Synthesis of stemofurans C, L and T using organomanganese arene chemistry; Revised structure for stemofuran L

Article abstract of DOI:10.1016/j.jorganchem.2017.09.034

The synthesis of stemofurans C, L and T was achieved using organomanganese arene complexes. The critical carbon-carbon bond between the C-2 position of benzofuran and the arene was established in a regioselective manner directed by the cationic manganese

Full text of DOI:10.1016/j.jorganchem.2017.09.034

Journal of Organometallic Chemistry 851 (2017) 218e224
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis of stemofurans C, L and T using organomanganese arene
chemistry; Revised structure for stemofuran L
,
William H. Miles a *, Cassidy M. Madison a, Christopher Y. Kim a, Daniel J. Sweitzer a,
Shelby D. Valent a, Dasan M. Thamattoor b
a Department of Chemistry, Lafayette College, Easton, PA 18042, USA
b Department of Chemistry, Colby College, Waterville, ME 04901, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of stemofurans C, L and T was achieved using organomanganese arene complexes. The
critical carbon-carbon bond between the C-2 position of benzofuran and the arene was established in a
regioselective manner directed by the cationic manganese tricarbonyl moiety. Oxidation of the resulting
dienyl complexes and cleavage of the methyl ethers gave the desired stemofuran products. The spec-
troscopic data for the originally proposed structure for stemofuran L did not match the synthesized
material, which prompted the synthesis of an isomer that did match the spectroscopic data. This revised
structure has been proposed as the correct structure for stemofuran L.
Received 28 June 2017
Received in revised form
19 September 2017
Accepted 21 September 2017
Available online 23 September 2017
Keywords:
Organomanganese arene
Stemofuran
© 2017 Elsevier B.V. All rights reserved.
Benzofuran
Nucleophile
1. Introduction
arylbenzofurans, compounds that have become increasingly
important [8e10].
Nucleophilic attack on arenes coordinated to transition metals is
one of the most important modes of reactivity in organometallic
chemistry [1]. Organomanganese arene complexes, which have
been exploited in many studies [1b,2-7], are notable for their
greater reactivity compared to the more extensively studied orga-
nochromium arene complexes [1a,1c]. The reactivity of nucleo-
Benzofurans represent a broad class of biologically important
compounds [8]. 2-Arylbenzofurans, an important subset of ben-
zofurans, have been isolated from various plants, and possess bio-
logical activity including antifungal, antibacterial, and anticancer
properties [9,10]. The Stemona genus is a particularly rich source of
2-arylbenzofurans named stemofurans. The stemofurans are char-
acterized by C-30 and C-50 oxygenation on the arene ring, and
methylation on the arene and/or benzofuran rings, with additional
oxygenation frequently occurring on the benzofuran moiety [9].
Some representative examples include stemofurans C (1a), T (1b),
and L (1c; originally proposed structure). In the course of our
synthetic studies, we suspected that 1c, the originally proposed
structure for stemofuran L, was incorrect based on the comparison
between the literature values of the NMR peaks and compound 1c
that we synthesized, and that isomeric 1d was the correct structure
(Fig. 1).
There have been many synthetic strategies employed for the
synthesis of 2-arylbenzofurans, in particular the SuzukieMiyaura
coupling of 2-(boronic acid)benzofurans with the appropriate aryl
bromide [11,12]. This method depends on ready access to the
necessary aryl bromide, which sometimes poses synthetic chal-
lenges with standard electrophilic aromatic substitution chemistry.
We recognized that a subset of stemofurans and related 2-
philes with
h
6-arene complexes, in which electron-donating
groups such as alkoxy and amino groups direct the nucleophile to
the meta-position, complements the standard electrophilic aro-
matic addition reactions to arenes [1e7]. The addition of carbon
nucleophiles to organomanganese arene complexes possessing
electron-donating substituents typically follows this pattern, but
there are a couple of noteworthy exceptions [3b,6]. Steric repulsion
inherent in more highly substituted arenes complexes (such as the
(3-methoxyestrone)Mn(CO)3þ) [3b] and/or the nature of the car-
bon nucleophile [6] leads to diminished selectivity. Even with these
potential complications, the general selectivity of these reactions
for nucleophilic attack at the meta-position to alkoxy groups sug-
gested a straightforward method for the synthesis of some 2-
* Corresponding author.
E-mail address: milesw@lafayette.edu (W.H. Miles).
https://doi.org/10.1016/j.jorganchem.2017.09.034
0022-328X/© 2017 Elsevier B.V. All rights reserved.

W.H. Miles et al. / Journal of Organometallic Chemistry 851 (2017) 218e224
219
Scheme 2. Synthesis of complexes 3.
Fig. 1. Structure of stemofurans C, L and T.
Two primary variables were explored in the addition of metal-
lated benzofuran 2 to arene complexes 3 to give
5-dienyl com-
arylbenzofurans, whose synthesis would be hampered due to the
difficulty of preparing the necessary aryl bromide starting material,
would be directly approachable using organomanganese arene
chemistry. In employing this synthetic methodology, we envi-
sioned the establishment of the critical carbon-carbon bond be-
tween C-200 and C10 by the addition of metallated benzofuran 2 to
organomanganese arene complexes 3 (Scheme 1). Although we
anticipated the addition would be directed meta by the two
methoxy groups on the arene, we also recognized that the presence
of additional methyl groups on the arene was a confounding vari-
able. This paper describes the synthesis of 2-arylbenzofurans 1a-
d as a test for this synthetic methodology, and in doing so, has
clarified the structure of stemofuran L.
h
plexes 6: solvent (Et2O, THF, CH2Cl2 and combinations thereof) and
the nature of the metal (Li or Mg). When reactions were conducted
in Et2O or THF, there was a problem achieving full conversion of the
starting material. In using the conditions we previously found most
advantageous for the synthesis of stilbenes (lithiation followed by
transmetallation with Mg(OEt2)2 [4b]), there was no reaction. The
best yields were obtained using the procedure described for the
addition of MeLi and PhLi to
The addition of lithiated benzofuran prepared in Et2O to a solution
of the
6-arene complexes 3 in CH2Cl2 gave fair to good yields
(33e85% yield) of the
5-dienyl complexes 6 (Scheme 3). Exami-
h
6-(3-methoxyestrone)Mn(CO)3þ [3b].
h
h
nation of the crude reaction mixtures indicated greater than 90%
selectivity for meta-addition of the benzofuran moiety to the two
methoxy substituents, although our analysis was hampered by the
inherent broadness of the NMR peaks of these crude products (we
2. Results and discussion
were unable to isolate and characterize any other h
5-dienyl com-
The required arenes were either commercially available (4a and
4b) or were prepared according to literature procedures (4c [13]
plexes besides 6). The major competing pathway that accounted for
some but not all of the yield loss was the decomplexation of the
arene, which led to recovery of arenes 4. Single crystal X-ray
and 4d [14]). In attempting to prepare
h
6-organomanganese ar-
ene complexes 3a and 3b by the complexation of the arene (4a and
4b) using the AgBF4/Mn(CO)5Br method, our yields were low
diffraction analysis of
h
5-dienyl complexes 6a, 6b, and 6d clearly
showed the addition of the nucleophile occurred at the meta-po-
sition to the two methoxy substituents as well as exo to manganese
(Fig. 2). The Mn(CO)3 tripod eclipsed the two methoxy substituents
(10e30%). As an alternative approach, we investigated the utility of
þ
h
6-(polyarene)Mn(CO)3 complexes as manganese tricarbonyl
transfer reagents [15]. The reaction of acenaphthene complex 5
with 1.5 equivalents of arene 4 gave excellent yields (91e96%) of
the corresponding organomanganese arene complexes 3 (Scheme
2) that were spectroscopically pure (>90%). Attempts to purify
these complexes invariably led to small amounts of decom-
plexation and decomposition, so complexes 3 were used without
purification in the next step.
and C6, an orientation typical of h
5-dienyl manganese complexes
[3b,5c]. Selected bond lengths and angles for complexes 6a, 6b, and
6d are given in Table 1.
Several oxidants have proved useful for the rearomatization and
Scheme 1. Retrosynthetic analysis.
Scheme 3. Synthesis of complexes 6.

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W.H. Miles et al. / Journal of Organometallic Chemistry 851 (2017) 218e224
Scheme 4. Oxidation of complexes 6.
Scheme 5. Synthesis of stemofuran C (1a).
[16], known to effect selective cleavage of the more hindered alkoxy
group. All of our attempts to selectively produce stemofuran T (1b)
met with failure; we invariably produced equal or greater yields of
iso-1b. Since there was also a balance between conversion and
cleavage of both methoxy groups to yield the diphenolic com-
pound, the best reaction conditions only gave a low yield of a
mixture of 1b and iso-1b (29% yield; Scheme 6). Unfortunately, we
were unable to achieve separation of the mixture either by flash
chromatography or recrystallization.
Fig. 2. X-ray crystal structures of complexes 6a, 6b, and 6d. Thermal ellipsoids shown
at 50% probability.
Table 1
Select bond lengths and angles for 6a, 6b, and 6d.
6a
6b
6d
The synthesis of 1c, reportedly isolated and identified from
Stemona curtisii [9c], was achieved by the use of BCl3, which has
been reported to be a very selective cleavage reagent in a notable
methodology study [13]. When 7c was reacted with an excess of
BCl3 for 2 days, 1c was isolated in 51% yield (Scheme 7). The crude
reaction mixture contained only 1c and unreacted 7c, indicating a
very high selectivity for the cleavage of the sterically hindered C-30
methoxy group. In examining the 1H and 13C NMR spectra of 7c,
however, there were serious inconsistencies with the reported
chemical shifts for stemofuran L as described in the original study
[9c], indicating that the structural assignment was mistaken. In
considering possible alternative structural assignments for stemo-
furan L, we hypothesized that 1d was a likely candidate based on
the spectroscopic evidence.
The synthesis of 1d was readily accomplished by the reaction
of 7d with a slight excess of BBr3, giving the desired compound 1d
(52% yield) as well as recovered 7d and a compound tentatively
identified as the diphenolic compound (Scheme 8). In examining
the 1H and 13C NMR spectra of 1d, there was good agreement
between the reported spectra for stemofuran L [9c] and 1d
(Table 2). The chemical shifts that were most diagnostic were of
the C-100 proton, the arene proton, and the methyl groups on the
2-aryl ring. The C-100 proton shifts for stemofuran L and 1d were
0.2 ppm upfield from 1c; the proton chemical shifts for the arene
proton of stemofuran L and 1d were 0.4 ppm upfield from 1c. In
the 13C NMR, the methyl groups of the 2-aryl ring exhibited a
significant 4e5 ppm difference depending on whether they were
in the C-20/C-60 or C-40 position, a comparison that held when
looking at the carbon chemical shift of the methyl groups of 7c
and 7d as well.
Bond length (Å)
C6-C1
C1-C2
C2-C3
C1-Mn
1.505(2)
1.396(2)
1.428(2)
2.1895(16)
2.1807(15)
2.1577(15)
1.515(2)
1.406(2)
1.422(2)
2.2052(14)
2.1890(14)
2.1459(14)
1.5194(19)
1.396(2)
1.4272(19)
2.2288(13)
2.1870(13)
2.1408(13)
C2-Mn
C3-Mn
Bond angle (ꢀ)
C6-C1-C2
C1-C2-C3
C20-C6-C1
Torsional angle (ꢀ)
C6-C1-C2-C3
118.59(14)
120.38(14)
115.66(14)
116.94(12)
120.33(13)
113.65(12)
117.42(12)
120.56(22)
115.93(11)
30.6(2)
30.41(19)
28.60(18)
decomplexation of h
5-dienyl manganese complexes. In using either
Jones reagent [3] or DDQ [4b], we obtained the desired products 7
but there were contamination issues that were difficult to resolve.
The reaction of 6 with ceric ammonium nitrate (CAN) [5b], how-
ever, cleanly gave 7 in good yields (58e93%; Scheme 4).
The synthesis of stemofurans 1 from dialkoxyarenes 7 requires
the cleavage of one or both of the methoxy groups to give phenolic
group(s). Several reagents have been shown to be effective for this
transformation including BBr3, BCl3, LiPPh2, and Me3SiI. In the case
of 7a, Lee [11a] used BBr3 as the cleavage reagent for the conversion
of 7a to stemofuran C (1a; 92% yield), which we verified to be an
effective reagent albeit under more vigorous conditions and in
slightly lower yields (77% yield; Scheme 5).
The synthesis of stemofuran T [9e] required the cleavage of the
methoxy group at the C-30 position of 7b, which we had hoped
would be achieved employing reagents such as BCl3 [13] and Me3SiI

W.H. Miles et al. / Journal of Organometallic Chemistry 851 (2017) 218e224
221
Scheme 6. Synthesis of stemofuran T (1b).
4. Experimental
All reactions were carried out under Ar. All glassware were dried
in the oven (110 ꢀC) before use. IR spectra were obtained on a FT-IR
spectrometer. The 1H and 13C NMR were recorded at 400 MHz and
100 MHz, respectively. All chemicals shifts in the 1H NMR are re-
ported in ppm relative toTMS (
d
¼ 0.00 ppm), CHCl3 ( ¼ 7.26 ppm),
d
or CH2Cl2 (
d
¼ 5.32 ppm), and in the 13C NMR are reported in ppm
relative to CDCl3 (
chromatography was performed on 60 Å silica gel (40e75 mm) or
d
¼ 77.16 ppm) and CH2Cl2 ( ¼ 53.84 ppm). Flash
d
Scheme 7. Synthesis of 1c.
neutral alumina. Et2O was distilled from sodium benzoketyl.
Methylene chloride and THF were dried over molecular sieves. 2,6-
dimethoxytoluene (4a) and 2,4-dimethoxytoluene (4b) were pur-
chased
from
commercial
sources.
1,5-dimethoxy-2,4-
dimethylbenzene (4d) [14] and acenaphthene complex 5 [15b]
were prepared according to the literature.
Crystals of 6a, 6b, and 6d for X-ray diffraction analysis were
prepared by slow evaporation from a heptane/Et2O solution. X-ray
data were acquired at 173 K on a Bruker D8 Quest Eco diffractom-
eter with graphite monochromated Mo
K
a
radiation
(l
¼ 0.71073 Å) and PHOTON 50™ CMOS (complementary metal-
oxide semiconductor) detector. The Bruker Apex 3 suite of pro-
grams was used to collect diffraction data [17]. The data reduction
software package Bruker SAINTþ [18] was used for to integrate the
frames with a narrow-frame algorithm and the multi-scan method
(SADABS) [19] was used to correct the data for absorption effects.
Processing of data was carried out with the Olex2 suite of programs
[20]. The Bruker SHELXTL software package [21] was used to
perform structure solution by direct methods, and refinement by
full-matrix least-squares on F2. All nonhydrogen atoms were
refined anisotropically with suggested weighting factors and the
hydrogens were calculated on a riding model. All cif files were
validated with the checkCIF/Platon facility of IUCr that was
accessed with Olex2 [20]. X-ray graphics were also produced with
Olex2 [20].
Scheme 8. Synthesis of 1d (revised structure of stemofuran L).
Table 2
Comparison of select 1H and13C chemical shifts (ppm) of stemofuran L, 1c, and 1d.
C/H
Stemofuran L [9c]
1c
1d
C-100
ArH
OCH3
ArCH3's
OCH3
H
6.63
6.83
6.63
6.51
6.92
6.52
3.82
3.78
3.88
2.01, 1.98
55.9
2.40, 2.19
55.7
2.03, 1.99
55.9
ArCH3
12.9, 12.6
13.2, 8.6
13.1, 12.7
3. Conclusion
4.1. 1,3-dimethoxy-2,4-dimethylbenzene (4c) [13]
The use of organomanganese arene complexes offers a simple
synthetic strategy to prepare many naturally occurring 2-
arylbenzofurans that is complementary to several current
methods. The synthesis of 1c and 1d, which has clarified the
structure of stemofuran L, exemplifies the power of organo-
manganese arene complexes to rapidly address issues in this field.
Although our synthetic efforts focused on the stemofurans, the use
of more substituted benzofurans and more elaborate arenes may
provide access to functionally rich 2-arylbenzofurans such as the
morusalfurans [10d] and lakoochins [10b]. The synthesis of ste-
mofuran T (1b), in which we were unsuccessful in the selective
cleavage of the methoxy groups of 7b, underscores the need to
distinguish between similar alkoxy groups earlier in the synthesis
of 1b and other related 2-arylbenzofurans.
To a stirred solution of 3-bromo-2,6-dimethoxytoluene [22]
(8.68 g, 37.6 mmol) in ether (80 mL) at ꢁ78 ꢀC was added n-BuLi
(1.6 M in hexane, 26.0 mL, 41.4 mmol) over 5 min. The reaction
mixture was stirred for 30 min at ꢁ78 ꢀC and allowed to warm to
ambient temperature over 30 min. The solution was cooled
to ꢁ78 ꢀC and methyl iodide (10 mL, 160 mmol) was added over
10 min. The solution was allowed to warm to room temperature
and stirred for 1 h. The reaction mixture was transferred with Et2O
(50 mL), washed with water (200 mL), brine (100 mL) and dried
over Na2SO4. The volatiles were removed on the rotary evaporator
to give 5.06 g (81%) of 4c as an orange oil. 1H NMR (400 MHz, CDCl3)
d
6.95 (d, J ¼ 8.1 Hz, 1H), 6.56 (d, J ¼ 8.4 Hz, 1H), 3.80 (s, 3H), 3.70 (s,
3H), 2.23 (s, 3H), 2.16 (s, 3H).

222
W.H. Miles et al. / Journal of Organometallic Chemistry 851 (2017) 218e224
4.2. General procedure for the synthesis of 3a-d
(3.22 mmol) of 3a). IR (CH2Cl2) 2011, 1929 cmꢁ1; 1H NMR (400 MHz,
CDCl3)
d
7.44 (d, J ¼ 7.0 Hz, 1H), 7.35 (d, J ¼ 8.1 Hz, 1H), 7.20 (t,
To a solution of acenaphthene complex 5 (3.80 g, 10.0 mmol) in
CH2Cl2 (50 mL) at 22 ꢀC was added arene 4 (15 mmol) in one
portion. The reaction mixture was heated to reflux for 20 h, cooled
to room temperature, and Et2O (150 mL) was added, which
precipitated 3. Complex 3 was filtered and washed with Et2O
(2 ꢂ 50 mL) to give 3 as a yellow solid. Although the complexes
were characterized by spectroscopic means, they gave unsatisfac-
tory C,H microanalysis. Attempts to purify them by recrystallization
invariably led to some decomposition, so they were used for the
next reaction as isolated from the initial reaction.
J ¼ 7.0 Hz, 1 H), 7.16 (t, J ¼ 7.2 Hz, 1H), 6.02 (s, 1H), 3.95 (t, J ¼ 6.0 Hz,
1H), 3.46 (s, 6H), 3.20 (d, J ¼ 6.2 Hz, 2H), 2.48 (s, 3H); 13C NMR
(100 MHz, CD2Cl2) d 220.9 (br),162.5,154.9,141.1,128.6,124.1,123.0,
121.1,111.4,100.7, 77.3, 55.3, 37.1, 36.6, 9.8; HRMS (DART-TOF, MHþ):
found 409.0486. C20H18MnO6 requires 409.0484.
4.3.2. 6-(2-benzofuranyl)-2,4-dimethoxy-1-
methylcyclohexadienylmanganese tricarbonyl (6b)
Yield: yellow solid (0.915 g, 66% yield based on 1.27
(3.23 mmol) of 3b). IR (CH2Cl2) 2012, 1925 cmꢁ1 1H NMR
(400 MHz, CD2Cl2)
g
;
d
7.44 (m, 1H), 7.37 (d, J ¼ 8.0 Hz, 1H) 7.23e7.13
4.2.1.
h
6-(2,6-dimethoxytoluene)manganese tricarbonyl
(m, 2H), 6.13 (s, 1H), 5.75 (d, J ¼ 1.8 Hz, 1H), 4.04 (d, J ¼ 6.2 Hz, 1H),
tetrafluoroborate (3a)
3.84 (s, 3H), 3.50 (s, 3H), 3.32 (dd, J ¼ 2.2, 6.2 Hz, 1H), 1.70 (s, 3H);
Yield: 3.63 g; 96%; IR (CH2Cl2) 2070, 2004 cmꢁ1
;
1H NMR
13C NMR (100 MHz, CD2Cl2)
d 220.1 (br), 160.8, 154.9, 140.3, 137.3,
(400 MHz, CD2Cl2)
d
6.87 (t, J ¼ 6.8 Hz, 1H), 5.99 (d, J ¼ 7.0 Hz, 2H),
128.6, 124.2, 123.0, 121.1, 111.4, 101.3, 56.1, 55.3, 55.1, 44.0, 39.1, 16.7;
HRMS (DART-TOF, MHþ): found 409.0481. C20H18MnO6 requires
409.0484.
4.10 (s, 6H), 2.22 (s, 3H); 13C NMR (100 MHz, CD2Cl2)
101.6, 89.4, 72.8, 59.0, 9.4.
d 216.2, 149.4,
4.2.2.
tetrafluoroborate (3b)
Yield: 3.58 g; 94%; IR (CH2Cl2) 2075 cmꢁ1, 1999 cmꢁ1
(400 MHz, CD2Cl2)
6.68 (d, J ¼ 7.0 Hz, 1H), 5.92 (d, J ¼ 2.2 Hz, 1H),
h
6-(2,4-dimethoxytoluene)manganese tricarbonyl
4.3.3. 6-(2-benzofuranyl)-2,4-dimethoxy-1,3-
dimethylcyclohexadienylmanganese tricarbonyl (6d)
Yield: yellow solid (0.450 g, 33% yield based on 1.313 g
;
1H NMR
d
(3.23 mmol) of 3d.) IR (CH2Cl2) 2007, 1925 cmꢁ1 1H NMR
;
5.74 (dd, J ¼ 2.2, 7.3 Hz, 1H), 4.10 (s, 3H), 4.06 (s, 3H), 2.25 (s, 3H);
(400 MHz, CDCl3)
7.21e7.12 (m, 2H), 6.12 (s, 1H), 5.60 (s, 1H), 3.96 (s, 1H), 3.84 (s, 6H),
1.70 (s, 6H); 13C NMR (100 MHz, CD2Cl2)
220.5 (br), 159.6, 154.9,
d
7.44 (d, J ¼ 7.9 Hz, 1H), 7.36 (d, J ¼ 7.9 Hz, 1H),
13C NMR (100 MHz, CD2Cl2)
72.7, 68.0, 58.6, 14.7.
d 215.5, 149.4, 148.9, 104.4, 104.3, 93.4,
d
136.0, 128.6, 124.1, 121.0, 111.4, 101.7, 55.3, 54.9, 51.2, 50.5, 16.6;
HRMS (DART-TOF, MHþ): found 423.0636. C21H20MnO6 requires
423.0640.
4.2.3.
h
6-(1,3-dimethoxy-2,4-dimethylbenzene)manganese
tricarbonyl terafluoroborate (3c)
Yield: 3.67 g. 94%; IR (CH2Cl2) 2071, 2009 cmꢁ1 1H NMR
;
(400 MHz, CD2Cl2)
d
6.69 (d, J ¼ 7.3 Hz, 1H), 6.03 (d, J ¼ 7.0 Hz, 1H),
4.3.4. 6-(2-benzofuranyl)-2,4-dimethoxy-3,5-
dimethylcyclohexadienylmanganese tricarbonyl (6c)
4.08 (s, 3H), 3.97 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H); 13C NMR
(100 MHz, CD2Cl2)
59.1, 15.6, 10.5.
d
215.8, 147.7, 145.8, 101.8, 100.0, 96.6, 75.1, 62.6,
To a solution of benzofuran (0.25 mL, 0.27 g, 2.3 mmol) in Et2O
(20 mL) was added n-BuLi (1.2 mL, 1.6 M, 1.9 mmol) over 5 min at
0
ꢀC and stirred for 2 h at 0 ꢀC. The lithiated benzofuran solution
4.2.4.
h
6-(1,3-dimethoxy-2,6-dimethylbenzene)manganese
was added via a cannula to a solution of 3c (0.511 g, 1.26 mmol) in
CH2Cl2 (10 mL) cooled to ꢁ78 ꢀC. The reaction was allowed to stir
at ꢁ78 ꢀC for 1 h, warmed to 0 ꢀC, and stirred for 15 min. The re-
action was quenched with water (5 mL), extracted with Et2O
(50 mL), the organic phase was washed with brine (50 mL), dried
over Na2SO4, and the volatiles were removed on the rotary evap-
orator to give the crude product. The product was dissolved in Et2O
and filtered through a plug of silica gel. Further purification by
recrystallization from petroleum ether gave 6c as a yellow solid
(0.45 g, 85% yield). IR (CH2Cl2) 2010, 1930 cmꢁ1; 1H NMR (400 MHz,
tricarbonyl terafluoroborate (3d)
Yield: 3.56 g, 91%; IR (CH2Cl2) 2065, 2001 cmꢁ1 1H NMR
;
(400 MHz, CD2Cl2)
d 6.47 (s, 1H), 6.22 (s, 1H), 4.20 (s, 6H), 2.22 (s,
6H); 13C NMR (100 MHz, CD2Cl2)
59.1, 14.8.
d 216.3, 147.8, 106.5, 91.5, 65.6,
4.3. General procedure for the synthesis of 6a, b and d
A solution of benzofuran (0.63 mL, 0.68 g, 5.7 mmol) in Et2O
(20 mL) was cooled to 0 ꢀC and n-BuLi (3.0 mL,1.6 M, 4.8 mmol) was
added dropwise over a few minutes and allowed to stir for 2 h at
0 ꢀC. The solution of lithiated benzofuran was added to a solution of
3 (3.22 mmol) in CH2Cl2 (25 mL) cooled to ꢁ78 ꢀC. After stirring for
45 min at ꢁ78 ꢀC, the dry ice-acetone bath was removed and the
reaction mixture was allowed to warm to room temperature over
1 h. The reaction mixture was quenched with saturated NH4Cl
(20 mL), transferred to a separatory funnel with additional EtOAc
(50 mL), separated, the aqueous extracted with EtOAc (2 ꢂ 75 mL),
and the combined organic phases were washed with brine (100 mL)
and dried over Na2SO4. The volatiles were removed on the rotary
evaporator to give the crude product, which was purified by col-
umn chromatography (hexanes/25% EtOAc/hexanes) to give 6 as a
yellow solid. Further purification by recrystallization with petro-
leum ether was necessary for 6b.
CDCl3)
d
7.45 (d, J ¼ 7.9 Hz, 1H), 7.35 (d, J ¼ 7.7 Hz,1H), 7.23e7.14 (m,
2H), 6.10 (s, 1H), 3.89 (d, J ¼ 5.9 Hz, 1H), 3.63 (s, 3H), 3.42 (s, 3H),
3.14 (d, J ¼ 6.2 Hz, 1H), 2.55 (s, 3H), 1.81 (s, 3H); 13C NMR (100 MHz,
CD2Cl2)
d 223.3, 160.8, 154.8, 139.3, 136.4, 128.6, 124.2, 123.1, 121.2,
111.3, 101.0, 78.7, 62.0, 59.7, 55.2, 43.3, 35.6, 17.3, 10.2. HRMS (DART-
TOF, MHþ): found 423.0641. C21H20MnO6 requires 423.0640.
4.4. General procedure for the synthesis of 7a-d
A mixture of sodium acetate (1.20 g, 14.6 mmol) and 6a (0.600 g,
1.47 mmol) in acetone (60 mL) was stirred rapidly as ceric ammo-
nium nitrate (4.52 g, 8.24 mmol) was added in 0.2e0.4 g portions
every 5 min. The reaction was stirred until TLC indicated that all of
the starting material 6a had reacted, usually within 15e30 min. The
reaction was quenched with water (20 mL) and extracted with 1:1
mixture of hexanes:ethyl acetate (2 ꢂ 80 mL; hexanes were used
for 7b). The volatiles were removed on the rotary evaporator to give
the crude product. The crude product was redissolved in a 1:1
mixture of hexanes:ether and filtered through a plug of silica gel to
4.3.1. 6-(2-benzofuranyl)-2,4-dimethoxy-3-
methylcyclohexadienylmanganese tricarbonyl (6a)
Yield: yellow solid (0.737 g, 53% yield based on 1.266 g

W.H. Miles et al. / Journal of Organometallic Chemistry 851 (2017) 218e224
223
give 7a as a tan solid (0.353 g, 90% yield). Both compounds 7a and
7b required no further purification but flash chromatography was
necessary for 7c (hexanes/40% toluene/hexanes) and 7d
(hexanes/10% EtOAc/hexanes).
reaction mixture was quenched with water (60 mL), the phases
separated, and the aqueous phase was extracted with additional
CH2Cl2 (50 mL). The organic layers were dried over Na2SO4 and the
volatile solvents were removed on the rotary evaporator. The
resulting crude product was purified by flash chromatography
(toluene / 5% EtOAc/toluene) to give a 45:55 mixture of 1b and
iso-1b (0.131 g, 29% yield) as a white solid. For 1b: 1H NMR
4.4.1. 2-(3,5-dimethoxy-4-methylphenyl)benzofuran 7a [11a]
Yield: tan solid (0.353 g, 90% yield based on 0.600 g (1.25 mmol)
of 6a): mp 85e86 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.57 (d, J ¼ 7.7 Hz,
1H), 7.53 (d, J ¼ 8.0 Hz, 1H), 7.30e7.21 (m, 2H), 7.04 (s, 2H), 7.00 (s,
1H), 3.93 (s, 6H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3)
158.7,
(400 MHz, CDCl3)
d
7.60 (d, J ¼ 7.7 Hz, 1H), 7.51 (d, J ¼ 8.0 Hz, 1H),
7.33e7.23 (m, 2H), 6.89 (d, J ¼ 2.6 Hz, 1H), 6.87 (s, 1H), 6.48 (d,
d
J ¼ 2.6 Hz, 1H), 4.96 (s, 1H), 3.86 (s, 3H), 2.34 (s, 3H); 13C NMR
156.5, 154.8, 129.4, 128.8, 124.2, 123.0, 120.9, 115.7, 111.2, 101.0,
100.6, 56.0, 8.5.
(400 MHz, CDCl3) d 159.3, 155.5, 155.3, 154.4, 131.7, 129.2, 124.4,
123.0, 121.1, 117.5, 111.3, 106.8, 106.0, 99.4, 55.9, 13.0. For iso-1b: 1H
NMR (400 MHz, CDCl3)
d
7.60 (d, J ¼ 7.7 Hz, 1H), 7.53 (d, J ¼ 8.4 Hz,
4.4.2. 2-(3,5-dimethoxy-2-methylphenyl)benzofuran (7b)
1H), 7.33e7.23 (m, 2H), 6.95 (d, J ¼ 2.6 Hz, 1H), 6.87 (s, 1H), 6.47 (d,
Yield: yellow solid (0.312 g, 93% yield based on 0.511 g
J ¼ 2.6 Hz,1H), 5.02 (s, 1H), 3.83 (s, 3H), 2.37 (s, 3H); 13C NMR
(1.25 mmol) of 6b). IR (CH2Cl2) 1604 cmꢁ1
;
1H NMR (400 MHz,
(400 MHz, CDCl3) d 158.3, 155.1, 154.5, 154.2, 132.2, 129.1, 124.4,
CDCl3)
2H), 6.94 (d, J ¼ 2.6 Hz, 1H), 6.87 (s, 1H), 5.52 (d, J ¼ 2.2 Hz, 1H), 3.87
(s, 3H), 3.86 (s, 3H), 2.35 (s, 3H); 13C NMR (400 MHz, CDCl3)
159.0,
158.4, 155.7, 154.4, 131.5, 129.2, 124.3, 122.9, 121.1, 117.7, 111.2, 105.9,
104.0, 99.3, 55.9, 55.4, 13.0; HRMS (DART-TOF, MHþ): found
269.1178. C17H17O3 requires 269.1172.
d
7.61 (d, J ¼ 7.3 Hz,1H), 7.54 (d, J ¼ 8.1 Hz,1H), 7.32e7.22 (m,
123.9, 121.1, 114.8, 111.2, 106.3, 105.8, 102.5, 55.6, 12.8.
d
4.7. Stemofuran L (originally proposed; 1c)
To
a
solution of 2-(30,50-dimethoxy-20,40-methylbenzene)
benzofuran (11b) (62.8 mg, 0.22 mmol) in CH2Cl2 (0.5 mL) was
added BCl3 (1.0 mL,1.0 M in CH2Cl2,1.0 mmol). The reaction mixture
was stirred at room temperature for 50 h, and then the reaction was
quenched with water (10 mL). Et2O (10 mL) and NaOH (4 mL,
0.25 M) were added, the phases separated, aqueous was extracted
with additional Et2O (5 mL). The combined organic layers were
washed with HCl (5 mL, 1.0 M), dried over Na2SO4, and volatile
solvents were removed on the rotary evaporator to afford a mixture
of 1c and starting material 7c. The crude product was purified by
column chromatography (hexanes / 20% EtOAc/hexanes) to give
1c (30 mg, 51% yield) as a tan solid; mp 97e100 ꢀC. 1H NMR
4.4.3. 2-(3,5-dimethoxy-2,4-dimethylphenyl)benzofuran (7c)
Yield: white solid (0.157 g, 79% yield based on 0.300 g
(0.711 mmol) of 6c); mp 93e94 ꢀC. IR (CH2Cl2) 1604 cmꢁ1; 1H NMR
(400 MHz, CDCl3)
7.31e7.22 (m, 2H), 7.12 (s, 1H), 6.86 (s, 1H), 3.90 (s, 3H), 3.74 (s, 3H),
2.43 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3)
158.0, 156.6,
d
7.60 (d, J ¼ 7.0 Hz, 1H), 7.53 (d, J ¼ 8.1 Hz, 1H),
d
155.8, 154.4, 129.3, 128.7, 124.3, 122.9, 121.7, 121.0, 120.7, 111.2, 106.1,
105.3, 60.3, 55.9, 13.8, 9.5; HRMS (DART-TOF, MHþ): found
283.1333. C18H19O3 requires 283.1334.
(400 MHz, CDCl3)
d
7.60 (d, J ¼ 7.7 Hz, 1H), 7.54 (d, J ¼ 7.5 Hz, 1H),
4.4.4. 2-(3,5-dimethoxy-2,6-dimethylphenyl)benzofuran (7d)
7.32e7.23 (m, 2H), 6.92 (s, 1H), 6.83 (d, J ¼ 0.8 Hz, 1H), 4.84 (s, 1H),
Yield: yellow oil (0.116 g, 58% yield based on 0.300
g
3.88 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3)
(0.711 mmol) of 6d). IR (CH2Cl2) 1592 cmꢁ1 1H NMR (400 MHz,
;
d
156.2, 156.0, 154.5, 153.1, 129.3, 128.6, 124.2, 122.9, 121.0, 114.7,
CDCl3)
d
7.62 (m, 1H), 7.51 (d, J ¼ 7.5 Hz, 1H), 7.31e7.24 (m, 2H), 6.63
112.5, 111,2, 105.3, 103.3, 55.9, 13.2, 8.6; HRMS (DART-TOF, MHþ):
found 269.1177. C17H17O3 requires 269.1178.
(d, J ¼ 0.7 Hz, 1H), 6.58 (s, 1H), 3.87 (s, 6H), 2.03 (s, 6H); 13C NMR
(100 MHz, CDCl3)
d 156.3, 154.9, 154.8, 132.5, 128.7, 123.9, 122.8,
120.9, 119.2, 111.4, 106.4, 96.9, 56.1, 13.0; HRMS (DART-TOF, MHþ):
found 283.1333. C18H19O3 requires 283.1334.
4.8. Stemofuran L (revised; 1d) [9c]
4.5. Stemofuran C (1a) [9a]
BBr3 (1.0 M in THF, 1.0 mL, 1.0 mmol) was added to 7d (0.266 g,
0.94 mmol) in CH2Cl2 (10 mL) at 0 ꢀC over 15 min. The reaction
mixture was stirred at 0 ꢀC for 1 h and then at room temperature for
15 min. Additional CH2Cl2 (40 mL) was added to the reaction
mixture, which was quenched with water (20 mL), separated, and
the organic phase was dried over Na2SO4. The volatile solvents were
removed on the rotary evaporator, and the crude material was
purified by column chromatography (hexanes/40% EtOAc/hex-
anes) to isolate 1d (0.138 g, 52%); mp 61e63 ꢀC. IR (CH2Cl2)
To a solution of 7a (0.294 g, 1.10 mmol) in CH2Cl2 (15 mL) was
added BBr3 (5 mL, 1 M in CH2Cl2, 5 mmol) dropwise over 2 min at
0 ꢀC. The reaction mixture was stirred for 5 min at 0 ꢀC and then at
22 ꢀC for 16 h. The reaction was quenched with ice water (15 mL),
the aqueous phase was extracted with additional CH2Cl2
(3 ꢂ 30 mL), the combined organic phases were dried over Na2SO4,
and the volatiles were removed on the rotary evaporator to give the
crude product. Purification by flash chromatography (silica gel;
hexanes/25% ethyl acetate/hexanes) gave 1a as a beige solid
(0.202 g, 77% yield): mp 200e201 ꢀC; 1H NMR (400 MHz, (CD3)2CO)
1599 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.62 (m, 1H), 7.51 (d,
J ¼ 8.1 Hz, 1H), 7.32e7.23 (m, 2H), 6.63 (s, 1H), 6.52 (s, 1H), 4.72 (s,
1H), 3.82 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H); 13C NMR (100 MHz,
d
8.39 (s, 2H), 7.59 (d, J ¼ 7.7 Hz, 1H), 7.50 (d, J ¼ 8.1 Hz, 1H), 7.28 (dt,
J ¼ 1.5, 7.7 Hz, 1H), 7.22 (dt, J ¼ 1.1, 7.5 Hz, 1H), 7.04 (s, 1H), 7.01 (s,
2H), 2.13 (s, 3H); 13C NMR (100 MHz, (CD3)2CO)
157.6, 157.2, 155.4,
CDCl3)
d 156.5, 154.9, 154.6, 152.3, 132.5, 128.8, 124.0, 122.9, 121.0,
119.9, 115.4, 111.4, 106.5, 100.1, 55.9, 13.1, 12.7; HRMS (DART-TOF,
MHþ): found 269.1176. C17H17O3 requires 269.1178.
d
130.2, 129.1, 124.9, 123.8, 121.7, 113.1, 111.6, 104.1, 101.4, 8.7.
4.6. Stemofuran T (1b) [9e]
Acknowledgements
BBr3 (2.2 mL, 1.0 M in CH2Cl2, 2.2 mmol) was added dropwise to
a solution of 7b (0.4894 g, 1.82 mmol) in CH2Cl2 (40 mL) at 0 ꢀC. The
reaction mixture was removed from the ice-water bath and stirred
at 22 ꢀC for 1 h, then re-cooled to 0 ꢀC and stirred for 2 h. The
Acknowledgement is made to the Donors of the American
Chemical Society Petroleum Research Fund for support of this
research. We gratefully acknowledge a grant from the Kresge
Foundation for the purchase a 400 MHz NMR spectrometer.

224
W.H. Miles et al. / Journal of Organometallic Chemistry 851 (2017) 218e224
(c) Z.G. Yang, K. Matsuzaki, S. Takamatsu, S. Kitanaka, Inhibitory effects of
Appendix A. Supplementary data
constituents from Morus alba var. multicaulis on differentiation of 3T3-L1 cells
and nitric oxide production in RAW264.7 cells, Molecules 16 (2011)
6010e6022;
(d) M.T. Ha, M.H. Tran, K.J. Ah, K.J. Jo, J. Kim, W.D. Kim, W.J. Cheon, M.H. Woo,
S.H. Ryu, B.S. Min, Potential pancreatic lipase inhibitory activity of phenolic
constituents from the root bark of Morus alba L, Bioorg. Med. Chem. Lett. 26
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Supplementary data related to this article can be found at
https://doi.org/10.1016/j.jorganchem.2017.09.034.
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