. H.; Kang, H.-U.; Jung, I.-
H.; Cho, C.-G. Org. Lett. 2010, 12, 2016−2018. (i) Satcharoen, V.;
McLean, N. J.; Kemp, S. C.; Camp, N. P.; Brown, R. D. C. Org. Lett.
2007, 9, 1867−1869.
(17) Hine, K. E.; Johnson, B. F. G.; Lewis, J. Chem. Commun. 1975,
81−82.
(18) Khanapure, S. P.; Biehl, E. R. J. Org. Chem. 1990, 55, 1471−
1475.
(10) Ley, S. V.; Schucht, O.; Thomas, A. W.; Murray, J. P. J. Chem.
Soc., Perkin Trans. 1 1999, 1251−1252.
(11) Birch, A. J.; Chamberlain, K. B. Org. Synth. 1977, 57, 107−112.
(12) Also available in nonracemic form and of known configuration:
(a) Birch, A. J.; Raverty, W. D.; Stephenson, G. R. Chem. Commun.
1980, 857−859. For other examples of enantiomerically pure
tricarbonyliron complexes, see: (b) Ali Khan, M.; Mahon, M. F.;
Stewart, A. J. W.; Lewis, S. E. Organometallics 2010, 29, 199−204.
(c) Palframan, M. J.; Kociok-Kohn, G.; Lewis, S. E. Org. Lett. 2011, 13,
̈
3150−3153. (d) Pilgrim, S.; Kociok-Kohn, G.; Lloyd, M. D.; Lewis, S.
̈
E. Chem. Commun. 2011, 47, 4799−4801. (e) Griffen, J. A.; le Coz, A.
M.; Kociok-Kohn, G.; Ali Khan, M.; Stewart, A. J. W.; Lewis, S. E. Org.
Biomol. Chem 2011, 9, 3920−3928. (f) Ali Khan, M.; Lowe, J. P.;
Johnson, A. L.; Stewart, A. J. W.; Lewis, S. E. Chem. Commun. 2011,
̈
47, 215−217. (g) Palframan, M. J.; Kociok-Kohn, G.; Lewis, S. E.
̈
Chem.Eur. J. 2012, 18, 4766−4774. (h) Howard, P. W.; Stephenson,
G. R.; Taylor, S. C. Chem. Commun. 1990, 1182−1184. (i) Stephenson,
G. R.; Howard, P. W.; Taylor, S. C. Chem. Commun. 1991, 127−129.
Examples of the use of Birch’s salt: (j) Pearson, A. J.; Dorange, I. B. J.
Org. Chem. 2001, 66, 3140−3145. (k) Knolker, H.-J.; Baum, E.;
̈
Heininger, M. Tetrahedron Lett. 1997, 38, 8024−8021. (l) Knolker, H.-
̈
J.; Schlechtingen, G. J. Chem. Soc., Perkin Trans. 1 1997, 349−350.
(m) Birch, A. J.; Dahler, P.; Narula, A. S.; Stephenson, G. R.
Tetrahedron Lett. 1980, 21, 3817−3820.
(13) Roe, C.; Sandoe, E. J.; Stephenson, G. R. Tetrahedron Lett. 2010,
51, 591−595.
(14) Crystallographic details. 10: C19H18FeO7, 414.18 g mol−1,
monoclinic, P21/c, a = 7.2560(6) Å, b = 19.1627(17) Å, c =
12.7919(11) Å, β = 96.110(2)°, V = 1768.5(3) Å3, Z = 4, T = 100 K,
ρcalc = 1.556 g cm−3, F(000) = 856, μ(Mo Kα) = 0.893 mm−1; 12262
data, 4034 unique (Rint = 0.0287), 316 parameters, final wR2 = 0.0848,
S = 1.033 (all data), R1 (3498 data with I > 2σ(I)) = 0.0335. 18b:
C36.5H41.5FeO7Si, 676.14 g mol−1, triclinic, P-1, a = 12.145(3) Å, b =
16.906(4) Å, c = 18.104(4) Å, α = 68.923(4)°, β = 84.618(4)°, γ =
78.411(4)°, V = 3396.9(12) Å3, Z = 4, T = 100 K, ρcalc = 1.322 g cm−3,
F(000) = 1426, μ(Mo Kα) = 0.527 mm−1; 18747 data, 12286 unique
(Rint = 0.0323), 838 parameters, final wR2 = 0.1568, S = 1.016 (all
data), R1 (9176 data with I > 2σ(I)) = 0.0601. 19a: C20H22FeO7,
430.23 g mol−1, monoclinic, P21/c, a = 21.2199(13) Å, b = 10.4053(7)
Å, c = 18.6446(12) Å, β = 108.283(1)°, V = 3908.9(4) Å3, Z = 8, T =
100 K, ρcalc = 1.462 g cm−3, F(000) = 1792, μ(Mo Kα) = 0.811 mm−1;
25378 data, 8751 unique (Rint = 0.0347), 677 parameters, final wR2 =
0.0937, S = 1.031 (all data), R1 (6898 data with I > 2σ(I)) = 0.0372.
Crystallographic data (excluding structure factors) for the structures in
this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication nos. CCDC 753051−
753053. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK:
http://www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi, e-mail: data_request@
ccdc.cam.ac.uk, or fax: +44 1223 336033.
(15) Ley, S. V.; Thomas, A. W.; Finch, H. J. Chem. Soc., Perkin Trans.
1 1999, 669−671.
(16) An important point raised by a reviewer is that the unexpected
regioisomer 19 might arise via a σ,π-allyl intermediate formed by
addition of hydride to the carbon bearing the OMe group in 16.
Oxidative addition into a C−H bond at the methylene group adjacent
to the C−Fe σ bond, to from a 3-aryl-6β-methoxy[(1,2,3-η)-cyclohexa-
1,3-dien-5-yl intermediate, followed by return of the hydrogen from
the Fe to C(1), could then account for the formation of the 2-aryl-5β-
methoxy[(1,2,3,4-η)-cyclohexa-1,3-diene complex.
9692
dx.doi.org/10.1021/jo301617f | J. Org. Chem. 2012, 77, 9684−9692