Cyclohexanones by Rh-mediated intramolecular C-H insertion

Article abstract of DOI:10.1021/jo4014996

Some long chain α-aryl α-diazo ketones under Rh catalysis cyclize efficiently to the corresponding cyclohexanones. This is in marked contrast to the cyclizations of α-diazo β-ketoesters, which consistently deliver cyclopentanone products.

Full text of DOI:10.1021/jo4014996

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Article
Cyclohexanones by Rh-Mediated Intramolecular C-H Insertion
Douglass Fleming Taber, Craig M. Paquette, Peiming Gu, and Weiwei Tian
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4014996 • Publication Date (Web): 29 Aug 2013
Downloaded from http://pubs.acs.org on September 9, 2013
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Cyclohexanones by Rh-Mediated Intramolecular C-H Insertion
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Douglass F. Taber*, Craig M. Paquette, Peiming Gu and Weiwei Tian
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716
taberdf@udel.edu
RECEIVED DATE (will be automatically inserted after manuscript is accepted)
Br
Br
O
O
Rh cat
N2
ABSTRACT: Some long chain α-aryl α-diazo ketones under Rh catalysis cyclize efficiently to
the corresponding cyclohexanones. This is in marked contrast to the cyclizations of α-diazo β-
ketoesters, that consistently deliver cyclopentanone products.
Introduction
Rhodium carbenes derived from α-aryl ketones1 can be electronically more
discriminating than the Rh carbenes derived from β-ketoesters. We have found that when this
discriminating carbene is applied in a intramolecular sense, with an electron rich C-H site six
atoms away, C-H insertion to form the six-membered ring (Eq. 1) can dominate.2 This is in
marked contrast to the cyclization of analogous α-diazo β-ketoesters, that consistently deliver
cyclopentanone products.3,4
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Br
Rh cat
Br
O
O
O
Br
(1)
+
N2
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1a
2a
3a
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Results and Discussion
We had developed the Rh-mediated cyclization of α-aryl α-diazo ketones as a reliable
protocol for preparing α-aryl cyclopentanones.1 In the course of what we anticipated would be
the routine cyclization of the diazo ketone 1a (Eq. 1) to the cyclopentanone 3a (13C NMR δ
217.6), we observed a dominant product 2a (13C NMR δ 209.0) that was clearly the
cyclohexanone, from Rh-mediated C-H insertion into the more electron rich methine.5 We have
surveyed (Table 1) the influence of the catalyst on the yield of this cyclization, and on the ratio
of products. Catalysts with strongly electron withdrawing ligands lead to diminished selectivity,
entries 3 and 4. Electron withdrawing ligands increase the electrophilicity of the rhodium-
stabilized carbene, leading to a more reactive carbene. Rh catalysts with more electron donating
ligands lead to a less electrophilic carbenes, thus allowing higher selectivity and yields for the
insertion, entries 1, 2, and 5. As the Du Bois6 catalyst Rh2(esp)2 is commercially available and
the pivalate is not, we used the Rh2(esp)2 catalyst for subsequent explorations.7
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Table 1: Cyclization of 1a to 2a vs. 3a
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a
2a : 3ab
yieldc
74%
catalyst
d
1
Rh2(oct)4
9.5:1.0
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e
92%
18%
Rh2(piv)4
f
2
3
11.7:1.0
7.5:1.0
Rh2(OAc)4
g
74%
92%
Rh2(tfa)4
4
5
5.3:1.0
h
Rh2(esp)4
10.6:1.0
a Reaction conditions: 1a (1.0 mmol) in hexanes (5.0 mL) was added to
0.003-0.005 equiv of Rh catalyst in hexanes (5.0 mL)), rt. b Ratios are
from GC-MS area %. c Combined chromatographed yield for the two
ketones. d oct = octanoate e piv = pivalate f OAc = acetate g tfa =
trifluoroacetate h esp = !,!,!',!'-tetramethyl-1,3-benzenedipropionate
[Ref. 6].
We next investigated the catalyst loading (Table 2). It was apparent that 5 mol % was
optimal. We also investigated the diazo transfer reaction (Table 3). We found that 2,4,6-
triisopropyl benzenesulfonyl azide (TIBSA) in toluene with DBU as the base delivered the diazo
ketone 1a most efficiently. p-Nitro benzenesulfonyl azide (pNBSA) gave comparable yields, but
the diazo ketone was more readily purified when TIBSA was used.
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Table 2: Catalyst loading screen
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9
catalyst loadinga
yieldb
50%
1
1%
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70%
92%
3%
5%
2
3
90%
4
10%
a Reaction conditions: 1a (1.0 mmol) in hexanes (5.0 mL) was added to
Rh2(esp)2 in hexanes (5.0 mL)), rt. b Combined chromatographed
yield for the two ketones.
Table 3: Diazo transfer optimization
reagenta
yieldb
75%
solvent
DCM
base
pNBSAc
DBUe
1
pNBSAc
pNBSAc
DBUe
DBUe
Toluene
78%
78%
2
3
Acetonitrile
pNBSAc
pNBSAc
TIBSAd
TEAf
NaH
DCM
THF
40%
60%
84%
4
5
6
DBUe
Toluene
a Reaction conditions The liquid base was added dropwise over 5 min
to the !-aryl ketone (1.0 mmol) and diazo transfer reagent (1.5 equiv)
in solvent (5.0 mL), rt. b Yields are for pure chromatographed diazo
ketone 1a. c pNBSA = p-nitrobenzenesulfonyl azide. d TIBSA = 2,4,6-
triisopropylbenzenesulfonyl azide. e DBU = 1,8-
f
diazabicyclo[5.4.0]unde-7-ene. TEA = triethylamine.
Preparation of the Substrates
With our first substrate optimized, we planned to investigate the effect of the electronics
of the aromatic ring on the C-H insertion. To easily prepare these substrates in gram quantities, a
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general strategy was developed. The initial aryl bromide 4 (Scheme 1) was converted into the
epoxide 6 by conversion to the Grignard reagent and coupling with allyl bromide, and then
exposure to mCPBA. Cu-catalyzed opening of the epoxide with the Grignard reagent derived
from 1-bromo-3-methylbutane followed by oxidation delivered the α-aryl ketone 7, that was
carried on to the diazo ketone 1.
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Scheme 1. Preparation of α-diazo α-aryl ketones
X
Mg;
X
X
mCPBA
O
Br
Br
6
4
5
X
yield
95%
yield
95%
a
Br
Cl
b
c
d
99%
95%
99%
99%
99%
99%
m-OCH3
H
MgBr
1.
X
X
TIBSA
DBU
2. PCC/
H5IO6
O
O
N2
7
1
yield
84%
yield
82%
92%
70%
95%
77%
69%
77%
We also planned to explore the effect of different activating groups at the site of
insertion. The diazo ketone 1e (Scheme 2) was readily prepared from 1,7-octadiene. The mono
epoxide formed by exposure to mCPBA was opened with the Grignard reagent derived from 1,4-
dibromobenzene to give the secondary alcohol 10. Ozonolysis followed by Wittig reaction, and
finally oxidation and diazo transfer delivered the desired diazo ketone 1e.
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Scheme 2. Preparation of the trisubstituted alkene
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9
MgBr
Br
HO
mCPBA
Br
O
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90%
80%
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9
10
Br
Br
HO
HO
PPh3
53%
O3; Ph3P
99%
O
11
12
H
Br
Br
TIBSA
O
O
H5IO6
N2
cat PCC
DBU
50%
95%
1e
13
The aryl-substituted substrate 1f (Scheme 3) was prepared by conversion of the
commercial alcohol 14 to the bromide 15. Epoxide 4a was opened with the Grignard reagent
derived from bromide 15. Oxidation of the resulting secondary alcohol followed by diazo
transfer delivered the diazo ketone 1f.
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Scheme 3. Synthesis of the bis arene
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9
OH
Br
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PBr3
63%
1. Mg; 6a
2. Dess-Martin
68%
CH3O
CH3O
14
15
Br
Br
O
O
TIBSA
DBU
83%
N2
OCH3
OCH3
16
1f
The synthesis of 19 (Scheme 4) proceeded from the commercial alcohol 17. Epoxidation
of the derived benzyl ether with mCPBA gave the epoxide 18. Opening of the epoxide 18 with
the Grignard reagent derived from 1,4-dibromobenzene followed by oxidation and diazo transfer
delivered the diazo ketone 1g.
Scheme 4. Synthesis of the benzyl ether
MgBr
O
OH
1.
O
1. BnBr/NaH
2. mCPBA
79%
Br
2. Dess-Martin
44%
17
18
Br
Br
O
O
O
O
TIBSA
DBU
83%
N2
19
1g
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Scope of the C-H Insertion
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We explored the cyclization of the α-aryl α-diazo ketones (Table 4) we had prepared. In
each case (Entries 1-6), cyclohexanone formation proceeded well with the Rh2(esp)2 catalyst.
The electronic contribution at the benzene ring was investigated, entries 1-4. Halogens in the
para position stabilize the carbene, leading to very good selectivities and yields. We also
investigated the effect of a meta methoxy group (entry 3). We observe a slight decrease in
selectivity for the insertion, suggesting that the meta methoxy arene is not quite as good at
stabilizing the electron deficient carbene, making it more reactive, and so less selective.
With a pendant trisubstituted alkene, we observed the C-H insertion product (entry 5),
with no cyclopropane.8 With a 4-methoxyphenyl substituent (entry 6) we observed exceptional
selectivity for the formation of the cyclohexanone. As had been previously observed9 with
conjugate addition to α-aryl cyclohexenones, the kinetic product was predominantly cis, 2f. This
smoothly equilibrated (Eq. 2) to the trans product 2f' on exposure to DBU.
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Br
Br
O
O
DBU
(2)
100%
2f
2f'
OCH3
OCH3
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Table 4. Cyclization of diazo ketones
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Yielda
94%
2 : 3b
Diazo Ketone
O
Product
Br
Br
O
1
10.8:1
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N2
2a
1a
Cl
Cl
O
O
2
3
82%
69%
15.8:1
N2
2b
2c
1b
O
O
8.6:1
OCH3
OCH3
N2
1c
O
O
4
79%
13.3:1
N2
2d
1d
Br
Br
Br
O
O
O
5
86%c 11.5:1
N2
1e
2e
Br
O
N2
6
72%
> 99:1
1f
2f
OCH3
OCH3
a Yields are for the pure chromatographed mixture of ketones. b Ratios
are by GC-MS of the product mixture. c The initial mixture of
diastereomers was equilibrated by exposure to DBU before
purification.
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We also observed formation of the tetrahydropyranone (Eq. 3) on exposure of the diazo
ketone 1g to the Rh2(esp)2 catalyst. The kinetically-formed cis product 2g was readily
equilibrated to trans 2g' on exposure to DBU.
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Br
O
Br
Br
O
O
Rh cat
58%
DBU
N2
(3)
O
100%
O
O
1g
2g
2g'
The α-aryl cyclohexanones prepared following this protocol will have many applications
in target-directed synthesis. The arene is also a useful starting point for further manipulation.
Following the procedure of Evans,10 for instance, Birch reduction of 21 (Scheme 5) followed by
ozonolysis delivered the β-keto ester 22.
Scheme 5: Cleavage of the aromatic ring
OH
O
Dibal
71%
NaH
OCH3
OCH3
Me sulfate
85%
2c
20
CH3O
CH3O
O
O
1. NH3/Li
OCH3
OCH3
2. O3
60%
21
22
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Mechanism of the Cyclization
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O
O
CO2CH3
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CO2CH3
Rh cat
N2
22
(4)
23
The results observed in this study are in marked contrast to those we reported1b for the
cyclization of α-diazo β-keto esters. With Rh2(OAc)4, for instance, 22 (Eq. 4) cleanly cyclized to
23. These results can be understood on considering (Scheme 6) the competing transition states
25 and 26.
Scheme 6. Competing transition states for C-H insertion
O
O
O
Rh
O
Rh
O
CH3O2C
CO2CH3
O
O
H
O
H
O
24
O
23
Rh
H
N2
H
H
H
25
22
O
O
O
O
Rh
O
Rh
O
O
O
O
24
H
O
H
2d
Rh
H
N2
H
H
H
26
1d
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It is generally11 thought that the selectivity of Rh-mediated C-H functionalization is due
to the transient formation of sigma complexes between the electrophilic Rh carbene and the
several target C-H bonds. Carbon-carbon bond formation proceeds as the carbene center
commits to the electron density in a particular C-H bond. It has recently been shown12 that the
Rh- and Ag-catalyzed intermolecular C-H insertions of push-pull stabilized carbenes, such as 26,
are significantly more tertiary selective than the same insertions of a Rh carbene 25 derived from
an α-diazo β-keto ester. This may be due to the more ready polarization of the intermediate
metal carbene complex 26, compared to 25, as they proceed to withdraw the electron density
from a target C-H bond. These initial observations12 were of an increased preference for tertiary
C-H insertion. Applied in an intramolecular sense, the result is a preference for cyclohexanone
rather than cyclopentanone formation.
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Conclusion
The cyclization of, e.g., 1e to 2e represents a significant increase in molecular
complexity.13 Cyclopentanone construction by Rh-mediated intramolecular C-H insertion has
found many applications in target-directed synthesis.3,4 We expect that the cyclohexanone
construction described here will similarly be useful.
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Experimental Section.
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General experimental: 1H NMR and 13C NMR spectra were recorded, as solutions in
deuteriochloroform (CDCl3) at 400 MHz and 100 MHz, respectively. 13C multiplicities were
determined with the aid of a JVERT pulse sequence, differentiating the signals for methyl and
methine carbons as "d" from methylene and quaternary carbons as "u". The infrared (IR) spectra
were determined as neat oils. Rf values indicated refer to thin layer chromatography (TLC) on 2.5
x 10 cm, 250 µm analytical plates coated with silica gel GF, unless otherwise noted, and
developed in the solvent system indicated. All glassware was oven dried and rinsed with dry
solvent before use. THF and diethyl ether were distilled from sodium metal/benzophenone ketyl
under dry nitrogen. MTBE is methyl tert-butyl ether and PE is 30-60 petroleum ether. TIBSA is
2,4,6-triisopropylbenzenesulfonyl azide. All reactions were conducted under N2 and stirred
magnetically. Product ratios, i.e. cyclohexanone vs. cyclopentanone, were determined via GC-
MS by integrating the product peaks directly. The method was an initial start of 70 oC for 2 min,
then a 20 oC/min ramp to 230 oC and a hold at 230 oC for 3 min. HRMS were obtained by a EI
method of ionization with a double focusing sector detector. Commercial m-
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chloroperoxybenzoic acid (MCPBA) was purified by dissolving in Et2O and washing with
K2HPO4 buffer pH = 7.5. The organic fraction was dried (Na2SO4) and concentrated.
1-(4-Bromophenyl)-6-methylheptan-2-one (7a): To a solution of 1,4-dibromobenzene (10.0 g, 42.7
mmol) in dry Et2O (200 mL) was added Mg turnings (1.50 g, 64.0 mmol). A chip of I2 was
added, and the mixture was brought to reflux. After the reaction initiated, brown color
developed, the heating was stopped and the reaction was allowed to complete. After the
exotherm stopped and most of the Mg was consumed, the mixture was cooled to 0 oC. Allyl
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bromide (10.2 g, 85.0 mmol) was added neat dropwise over 5 min. The mixture was allowed to
warm to rt for 2 h. The mixture was quenched with saturated aqueous NH4Cl, and then
partitioned between Et2O and, sequentially, 1 M aqueous HCl and brine. The organic extract was
dried (Na2SO4) and concentrated. The residue was chromatographed to yield the alkene 5a (7.98
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g, 95% yield) as a colorless oil, TLC Rf (5% MTBE/PE) = 0.80; H NMR δ 3.34 (d, J = 6.9 Hz,
2H), 5.14-5.05 (m, 2H), 6.02-5.87 (m, 1H), 7.07 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H);
13C NMR δ u: 136.7, 120.1, 119.1, 116.3, 39.6; d: 133.1, 131.4; 1H NMR data matches published
spectra.14
To a solution of the alkene 5a (7.98 g, 40.72 mmol) in dry CH2Cl2 (150 mL) at 0 oC was
added mCPBA (8.43 g, 48.86 mmol). After stirring at 0 oC for 2 h, the reaction mixture was
quenched with 1 M aqueous NaOH, and then partitioned between CH2Cl2 and, sequentially,
water and brine. The organic extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to yield the epoxide 6a (8.20 g, 95% yield) as a colorless oil, TLC Rf (5%
MTBE/PE) = 0.38; 1H NMR δ 2.51 (dd, J = 2.4, 4.8 Hz, 1 H), 2.76 -2.82 (m, 3H), 3.08-3.14 (m,
1H), 7.10 - 7.14 (d, J = 8.4Hz, 2H), 7.40 - 7.43 (d, J = 8.4 Hz, 2H); 13C NMR δ u 136.2, 120.7,
46.8, 38.1; d 131.7, 130.9, 52.2; 1H NMR data matches published spectra.15
To a solution of 1-bromo-3-methylbutane (11.68 g, 77.36 mmol) in dry THF (200 mL) was
added Mg turnings (2.32 g, 96.7 mmol). The reaction was initiated with an I2 chip and heating to
reflux. Once the exotherm stopped the mixture was cooled to -30 oC. CuBr . Me2S complex
(0.279 g, 3.87 mmol) was added, followed by a solution of the epoxide 6a (8.20 g, 38.68 mmol)
in THF (50 mL) added dropwise over 5 min. After being allowed to warm to rt the mixture was
quenched with saturated aqueous NH4Cl, and then partitioned between Et2O and, sequentially, 1
M aqueous HCl and brine. The organic extract was dried (Na2SO4) and concentrated. The residue
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was chromatographed to yield the alcohol (10.21 g, 93% yield) as a colorless oil, TLC Rf (10%
MTBE/PE) = 0.40. To a solution of the alcohol (10.21 g, 35.97 mmol) in CH3CN (150 mL) was
added pyridinium chlorochromate (PCC) (0.155 g, 0.72 mmol) followed by periodic acid(9.84 g,
43.16 mmol).16 After 30 min the mixture was filtered through a short pad of celite eluting with
Et2O. The filtrate was concentrated and the residue was chromatographed to yield ketone 7a
(9.02 g, 74% yield from 1,4-dibromobenzene) as a clear oil, TLC Rf (10% MTBE/PE) = 0.42; 1H
NMR δ 0.83 (s, 3 H), 0.86 (s, 3 H), 1.09 -1.14 (m, 2 H), 1.47 -1.59 (m, 3 H), 2.40 - 2.44 (m, 2
H), 3.63 (s, 2 H), 7.06 - 7.09 (d, J = 8.4 Hz, 2 H), 7.43 -7.46 (d, J = 8.4 Hz, 2 H); 13C NMR δ u:
207.8, 133.3, 121.0, 49.3, 42.5, 38.3, 21.6; d: 131.8, 131.1, 27.8, 22.5 (2); IR (film) 2953, 1711,
1488, 1069, 799 cm-1; HRMS calcd. C14H20BrO [M+H] 283.0698, found 283.0687.
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2-(4-Bromophenyl)-3,3-dimethylcyclohexanone (2a): To a solution of the ketone 7a (0.10 g,
0.35 mmol) in toluene (3.0 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.11 g,
0.71 mmol) followed by triisopropylbenzenesulfonyl azide (TIBSA) (0.13 g, 0.42 mmol). The
mixture was kept in the dark for 30 min. The mixture was then chromatographed directly to yield
the diazo ketone 1a (0.092 g, 84% yield) as orange crystals, TLC Rf (10% MTBE/PE) = 0.39. 1H
NMR δ 0.84 (s, 3 H), 0.90 (s, 3 H), 1.20 -1.30 (m, 2 H), 1.52 -1.58 (m, 1 H), 1.67 - 1.75 (m, 2
H), 2.56 - 2.59 (m, 2 H), 7.40 - 7.43 (d, J = 7.8 Hz, 2 H), 7.50 - 7.53 (d, J = 7.8 Hz, 2 H); 13C
NMR δ u: 192.6, 124.7, 120.4, 39.4, 38.4, 22.5; d: 132.1, 127.0, 27.9, 22.5; The diazo ketone 1a
(0.092 g, 0.29 mmol) was then taken into a glovebox. To a slurry of Rh2(esp)2 (0.011 g, 0.014
mmol) in hexanes (10 mL) was added the diazo ketone 1a in hexanes (10 mL) dropwise over 10
min. After 5 min the mixture was removed from the glovebox, and chromatographed directly to
obtain a mixture of the cyclized products 2a with a little 3a (0.078 g, 79% yield from 7a) TLC Rf
(10% MTBE/PE) = 0.42; 1H NMR δ 0.77 (s, 3 H), 0.82 (s, 3 H), 1.65 - 1.68 (m, 1 H), 1.78 - 1.81
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(m, 1 H), 1.92 - 1.95 (m, 2 H), 2.34 - 2.42 (m, 2 H), 3.39 (s, 1 H), 6.99 (d, J = 8.4 Hz, 2 H), 7.34
- 7.38 (d, J = 8.4 Hz, 2 H); 13C NMR δ u: 209.0, 132.9, 121.0, 41.5, 40.9, 40.7, 22.5; d: 132.9,
130.6, 66.8, 30.5, 21.8; IR (film) 2957, 1709, 1265, 754 cm-1; HRMS [M+Na] calcd.
C14H17BrNaO 303.0360, found 303.0350. GC-MS Rt for 2a was 12.00 min, and for 3a the Rt was
11.89 min. The integrated ratio of the peaks was 10.6:1.0. Upon closer inspection of the 13C
NMR we observed a peak at δ 217.6 corresponding to the cyclopentanone.
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1-(4-Chlorophenyl)-6-methylheptan-2-one (7b): To a solution of 1-bromo-4-chlorobenzene
(4.00 g, 20.9 mmol) in dry Et2O (100 mL) was added Mg turnings (0.75 g, 31.4 mmol). A chip of
I2 was added, and the mixture was brought to reflux. After the reaction initiated, a brown color
developed, the heating was stopped and the reaction was allowed to complete. After the
exotherm stopped and most of the Mg was consumed, the mixture was cooled to 0 oC. Allyl
bromide (3.05 g, 25.4 mmol) was added neat dropwise over 5 min. The mixture was allowed to
warm to rt for 2 h. The mixture was quenched with saturated aqueous NH4Cl, and then
partitioned between Et2O and, sequentially, 1 M aqueous HCl and brine. The organic extract was
dried (Na2SO4) and concentrated. The residue was chromatographed to yield the alkene 5b (3.17
g, 99% yield) as a colorless oil, TLC Rf (5% MTBE/PE) = 0.85; 1H NMR δ 3.32 (d, J = 6.6 Hz,
2H), 5.09 - 5.03 (m, 2H), 5.98 - 5.85 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H) ;
13C NMR δ u: 39.51, 116.26, 131.82, 138.45; d: 128.24, 129.06, 136.90; 1H NMR data matches
published spectra.17
To a solution of the alkene 5b (3.17 g, 20.8 mmol) in dry CH2Cl2 (100 mL) at 0 oC was
added mCPBA (4.31 g, 24.04 mmol). After stirring at 0 oC for 2 h, the mixture was quenched
with 1 M aqueous NaOH, and then partitioned between CH2Cl2 and, sequentially, water and
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brine. The organic extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to yield the epoxide 6b (3.45 g, 99% yield) as a colorless oil, TLC Rf (5%
MTBE/PE) = 0.42; 1H NMR δ 2.48 - 2.60 (m, 1H), 2.82 (t, J = 4.2 Hz, 1H), 2.87 (d, J = 5.3 Hz,
2H), 3.11 - 3.20 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.26 - 7.36 (m, 2H); 13C NMR δ u: 135.5,
132.5, 46.7, 38.0; d: 130.3, 128.6, 52.1; IR(film) 3029, 2917, 1446, 1454, 1409 cm-1; 1H NMR
data matches published spectra.18
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To a solution of 1-bromo-3-methylbutane (6.22 g, 41.18 mmol) in dry THF (100 mL) was
added Mg turnings (1.23 g, 51.47 mmol). The reaction was initiated with an I2 chip and heating
to reflux. Once the exotherm stopped the mixture was cooled to -30 oC. CuBr . Me2S complex
(0.42 g, 2.06 mmol) was added, followed by a solution of the epoxide 6b (3.45 g, 20.59 mmol) in
THF (0 mL) added dropwise over 5 min. After being allowed to warm to rt the mixture was
quenched with saturated aqueous NH4Cl, and then partitioned between Et2O and, sequentially, 1
M aqueous HCl and brine. The organic extract was dried (Na2SO4) and concentrated. The residue
was chromatographed to yield the alcohol (4.69 g, 95% yield) as a colorless oil, TLC Rf (10%
MTBE/PE) = 0.42. To a solution of the alcohol (4.69 g, 23.45 mmol) in CH3CN (100 mL) was
added PCC (0.084 g, 0.39 mmol) followed by H5IO6 (5.34 g, 6.93 mmol). After 30 min the
mixture was filtered through a short pad of celite eluting with Et2O. The filtrate was concentrated
and the residue was chromatographed to yield the ketone 7b (4.58 g, 72% yield from 1-bromo-4-
chlorobenzene) as a yellow oil , TLC Rf (10% MTBE/PE) = 0.5; 1H NMR δ 0.77 (s, 3H), 0.92
(s, 3H), 1.14 (dd, J = 8.6, 7.3 Hz, 2H), 1.47 - 1.67 (m, 3H), 2.45 (t, J = 7.4 Hz, 2H), 3.68 (s, 2H),
7.11 - 7.19 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H); 13C NMR δ u: 208.0, 132.9, 132.7, 49.2,
42.4, 38.3, 21.5; d: 129.2, 128.8, 27.0, 22.4; IR(film) 2938, 1712, 1491, 1461, 1407 cm-1; HRMS
calcd. C14H19ClO 238.1124, found 238.1131.
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2-(4-Chlorophenyl)-3,3-dimethylcyclohexanone (2b): To a solution of the ketone 7b (0.20 g,
0.84 mmol) in toluene (4.0 mL) was added DBU (0.16 g, 1.05 mmol) followed by TIBSA (0.39
g, 1.26 mmol). The mixture was kept in the dark for 30 min. The mixture was then
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chromatographed directly to yield the diazo ketone 1b (0.20 g, 92% yield) as orange crystals,
TLC Rf (10% MTBE/PE) = 0.40; 1H NMR δ 0.88 (s, 3H), 0.94 (s, 3H), 1.20 - 1.34 (m, 3H), 1.59
(m, 2H), 1.67 - 1.78 (m, 2H), 2.60 (t, J = 7.5 Hz, 2H), 7.36 - 7.43 (d, J = 7.8 Hz, 2H), 7.46 - 7.52
(d, J = 7.8 Hz, 2H); 13C NMR δ u: 192.6, 124.7, 120.4, 39.4, 38.4, 22.5; d: 132.1, 127.0, 27.9,
22.5; The diazo ketone 1b (0.20 g, 0.75 mmol) was then taken into a glovebox. To a slurry of
Rh2(esp)2 (0.028 g, 0.037 mmol) in hexanes (10 mL) was added the diazo ketone 1b in hexanes
(10 mL) dropwise over 10 min. After 5 min the mixture was removed from the glovebox, and
chromatographed directly to obtain the mixture of cyclized products 2b and 3b (0.150 g, 75%
yield from 7b) TLC Rf (30% MTBE/PE) = 0.62; 1H NMR δ 0.89 (s, 3H), 0.94 (s, 3H), 1.70 -
1.81 (m, 1H), 1.83 - 1.94 (m, 1H), 1.98 - 2.12 (m, 2H), 2.40 - 2.57 (m, 2H), 3.51 (s, 1H), 7.15 (d,
J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H); 13C NMR δ u: 209.2, 133.2, 132.4, 41.5, 40.8, 40.7,
25.6; d: 131.6, 127.6, 27.5, 66.6, 30.5, 21.3; IR(film) 2948, 2859, 1707, 1491, 1451 cm-1; HRMS
calcd. C14H17ClO 236.0968, found 236.0962. GC-MS Rt for 2b was 11.94 min and for 3b the Rt
was 11.83 min. The integrated ratio of the peaks was 15.6:1.0. Upon closer inspection of the 13C
NMR we observed a peak at δ 216.9 corresponding to the cyclopentanone.
1-(3-Methoxyphenyl)-6-methylheptan-2-one (7c): To a solution of 3-bromoanisole (4.00 g,
21.4 mmol) in dry Et2O (100 mL) was added Mg turnings (0.77 g, 32.0 mmol). A chip of I2 was
added, and the mixture was brought to reflux. After the reaction initiated, a brown color
developed, the heating was stopped and the reaction was allowed to complete. After the
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exotherm stopped and most of the Mg was consumed, the mixture was cooled to 0 oC. Allyl
bromide (3.10 g, 25.7 mmol) was added neat dropwise over 5 min. The mixture was allowed to
warm to rt for 2 h. The mixture was quenched with saturated aqueous NH4Cl, and then
partitioned between Et2O and, sequentially, 1 M aqueous HCl and brine. The organic extract was
dried (Na2SO4) and concentrated. The residue was chromatographed to yield the alkene 5c (3.00
g, 95% yield) as a colorless oil, TLC Rf (10% MTBE/PE) =0.69. ; 1H NMR δ 3.37 (d, J = 6.7 Hz,
2H), 3.80 (s, 3H), 5.12 - 5.06 (m, 2H), 5.96 (ddt, J = 6.6, 10.5, 16.9 Hz, 1H), 6.74 (s, 1H), 6.80 -
6.76 (m, 2H), 7.23 - 7.19 (m, 1H); 13C NMR δ u: 159.6, 142.7, 115.9, 40.28; d: 137.2, 129.4,
121.0, 114.2, 111.5, 55.16; 1H NMR data matches published spectra.19
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To a solution of the alkene 5c (3.00 g, 20.28 mmol) in dry CH2Cl2 (100 mL) at 0 oC was
added mCPBA (4.19 g, 24.33 mmol). After stirring at 0 oC for 2 h, the mixture mixture was
quenched with 1 M aqueous NaOH, and then partitioned between CH2Cl2 and, sequentially,
water and brine. The organic extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to yield the epoxide 6c (3.29 g, 99% yield) as a colorless oil, TLC Rf (5%
MTBE/PE) = 0.33; 1H NMR δ 2.59 (dd, J = 4.9, 2.6 Hz, 1H), 2.77 - 2.85 (m, 2H), 2.88 - 3.00 (m,
1H), 3.13 - 3.21 (m, 1H), 3.83 (s, 3H), 6.78 - 6.91 (m, 3H), 7.20 - 7.27 (m, 1H); 13C NMR δ u:
159.7, 138.7, 46.9, 38.8; d: 129.5, 121.3, 114.7, 111.9, 55.3, 52.4; IR(film) 3078, 2939, 1600,
1489, 1259 cm-1; 1H NMR data matches published spectra.20
To a solution of 1-bromo-3-methylbutane (6.06 g, 40.15 mmol) in dry THF (100 mL) was
added Mg turnings (1.20 g, 50.17 mmol). The reaction was initiated with an I2 chip and heating
to reflux. Once the exotherm stopped, the mixture was cooled to -30 oC. CuBr . Me2S complex
(0.412 g, 2.01 mmol) was added, followed by a solution of the epoxide (3.29 g, 20.07 mmol) in
THF (50 mL) added dropwise over 5 min. After being allowed to warm to rt the mixture was
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quenched with saturated aqueous NH4Cl, and then partitioned between Et2O and, sequentially, 1
M aqueous HCl and brine. The organic extract was dried (Na2SO4) and concentrated. The residue
was chromatographed to yield the alcohol (4.64 g, 98% yield) as a yellow oil, TLC Rf (30%
MTBE/PE) = 0.63. To a solution of the alcohol (4.64 g, 19.66 mmol) in CH3CN (100 mL) was
added PCC (0.084 g, 0.0.39 mmol) followed by H5IO6 (5.38 g, 23.59 mmol). After 30 min the
mixture was filtered through a short pad of celite eluting with Et2O. The filtrate was concentrated
and the residue was chromatographed to yield the ketone 7c (3.34 g, 67% yield from 3-
bromoanisole) as a yellow oil, TLC Rf (30% MTBE/PE) = 0.69; 1H NMR δ 0.84 (s, 3H), 0.87 (s,
3H), 1.07 - 1.18 (m, 2H), 1.44 - 1.63 (m, 4H), 2.44 (t, J = 7.4 Hz, 2H), 3.67 (s, 2H), 3.82 (s, 3H),
6.73 - 6.88 (m, 3H), 7.26 (d, J = 7.8 Hz, 1H); 13C NMR δ u: 208.6, 159.7, 135.8, 50.2, 42.1, 38.3,
21.6; d: 129.7, 121.7, 114.9, 112.4, 55.2, 27.8, 22.4; IR(film) 2948, 1707, 1594, 1486, 1456 cm-1;
HRMS calcd. C15H22O2 234.1620, found 234.1612.
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2-(3-Methoxyphenyl)-3,3-dimethylcyclohexanone (2c): To a solution of the ketone 7c (0.200
g, 0.85 mmol) in toluene (4.0 mL) was added DBU (0.17 g, 1.18 mmol) followed by TIBSA
(0.40 g, 1.28 mmol). The mixture was kept in the dark for 30 min. The mixture was then
chromatographed directly to yield the diazo ketone 1c (0.156 g, 70% yield) as orange crystals,
TLC Rf (30% MTBE/PE) = 0.69; 1H NMR δ ppm 0.91 (s, 3H), 0.93 (s, 3H), 1.19 - 1.34 (m, 2H),
1.52 - 1.64 (m, 2H), 1.64 - 1.78 (m, 2H), 2.60 (t, J = 7.4 Hz, 2H), 3.95 (s, 3H), 6.82 (dd, J = 8.3,
2.2 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 7.20 - 7.25 (m, 1H); 13C NMR δ u: 192.6, 160.0, 124.1,
39.5, 38.4, 22.5; d: 129.9, 121.9, 115.2, 112.6, 55.3, 27.9, 22.5; The diazo ketone 1c (0.15 g, 0.57
mmol) was then taken into a glovebox. To a slurry of Rh2(esp)2 (0.021 g, 0.028 mmol) in
hexanes (10 mL) was added the diazo ketone 1c in hexanes (10 mL) dropwise over 10 min. After
5 min the mixture was removed from the glovebox, and chromatographed directly to obtain the
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cyclized products 2c with a little 3c (0.097 g, 48% yield from 7c) as a white solid MP = 54-55
oC, TLC Rf (30% MTBE/PE) =0.66; 1H NMR δ 0.89 (s, 3H), 0.96 (s, 3 H), 1.71 - 1.91 (m, 2H),
2.03 (dt, J = 6.2, 3.9 Hz, 2H), 2.38 - 2.59 (m, 2H), 3.48 (s, 1H), 3.82 (s, 3H), 6.73 - 6.87 (m, 3H),
7.25 (t, J = 7.8 Hz, 1H); 13C NMR δ u: 209.5, 158.7, 136.4, 41.5, 40.7, 40.6, 22.3; d: 132.4,
128.3, 123.6, 117.3, 111.9, 67.4, 55.1, 30.6, 22.5; IR(film) 2954, 2870, 1711, 1601, 1583 cm-1;
HRMS calcd. C15H20O2 232.1463, found 232.1468. GC-MS Rt for 2c was 11.59 min, and for 3c
was 11.53 min. By integration the ratio of the peaks was 8.6:1.0. Upon closer inspection of the
13C NMR we observed a peak at δ 217.6 corresponding to the cyclopentanone.
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6-Methyl-1-phenylheptan-2-one (7d): To a solution of bromobenzene (4.00 g, 25.5 mmol) in
dry Et2O (100 mL) was added Mg turnings (0.92 g, 38.2 mmol). A chip of I2 was added, and the
mixture was brought to reflux. After the reaction initiated, a brown color developed, the heating
was stopped and the reaction was allowed to complete. After the exotherm stopped, and most of
the Mg was consumed the mixture was cooled to 0 oC. Allyl bromide (3.69 g, 30.6 mmol) was
added neat dropwise over 5 min. The mixture was allowed to warm to rt for 2 h. The mixture
was quenched with saturated aqueous NH4Cl, and then partitioned between Et2O and,
sequentially, 1 M aqueous HCl and brine. The organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to yield the alkene 5d (2.97 g, 99% yield) as a
colorless oil, TLC Rf (5% MTBE/PE) = 0.80; 1H NMR δ 3.37 (d, J = 6.7 Hz, 2H), 5.10-5.03 (m,
2H), 6.03-5.89 (m, 1H), 7.30 - 7.16 (m, 5H); 13C NMR δ u: 120.2, 115.8, 40.2; d: 137.5, 128.8,
127.1, 126.7; 1H NMR data matches published spectra.20
To a solution of the alkene 5d (2.97 g, 25.19 mmol) in dry CH2Cl2 (100 mL) at 0 oC was
added mCPBA (5.21 g, 30.23 mmol). After stirring at 0 oC for 2 h, the mixture mixture was
quenched with 1 M aqueous NaOH, and then partitioned between CH2Cl2 and, sequentially,
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water and brine. The organic extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to yield the epoxide 6d (3.34 g, 99% yield) as a colorless oil, TLC Rf (5%
MTBE/PE) = 0.38; 1H NMR δ 2.58 (dd, J = 4.9, 2.6 Hz, 1H), 2.78 - 2.89 (m, 2H), 2.91 - 3.01 (m,
1H), 3.19 (dd, J = 3.5, 2.8 Hz, 1H), 7.26 - 7.30 (m, 3H), 7.34 (d, J = 6.5 Hz, 2H); 13C NMR δ u:
137.1, 46.9, 38.7; d; 129.0, 128.5, 126.6, 52.4; IR(film) 3029, 2917, 1496, 1459 cm-1; 1H NMR
data matches published spectra.21
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To a solution of 1-bromo-3-methylbutane (7.53 g, 49.86 mmol) in dry THF (150 mL) was
added Mg turnings (1.49 g, 62.35 mmol). The mixture was initiated with an I2 chip and heating
to reflux. Once the exotherm stopped the mixture was cooled to -30 oC. CuBr . Me2S complex
(0.51 g, 2.49 mmol) was added, followed by a solution of the epoxide 6d (3.34 g, 24.94 mmol) in
THF (50 mL) added dropwise over 5 min. After being held overnight the mixture was quenched
with saturated aqueous NH4Cl, and then partitioned between Et2O and, sequentially, 1 M
aqueous HCl and brine. The organic extract was dried (Na2SO4) and concentrated. The residue
was chromatographed to yield the alcohol (4.36 g, 85% yield) as a colorless oil, TLC Rf (10%
MTBE/PE) = 0.50. To a solution of the alcohol (4.36 g, 21.20 mmol) in CH3CN (20 mL) was
added PCC (0.091 g, 0.424 mmol) followed by H5IO6 (5.80 g, 25.44 mmol). After 30 min the
mixture was filtered through a short pad of celite eluting with Et2O. The filtrate was concentrated
and the residue was chromatographed to yield the ketone 7d (3.09 g, 75% yield from
bromobenzene) as a clear oil, TLC Rf (10% MTBE/PE) = 0.55; 1H NMR δ 0.83 (s, 3H), 0.87 (s,
3H), 1.08 - 1.16 (m, 2H), 1.45 - 1.63 (m, 3H), 2.45 (t, J = 7. 5 Hz, 2H), 3.70 (s, 2H), 7.20 - 7.25
(m, 3H), 7.35 (d, J = 7.6 Hz, 2H); 13C NMR δ u: 208.7, 129.4, 50.1, 42.2, 38.3, 21.6; d: 129.4,
128.7, 126.9, 27.8, 22.4; IR(film) 2938, 1707, 1594, 1486, 1461 cm-1; HRMS calcd. C14H20O
204.1514, found 204.1519.
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3,3-Dimethyl-2-phenylcyclohexanone (2d): To a solution of the ketone 7d (0.20 g, 0.98 mmol)
in toluene (5.0 mL) was added DBU (0.20 g, 1.31 mmol) followed by TIBSA (0.46 g, 1.48
mmol). The mixture was kept in the dark for 30 min. The mixture was then chromatographed
directly to yield the diazo ketone 1d (0.21 g, 95% yield) as orange crystals, TLC Rf (10%
MTBE/PE) =0.46; 1H NMR δ 0.88 (s, 3H), 0.94 (s, 3H), 1.21 - 1.31 (m, 3H), 1.58 (m, 2H), 1.67
- 1.78 (m, 2H), 2.60 (t, J = 7.4 Hz, 2H), 7.27 - 7.30 (m, 1H), 7.40 - 7.47 (d, J = 7.8 Hz, 2H), 7.54
(d, J = 7.8 Hz, 2H); 13C NMR δ u: 132.1, 124.7, 39.1, 29.3, 27.1, 25.7; d: 131.9, 128.7, 124.0,
25.7, 17.7; The diazo ketone 1d (0.224 g, 0.91 mmol) was then taken into a glovebox. To a
slurry of Rh2(esp)2 (0.034 g, 0.045 mmol) in hexanes (10 mL) was added the diazo in hexanes
(10 mL) dropwise over 10 min. After 5 min the mixture was removed from the glovebox, and
chromatographed directly to obtain the cyclized products 2d with a little 3d (0.150 g, 75% yield
from 7d) as a clear oil, TLC Rf (30% MTBE/PE) =0.5; 1H NMR δ 0.88 (s, 3H) 0.95 (s, 3H) 1.72
- 1.82 (m, 1H) 1.84 - 1.94 (m, 1H) 1.97 - 2.09 (m, 2H) 2.40 - 2.59 (m, 2H) 7.20 - 7.23 (m, 2H)
7.27 - 7.36 (m, 3H); 13C NMR δ u: 209.6, 134.8, 41.5, 40.8, 40.7, 23.8; d: 131.1, 126.9, 126.8,
67.4, 29.8, 17.5; IR(film) 3036, 2948, 2869, 1707, 1486 cm-1; HRMS calcd. C14H18O 202.1358,
found 202.1359. GC-MS Rt for 2d was 10.89 min for 3d the Rt was 10.81 min. Integration of the
peaks found a 13.1:1.0 ratio of 2d vs. 3d. Upon closer inspection of the 13C NMR we observed a
peak at δ 217.5 corresponding to the cyclopentanone.
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1-(4-Bromophenyl)oct-7-en-2-ol (10): To a solution of 1,7-octadiene (5.00 g, 45.5 mmol) in
CH2Cl2 (200 mL) was added mCPBA (8.60 g, 49.9 mmol) The mixture was stirred at 0 oC for 2
h. The mixture was quenched with 1 M aqueous NaOH and the partitioned between brine, and
CH2Cl2. The organic extracts were dried (Na2SO4), and concentrated. The residue was then
chromatographed to yield the mono epoxide 9 (5.15 g, 90% yield) as clear oil. TLC Rf (10%
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MTBE/PE) =0.58; 1H NMR δ 1.41 - 1.64 (m, 6H), 2.09 (d, J = 6.3 Hz, 2H), 2.49 (dd, J = 5.1, 2.8
Hz, 1H), 2.71 - 2.81 (m, 1H), 2.93 (dd, J = 3.7, 2.9 Hz, 1H), 4.91 - 5.09 (m, 2H), 5.83 (ddt, J =
17.0, 10.3, 6.7 Hz, 1H); 13C NMR δ u: 114.5, 47.1, 33.6, 32.3, 28.6, 25.4; d: 138.7, 52.3;
IR(film) 3046, 2987, 2918, 2850, 1638 cm-1; 1H NMR data matches published spectra.22
To a solution of 1,4-dibromobenzene (19.29 g, 81.74 mmol) in Et2O (200 mL) was added Mg
turnings (2.45 g, 102.17 mmol) The reaction was initiated with I2 and brought to reflux. Once the
exotherm stopped the mixture was cooled to -30 oC. CuBr . Me2S complex (0.838 g, 4.09 mmol)
was added, followed by a solution of the epoxide 9 (5.15 g, 40.87 mmol) in Et2O (100 mL)
added dropwise over 5 min. The mixture was allowed to warm to rt, and then quenched with
saturated aqueous NH4Cl, and then partitioned between Et2O and, sequentially, 1 M aqueous HCl
and brine. The organic extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to yield the alcohol 10 (9.23 g, 72% yield from 1,7-octadiene) as a white solid
MP = 65-68 oC: TLC Rf (30% MTBE/PE) = 0.5; 1H NMR δ 1.38 - 1.56 (m, 7H), 2.02 - 2.14 (m,
2H), 2.64 (dd, J = 13.6, 8.3 Hz, 1H), 2.80 (dd, J = 13.6, 4.3 Hz, 1H), 3.81 (dt, J = 8.0, 3.9 Hz,
1H), 4.91 - 5.08 (m, 2H), 5.83 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 7.12 (d, J = 8.3 Hz, 2H), 7.46 (d,
J = 8.3 Hz, 2H); 13C NMR δ u: 137.6, 120.3, 114.5, 43.3, 36.6, 33.7, 28.8, 25.1; d: 138.3, 131.5,
131.1, 72.3; IR(film) 3344, 3266, 2918, 2866, 2348 cm-1; HRMS calcd. C14H19BrO 282.0619,
found 282.0621.
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7-(4-Bromophenyl)-6-hydroxyheptanal (11): To a solution of the alcohol 10 (1.00 g, 3.53
mmol) in CH2Cl2:MeOH (6:1, 20 mL) at -78 oC was sparged O3. Once the solution turned a blue
color the mixture was quenched with PPh3 (0.92 g, 3.53 mmol) The residue was
chromatographed directly to yield the aldehyde 11 (0.99 g, 99% yield) as a white solid MP = 72-
75 oC: TLC Rf (60% MTBE/PE) = 0.36; 1H NMR δ 1.39 - 1.76 (m, 6H), 2.48 (td, J = 7.2, 1.5 Hz,
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2H), 2.57 - 2.70 (m, 1H), 2.73 - 2.85 (m, 1 H), 3.82 (d, J = 3.8 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 2
H), 7.46 (d, J = 8.3 Hz, 2H), 9.80 (s, 1H); 13C NMR δ u: 137.4, 120.4, 43.8, 43.4, 36.4, 25.2,
21.9; d: 202.6, 131.0, 131.2, 72.1; IR(film) 3341(broad), 2916, 2850, 2722, 1707, 1481 cm-1;
HRMS calcd. C13H17BrO2 284.0412, found 284.0418.
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1-(4-Bromophenyl)-8-methylnon-7-en-2-ol (12): To a solution of the alcohol 11 (0.40 g, 1.40
mmol) in THF (5.0 mL) at 0 oC was added KOtBu (0.63 g, 5.60 mmol). The solution was stirred
for 10 min. Isopropyltriphenylphosphonium bromide (1.21 g, 2.80 mmol) was added. After being
allowed to warm to rt mixture was quenched with 1 M aqueous HCl, and then partitioned
between Et2O and brine. The organic extract was dried (Na2SO4) and concentrated. The residue
was chromatographed to yield the alkene 12 (0.231 g, 53% yield) as a white solid MP = 50-53
oC: TLC Rf (60% MTBE/PE) = 0.7; 1H NMR δ 1.37 (dd, J = 3.5, 1.5 Hz, 3H), 1.44 - 1.54 (m,
4H), 1.61 (s, 3H), 1.71 (s, 3H), 2.00 (d, J = 6.8 Hz, 2H), 2.63 (dd, J = 13.6, 8.3 Hz, 1H), 2.79
(dd, J = 13.6, 4.3 Hz, 1H), 3.80 (bs, 1H), 5.07 - 5.20 (m, 1H), 7.12 (d, J = 8.3 Hz, 2H), 7.45 (d, J
= 8.3 Hz, 2 H); 13C NMR δ u: 137.6, 120.3, 43.3, 36.8, 29.8, 27.9, 25.7; d: 131.5, 131.1, 124.5,
72.7, 25.3, 17.7; IR(film) 3390(broad), 2927, 2856, 1687, 1487 cm-1; HRMS calcd. C16H23BrO
310.0923, found 310.0926.
1-(4-Bromophenyl)-8-methylnon-7-en-2-one (13): To a solution of the alcohol 12 (0.230 g,
0.79 mmol) in CH3CN (3.0 mL) was added PCC (0.003 g, 0.014 mmol) followed by H5IO6 (0.18
g, 0.81 mmol). After 30 min the mixture was filtered through a short pad of celite eluting with
Et2O. The filtrate was concentrated and the residue was chromatographed to yield the ketone 13
(0.219 g, 95% yield) as a yellow oil, TLC Rf (30% MTBE/PE) = 0.69; 1H NMR δ 1.17 - 1.40 (m,
3H), 1.69 (s, 3H), 1.69 (s, 3H), 1.96 (q, J = 7.3 Hz, 2H), 2.47 (t, J = 7.3 Hz, 2H), 3.66 (s, 2H),
5.08 (tt, J = 7.2, 1.3 Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H); 13C NMR δ u:
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207.8, 133.2, 121.0, 49.2, 42.1, 29.2, 27.7, 23.3; d: 131.7, 131.1, 23.5, 17.7; IR(film) 2926, 2850,
1712, 1487, 1447 cm-1; HRMS calcd. C16H21BrO 308.0776, found 308.0764.
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2-(4-Bromophenyl)-3-(2-methylprop-1-enyl)cyclohexanone (2e): To a solution of the ketone
13 (0.120 g, 0.38 mmol) in toluene (2.0 mL) was added DBU (0.09 g, 0.59 mmol) followed by
TIBSA (0.19 g, 0.61 mmol). The mixture was kept in the dark for 30 min. The mixture was then
chromatographed directly to yield the diazo ketone 1e (0.063 g, 50% yield) as orange crystals,
TLC Rf (30% MTBE/PE) = 0.76; 1H NMR δ ppm 1.41 (q, J = 7.5 Hz, 2H), 1.60 (s, 3H), 1.68 (s,
3H) 2.03 (q, J = 7.3 Hz, 2H) 2.38 (s, 1H) 2.61 (t, J = 7.5 Hz, 2H) 5.12 (ddd, J = 7.1, 5.8, 1.3 Hz,
1H) 7.43 (d, J = 8.8 Hz, 2H) 7.50 - 7.58 (d, J = 8.8 Hz, 2H); 13C NMR δ u: 131.9, 124.0, 39.1,
29.4, 27.8, 24.2; d: 132.1, 124.0, 25.8, 17.7; The diazo ketone 1e (0.069 g, 0.188 mmol) was then
taken into a glovebox. To a slurry of Rh2(esp)2 (0.008 g, 0.010 mmol) in hexanes (10 mL) was
added the diazo ketone 1e in hexanes (10 mL) dropwise over 10 min. After 5 min the mixture
was removed from the glovebox, and chromatographed directly to obtain the cyclized products
2e with a little 3e as a colorless oil (0.051 g, 43% yield from 13), TLC Rf (30% MTBE/PE) =
0.66 1H NMR δ 1.34 (s, 3H), 1.51 (s, 3H), 1.62 - 1.74 (m, 1H), 1.79 - 2.01 (m, 2H), 2.09 - 2.25
(m, 1H), 2.43 - 2.63 (m, 2H), 2.78 - 2.93 (m, 1H), 3.33 (d, J = 11.6 Hz, 1H), 4.84 (dt, J = 9.4,
1.26 Hz, 1H), 6.92 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H); 13C NMR δ u: 209.3, 136.5,
132.2, 120.5, 41.3, 32.8, 23.3; d: 131.2, 130.7, 128.4, 62.3, 45.2, 25.5, 17.5; IR(film) 2928, 2859,
1707, 1486, 1447 cm-1; HRMS calcd. C16H19BrO 306.0619, found 306.0625. GC-MS Rt for 2e
was 12.93 min for 3e the Rt was 13.10 min. Integration of the peaks showed a 11.5:1.0 ratio of
2e to 3e. Upon closer inspection of the 13C NMR we observed a peak at δ 217.4 corresponding to
the cyclopentanone.
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1-(4-Bromophenyl)-6-(4-methoxyphenyl)hexan-2-one (16): To a stirred solution of 3-(4-
methoxyphenyl) propan-1-ol 14 (2.00 g, 13.15 mmol) in Et2O (50 mL) was added PBr3 (1.33 g,
4.98 mmol) at 0 oC. The mixture was heated to reflux for 2.5 h, then quenched with water, and
partitioned between Et2O and aqueous NaHCO3. The organic extract was dried (Na2SO4) and
concentrated. The residue was chromatographed to afford the bromide 15 (1.77 g, 63% yield), as
a colorless oil, TLC Rf (MTBE/petroleum ether = 30%) = 0.77; 1H NMR δ 2.15 (m, 2H), 2.72 (t,
J = 6.8 Hz, 2H), 3.38 (t, J = 6.8 Hz, 2H), 3.79 (s, 3H), 6.82 - 6.91 (m, 2H),7.10 - 7.26 (m, 2H);
13C NMR δ u: 158.0, 132.6, 34.4, 33.1, 33.0; d: 129.5 113.9, 55.3; 1H NMR data matches
published spectra.23
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To a stirred solution of the bromide 15 (1.77 g, 8.27 mmol) in THF (50 mL) was added Mg
turnings (0.396 g, 16.54 mmol) and I2 at room temperature. The reaction mixture was heated to
reflux for 1 h, then powdered CuBr . Me2S (0.016 g, 0.82 mmol) was added at -30 oC. The
reaction mixture was stirred for 5 min at this temperature and the cooling bath was removed.
After 10 min, the cooling bath was replaced and a solution of the epoxide 6a (1.75 g, 8.27 mmol)
in THF (5.0 mL) was added during 1 min. The reaction mixture was stirred for 20 min at -30 to -
20 oC. The reaction mixture was partitioned between CH2Cl2, and saturated aqueous NH4Cl. The
organic extract was dried (Na2SO4) and concentrated. The residue was chromatographed to
afford the alcohol as a colorless oil. To a stirred solution of the alcohol was added Dess-Martin
periodinane (3.74 g, 8.80 mmol) at 0 oC. After an additional 3 h at rt, the reaction mixture was
filtered through a pad of silica gel, and washed with Et2O. The filtrate was concentrated and the
residue was chromatographed to afford the ketone 16 (2.04 g, 43% yield from 14) as a colorless
oil, TLC Rf (MTBE/petroleum ether = 10%) = 0.38; 1H NMR δ 1.51 - 1.61 (m, 4H), 2.45 (t, J =
7.2 Hz, 2H), 2.52 (t, J = 7.2 Hz, 2H), 3.61 (s, 2H), 3.78 (s, 3H), 6.80 - 6.83 (m, 2H), 7.03 - 7.06
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(m, 4H), 7.42 - 7.46 (m, 2H); 13C NMR δ u: 207.6, 157.8, 134.2, 133.2, 121.0, 49.3, 42.0, 34.7,
31.0, 23.3; d: 131.8, 131.1, 129.2, 113.8, 55.3; IR (film) 3429, 2934, 1712, 1643, 1512 cm-1;
HRMS calcd. C19H22BrO2 [M+H] 361.0803, found 361.0816.
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cis-2-(4-Bromophenyl)-3-(4-methoxyphenyl)cyclohexanone (2f): To a stirred solution of the
ketone (0.250 g, 0.692 mmol) in toluene (8.0 mL) was added TIBSA (0.26 g, 0.84 mmol) at rt.
DBU (0.32 g, 2.10 mmol) was added dropwise over 1 min. The reaction mixture was stirred for
20 min at rt, then chromatographed to afford the diazo ketone 1f (0.220 g, 83% yield), as a
yellow oil, TLC Rf (MTBE/petroleum ether = 10%) = 0.34. 1H NMR δ 1.63 - 1.78 (m, 4H), 2.57
- 2.61 (m, 4H), 3.78 (s, 3H), 6.80 - 6.83 (m, 2H), 7.06 - 7.09 (m, 2H), 7.38 (d, J = 7.6 Hz, 2H),
7.50 - 7.53 (m, 2 H); 13C NMR δ u: 192.3, 157.8, 134.1, 124.7, 120.5, 39.0, 34.7, 31.1, 24.1; d:
134.1, 129.3, 127.0, 113.8, 55.3; The diazo ketone 1f (0.220 g, 0.57 mmol) was then taken into a
glovebox. To a slurry of Rh2(esp)2 (0.021 g, 0.028 mmol) in hexanes (10 mL) was added the
diazo ketone 1f in hexanes (10 mL) dropwise over 10 min. After 5 min the mixture was removed
from the glovebox, and chromatographed directly to obtain the cyclized product 2f (0.186 g,
60% yield from 16), as a colorless oil, TLC Rf (MTBE/petroleum ether = 20%) = 0.29; 1H NMR
δ 1.92 - 1.96 (m, 1H), 2.10 - 2.21 (m, 3H), 2.57 - 2.70 (m, 2H), 3.57 - 3.61 (m, 1H), 3.74 (s, 3H),
3.98 (d, J = 5.6 Hz, 1H), 6.73 - 6.76 (m, 2H), 6.85 - 6.92 (m, 4H), 7.23 - 7.26 (m, 2H); 13C NMR
δ u: 210.1, 158.2, 135.4, 133.2, 120.8, 40.8, 29.6, 23.2; d: 131.4, 131.0, 129.2, 113.7, 60.5, 55.2,
47.9; IR (film) 2934, 1706, 1609, 1512, 1248, 808 cm-1; HRMS [M+Na] calcd. C19H19BrO2Na
381.0466, found 381.0461. Further elution gave the trans cyclohexanone as a colorless oil (3 mg,
4% yield), TLC Rf (MTBE/ petroleum ether = 20%) = 0.26. GC-MS analysis showed only the
cyclohexanone product.
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trans-2-(4-Bromophenyl)-3-(4-methoxyphenyl)cyclohexanone (2f'): To a stirred solution of 2f
(0.020 g, 0.057 mmol) in CH2Cl2 (0.5 mL) was added a few drops of DBU at rt. After 1 h, silica
gel was added and the mixture was concentrated and the residue was chromatographed to afford
the cyclohexanone 2f' as a colorless oil (0.012 g, 63% yield), TLC Rf (MTBE/ petroleum ether =
20%) = 0.26; 1H NMR δ 1.84 - 2.13 (m, 3H), 2.20 - 2.25 (m, 1H), 2.57 - 2.63 (m, 2H), 3.11 (td, J
= 11.6 Hz, 4.0 Hz, 1H), 3.71 - 3.78 (m, 4H), 6.67 - 6.69 (m, 2H), 6.78 - 6.81 (m, 2H), 6.92 - 6.94
(m, 2H), 7.25 - 7.28 (m, 2H); 13C NMR δ u: 208.4, 158.0, 135.9, 134.8, 120.5, 42.0, 34.8, 26.1;
d: 131.2, 131.1, 128.1, 113.8, 63.4, 55.1, 51.6; IR (film) 2931, 1706, 1611, 1512, 1248, 802 cm-1;
HRMS [M+Na] calcd. C19H19BrO2Na 381.0466, found 381.0461.
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17
18
19
20
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4-(Benzyloxy)-1-(4-bromophenyl)butan-2-one (19): To a slurry of NaH (4.40 g, 38.3 mmol ),
in THF (100 mL) and TBAI (0.51 g, 1.38 mmol) was added homoallylic alcohol 17 (2.00 g, 27.7
mmol). Benzyl bromide (9.49 g, 55.5 mmol) was added neat dropwise over 1 min. The solution
was refluxed for 3 h then quenched with 1 M aqueous HCl, then partitioned between Et2O and
brine. The organic extract was dried (Na2SO4) and concentrated. The residue was dissolved into
CH2Cl2 (100 mL) at 0 oC mCPBA (1.40 g, 8.14 mmol) was added. The mixture was stirred at 0
oC for 3 h, then quenched with 1 M aqueous NaOH, then partitioned between CH2Cl2 and brine.
The organic extract was dried (Na2SO4) and concentrated. The residue was purified by column
chromatography to yield the epoxide 18 (3.89 g, 79% yield), as a clear oil. TLC Rf (MTBE/
petroleum ether = 30%) = 0.26; 1H NMR δ 1.82 – 1.75 (m, 1H), 1.96 – 1.90 (m, 1H), 2.54 (dd, J
= 5.0, 2.8 Hz, 1H), 2.80 (t, J = 4.3 Hz, 1H), 3.11 – 3.07 (m, 1H), 3.67 – 3.60 (m, 2H), 4.54 (s,
2H), 7.23 – 7.19 (m, 5H); 13C NMR δ 138.2, 128.4, 127.6, 73.1, 67.0, 50.1, 47.1, 32.9; 1H NMR
data matches published spectra.24
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