Synthesis of Substituted 1,4-Dioxenes through O-H Insertion and Cyclization Using Keto-Diazo Compounds

Article abstract of DOI:10.1021/acs.joc.6b02134

1,4-Dioxenes present interesting potential as synthetic intermediates and as unusual motifs for incorporation into biologically active compounds. Here, an efficient synthesis of functionalized 1,4-dioxenes is achieved in two steps. Using keto-diazo compounds, a ruthenium catalyzed O-H insertion with β-halohydrins followed by treatment with base results in cyclization with excellent selectivity, through O-alkylation of the keto-enolate. A variety of halohydrins and anion-stabilizing groups in the diazo-component are tolerated, affording novel functionalized dioxenes. Enantioenriched β-bromohydrins provide enantioenriched 1,4-dioxenes.

Full text of DOI:10.1021/acs.joc.6b02134

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Note
Synthesis of Substituted 1,4-Dioxenes through O–H
Insertion and Cyclization Using Keto-Diazo Compounds
Owen A Davis, Rosemary A Croft, and James A. Bull
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02134 • Publication Date (Web): 10 Oct 2016
Downloaded from http://pubs.acs.org on October 13, 2016
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Synthesis of Substituted 1,4-Dioxenes through O–H Insertion and Cyclization
Using Keto-Diazo Compounds
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Owen A. Davis, Rosemary A. Croft, and James A. Bull*
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
*E-mail: j.bull@imperial.ac.uk
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G
R
N2 HO
O
R'
G
R
O
O
R'
G
R
O
O
R'
Ru-cat.
cyclization
O–H insertion
X
X
Cl
Cl
O
P
O
H
H
O
EtO2C
O
O
O
O
O
EtO
EtO
EtO
Ph
N
H
O
O
O
ABSTRACT: 1,4-Dioxenes present interesting potential as synthetic intermediates, and as unusual
motifs for incorporation into biologically active compounds. Here, an efficient synthesis of
functionalized 1,4-dioxenes is achieved in two steps. Using keto-diazo compounds, a ruthenium
catalyzed O–H insertion with b-halohydrins followed by treatment with base results in cyclization with
excellent selectivity, through O–alkylation of the keto-enolate. A variety of halohydrins and anion-
stabilizing groups in the diazo-component are tolerated, affording novel functionalized dioxenes.
Enantioenriched b-bromohydrins provide enantioenriched 1,4-dioxenes.
In early stage drug discovery there is considerable interest in the incorporation of novel motifs,
and more sp3 rich, less planar structures to aid in the exploration of novel chemical and intellectual
property (IP) space.1,2 1,4-Dioxenes are partially saturated oxygen heterocycles that may present
interesting potential in this context, but which remain relatively unexplored. Most commonly these
heterocycles have been used as synthetic intermediates in the preparation of dioxanes through reaction
of the olefin. Reactions of dioxenes include cyclopropanation with diazo compounds,3 Paternò-Büchi
reactions,4 and other reactions.5 Fluorinated derivatives have been used in materials science as
monomers for polymerization with applications in the production of films and coatings.6 Within
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agrochemistry, 1,4-dioxene-containing compounds have been shown to act as bioisosteres for 1,4-
oxathenes exhibiting fungicidal properties; dioxincarboxamide showed increased fungicidal activity
compared with systemic fungicide Carboxin (Figure 1).7,8 To date their uses as motifs in medicinal
chemistry has been limited to tool compounds as allosteric receptors of mAChRs for investigating
Alzheimer’s disease and schizophrenia.9 There are examples in patents describing activity towards
targets including inhibitors of the HIV virus,10 Nrf2 inhibitors,11 and antibacterial activity.12
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OMe
O
X
Y
N
N
O
H
O
O
O
S
N
Me
H
Carboxin X = S, Y = H
Dioxincarboxamide X = O, Y = Me
fungicidal activity against bean rust M4 postive allosteric modulator
H
O
N
S
O
O
N
Cl
O
O
O
O
O
O
iPrO2C
N
N
H
inhibitor of HIV virus
Nrf2 inhibitor
Figure 1. Examples of 1,4-dioxenes in biologically active compounds
Dioxenes have been prepared by the alkylation of ethylene glycol,7,13 displacement of 1,2-
dihaloethanes with symmetrical benzoin derivatives,14 or direct functionalization of unsubstituted 1,4-
dioxene.15,5a However, these approaches do not allow facile incorporation of substituents at the sp3
hybridized 5- and 6-positions, and there remain few methods to generate functionalized dioxene
derivatives. In 1999, Zercher and co-workers reported a procedure to form 2,3,5,6-substituted dioxenes
involving a Rh(II)-catalyzed O–H insertion with symmetrical 1,2-diols followed by hemi-acetal
formation and acid catalyzed dehydration (Scheme 1a).16 More recently, Lacour and co-workers
described the synthesis of tri- and tetrasubstituted 1,4-dioxenes through a Ru-catalyzed ring expansion
of epoxides with retention of stereochemistry, along with a minor deoxygenation product (Scheme
1b).17
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As part of our interest in the synthesis of new functionalized heterocycles as fragments and
lead-like compounds for drug discovery, we recently reported an efficient synthesis of oxetanes by a 2-
step O–H insertion/C–C bond forming cyclization strategy (Scheme 1c).18,19 A variety of functionalized
diazo-compounds could be employed, to form oxetane products in high yield.18b Following this work,
we were interested in alternative diazo compounds where cyclization to form 4- or 6-membered rings
may compete, and consequently investigated diazo compounds derived from b-ketoesters toward the
synthesis of dioxenes. In this Note we report the preparation of functionalized di-, tri- and tetra-
substituted 1,4-dioxenes by a 2-step ruthenium catalyzed O–H insertion/anionic C–O bond forming
cyclization using functionalized bromohydrins and keto-diazo compounds (Scheme 1d).
Scheme 1. Synthetic strategies for the preparation of 1,4-dioxenes and oxetanes using diazo-
compounds
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a) Zercher 1999, ref 16
H
R1O2C
R1O2C
O
O
R3
R3
R1O2C
O
O
R3
R3
i) ArN3
iii) p-TsOH
H2O
–
ii) Rh(II) cat.
HO
R2
R2
R2
O
R3
OH
HO
R3
b) Lacour 2014, ref 17
R1O2C
R3
R3
R1O2C
R2
O
O
R3
R3
N2
O
Ru(II) cat.
O
R2
c) Previous work: Synthesis of functionalised oxetanes, ref 18
HO
E1
N2
i) Rh cat. O–H insertion
O
R
R
E1
E2
E2
ii) C–C bond forming
cyclization
X
d) This work: synthesis of functionalised 1,4-dioxenes
E =
CO2Et
PO(OEt)2 aryl
SO2Ph
R1, R2 =
alkyl
HO
E
O
O
E
N2
O
i) Ru cat. O–H insertion
R2
X
R2
ii) C–O bond forming
cyclization
R1
R1
COR
Our initial investigations targeted 3-methyl-1,4-dioxene-2-carboxylate 3, reacting a-diazo-b-
ketoester 1 with bromoethanol (Scheme 2). Using previously successful conditions for O–H insertion
(conditions A) with catalytic [Rh2(OAc)4] did afford the desired ether product 2 but with variable
yields and formation of an unexpected and inseparable side-product (2-bromoethyl ethyl carbonate).
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Investigations into the cyclization at this stage showed promising results. Varied conditions,
changing solvent and base combinations gave successful cyclization to generate dioxenes, in all cases
occurring selectively through the oxygen atom to give the dioxene products without formation of the
possible oxetane.
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Scheme 2. Synthesis of 1,4-dioxene 3 by O–H insertion and cyclization
EtO2C
N2
O
HO
EtO2C
O
EtO2C
O
O
NaH, DMF
85%
Br
Conditions
Br
O
1
2
3
Conditions:
A: Rh2(OAc)4 (0.5 mol%), PhH, 80 °C
B: [CpRu(MeCN)3][PF6] (1 mol%), 1,10-Phen (1 mol%), DCE, 60 °C, 1h
Yield 2
<5-39%
86%
The encouraging cyclization attempts prompted us to explore alternative catalytic systems to
improve the efficiency of the O–H insertion step. Lacour reported a Ru-catalyst for the O–H insertion
of keto-ester diazo compounds in the alcohol as solvent ([CpRu(MeCN)3][PF6] (2.5 mol%), 1,10-
phenanthroline (2.5 mol%)).20 Pleasingly, using this catalyst with excess bromoethanol (3 equiv) in
DCE at 60 ºC afforded ether 2 in 53% yield without formation of the side product.21 On further
optimization, the excess of bromoethanol was decreased without affecting the yield by increasing
reaction concentration and reducing the catalyst loading to 1 mol%, strictly maintaining a 1:1 Ru:phen
ratio.21 By using a small excess of diazo compound 1 (1.2 equiv), an 86% isolated yield of bromide 2
was obtained (Scheme 2; Conditions B).
An excellent yield of 1,4-dioxene 3 was then obtained on treating 2 with NaH in DMF at 0 °C
for 1 h. The 6-membered dioxene ring was formed exclusively with no evidence for formation of the
oxetane keto-ester that would occur through C-alkylation, which we had observed exclusively in
previous work. The reaction sequence was similarly successful using a tosylate leaving group.
Performing the O–H insertion on 2-tosyloxyethanol to afford 2a (not shown) and cyclisation under the
same conditions gave yields of 92% and 88% respectively.22
With these optimized conditions, the introduction of substituents onto 2-bromoethanol was
examined to form chiral 2,3,6-trisubstituted 1,4-dioxenes. Both aryl and alkyl substituents were
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examined using readily available b-halohydrins (4, Scheme 3). With the substituted b-halohydrins, the
O–H insertion required a longer reaction time (15 h) to achieve high yields presumably due to
increased steric demands. Similarly, cyclization required warming to 25 °C for 30 min to obtain the
1,4-dioxenes, such as 6a, in an excellent yield. Using the corresponding enantioenriched b-
bromohydrin (93% ee, (S)-4a), gave the enantioenriched 1,4-dioxene ((S)-6a) with retention of ee (92%
ee).23
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Scheme 3. Synthesis of 2,3,6- and 2,3,5-trisubstituted dioxenes, and 2,3,5,6-tetrasubstituted dioxenesa
EtO2C
N2 HO
EtO2C
O
EtO2C
O
Ru-cat.
i)b,c
cyclization
R
R
R
ii)d
O
X
O
X
O
1
4a-4i X = Br, Cl
5a-5i
6a-6i
Cl
Cl
EtO2C
O
EtO2C
O
O
EtO2C
O
OMe
O
O
6a
6b
i) 81%; ii) 94%
6c
i) 91%; ii) 91% rac
i) 76%; ii) 84%
i) 90%; ii) 85% (92% ee (S)-6a)e
i)f 91%; ii)g 80%
EtO2C
O
EtO2C
O
O
EtO2C
O
O
OTBS
Cl
O
6d
6e
6f
i)h 71%; ii) 90%
i)h 67%; ii) 90%
i) 84%; ii) 78%
H
H
EtO2C
O
EtO2C
O
O
EtO2C
O
O
O
H
H
6g
6h
i) 73%; ii) 91%
6i
i) 87%; ii) 89%
i) 87%; ii) 96%
Diazo 1
EtO2C
O
O
HO
EtO2C
O
O
i)
ii)
+
EtO2C
47%
Cl
O
Cl
COMe
4j
5j
6j
34%
7
20%
aYields quoted for separate steps i) and ii). bConditions i for O–H insertion: b-halohydrin 4 (1.0 mmol),
1 (1.2 equiv), [CpRu(MeCN)3][PF6] (1.0 mol%), 1,10-phenanthroline (1.0 mol%), 1,2-dichloroethane,
c
d
0.5 M, 60 °C, 15 h. Bromohydrin used (X = Br) unless stated. Conditions ii for cyclization: 5 (0.5
mmol), NaH (1.2 equiv), DMF, 0.025 M, 0 °C, 60 min; then 25 °C, 30 min. eUsing enantioenriched b-
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bromohydrin (93% ee). fReaction on 8.0 mmol scale. gReaction on 5.0 mmol scale. hUsed chlorohydrin;
X = Cl.
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Both electron-rich and electron-poor aromatic substituents gave similar high yields for both
steps (6b and 6c). To demonstrate the scalability of the procedure, dichlorophenyl derivative 6c was
prepared on a larger scale, affording >1 g of the dioxene. Alkyl substituents could be incorporated at
the 6-position of the 1,4-dioxenes using the same conditions employed for the aryl substituents (6d-f).
Pleasingly, the cyclization was effective when chlorides were utilized as the leaving group (6e-f).
When using the secondary alcohol derivatives, this procedure gives access to 2,3,6-trisubstituted
dioxenes as complementary regioisomers to those accessed by Lacour.17 Alternatively, the 2,3,5-
trisubstituted dioxene 6g was formed from 2-bromo-2-cyclohexylethan-1-ol, also with excellent yield,
with cyclization at the secondary bromide. The scope was then expanded to include fused ring
tetrasubstituted dioxene derivatives (6h-i), from trans-2-bromocyclopentan-1-ol, and trans-2-bromo-1-
indanol in excellent yields over the two steps for both examples. When using tertiary alcohol, 1-chloro-
2-methyl-propanol 4j, a reduced yield (47%) was obtained for the O–H insertion (5j). Interestingly,
when subjected to the standard cyclization conditions, while the desired 2,3,6,6-tetrasubstituted 1,4-
dioxene 6j was formed as the major product (34%), the 2,2,4,4-tetrasubstituted oxetane 7 was also
formed. This may be due a favorable conformation for cyclization to the 4-membered ring being
enforced by the gem-dimethyl group.
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Next, we examined the functional groups on the diazo compound in order to generate
functionalized 1,4-dioxenes (Table 1). Diazo compounds 8a,b (R = iPr and Ph respectively) were
examined to probe for the effect of the ketone substituent. Both were well tolerated through the O–H
insertion and cyclization steps to form dioxenes 10a,b, with a reaction time of 15 h providing high
conversions. Pleasingly, the use of different anion stabilizing groups on the diazo component was also
successful, allowing for the synthesis of novel 2-sulfonyl (10c) and 2-phosphonyl 1,4-dioxenes (10d)
with good yields. The same conditions were used in each case, with the exception of diazo 8c, which
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gave a low yield for the OH insertion using the Ru catalyst (33% yield). Here, in the absence of an ester
group, the use of [Rh2(OAc)4] with 8c gave a much improved 84% yield.
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Table 1. Synthesis of functionalized 2,3-disubstituted dioxenes.a
7
8
9
E
N2 HO
E
R
O
E
R
O
O
Ru-cat.
i)a
cyclization
ii)b
R
O
Br
O
Br
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8a–8d
9a–9d
10a–10d
entry
1
R
E
Yield 9 (%) Yield 10 (%)
iPr
CO2Et
a
b
c
84
89
80
79
90
2
3
4
Ph
CO2Et
SO2Ph
85
Me
Me
84c
61
PO(OEt)2
d
aO–H insertion conditions: 2-bromoethanol (1.0 mmol), 8 (1.2 equiv.), [CpRu(MeCN)3][PF6] (1.0
b
mol%), 1,10-phenanthroline (1.0 mol%), 1,2-dichloroethane, 0.5 M, 60 °C, 15 h. Cyclization
conditions: 9 (0.3–0.4 mmol), NaH (1.2 equiv.), DMF, 0.025 M, 0 °C for 60 min; then 25 °C, 30 min.
cO–H insertion conditions for 8c: 2-bromoethanol (0.5 mmol), 8 (1.1 equiv.), [Rh2(OAc)4] (0.5 mol %),
PhH, 0.1 M, 80 °C, 90 min.
An unusual result was observed when diketone diazo 8e was employed, targeting bicyclic 1,4-
dioxene 10e, whereby cyclization occurred directly under the O–H insertion reaction conditions
(Scheme 4). Dioxene 10e was formed in low yield (21%), with ether 9e only observed in ca 1% yield.24
Following O–H insertion the enol tautomer is likely to form readily, due to the relatively increased
acidity of the methine proton, at the same time positioning the oxygen atom suitably to react.
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Scheme 4. Formation of bicyclic dioxene 10e with in situ cyclization, and intramolecular C–H
insertion from diazo 8f.
5
6
7
8
O
O
O
N2 HO
O
O
O
O
Ru-cat.
60 °C
21%
Br
OH Br
9
9e
10e
8e
10
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O
N
Rh2(OAc)4
PhH, 80 ºC
O
HO
N2
O
N
40%
Br
COMe
H H
11
8f
Attempts to form dioxenes from piperidine amide keto diazo compound 8f were unsuccessful;
using the Ru catalyst gave no reaction, presumably due to the Lewis basicity of the bulky amide.
Interestingly, using Rh2(OAc)4 an intramolecular C–H insertion reaction occurred with a 40% yield,
forming b-lactam 11 as a single diasteroisomer (Scheme 4).25,26 As an alternative route to amide
derivatives, the ester of dioxene 6c was readily hydrolyzed with 1 M NaOH in EtOH to generate
carboxylate sodium salt 12 (Scheme 5). This salt successfully underwent amide coupling with
pyrrolidine, using HATU, yielding amide 13. Similar amide coupling with m-toluidine, generated a 6-
substituted derivative of dioxincarboxamide 14 (Figure 1). Alternatively, reduction of the ester with
DIBAL formed the alcohol product 15 in high yield. Many of these derivatives present interesting
shape and physicochemical properties as lead-like compounds.
Scheme 5. Derivatization of 1,4-dioxene 6c.
O
pyrrolidine
92% (2 steps)
O
O
Ar
N
EtO2C
O
O
Ar
NaO2C
O
Ar
HATU
DIPEA
1 N NaOH
13
EtOH, 110 °C
DMF, 40 °C
O
O
12
6c
O
O
Ar
m-toluidine
93%
N
H
14
(2 steps)
O
Ar
DIBAL, Tol
HO
Cl
Cl
Ar =
O
15
–78 ºC to 0 ºC
89%
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In summary, we have described an efficient 2-step strategy for the preparation of diversely
functionalized 1,4-dioxenes through a Ru-catalyzed O–H insertion and cyclization. Choice of
substituents on the bromohydrin affords control of substitution pattern on the dioxene products. A
variety of anion stabilizing functional groups were tolerated in both O–H insertion and C–O cyclization
steps, affording functionalized dioxenes. A diverse range of functional groups could be incorporated at
the 2-, 3-, 5- and 6- positions of the dioxene ring, allowing for exploration of novel chemical space.
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EXPERIMENTAL SECTION
General Experimental Considerations. All nonaqueous reactions were run under an inert atmosphere
(argon) with flame-dried glassware and anhydrous solvents using standard techniques. Anhydrous
solvents were obtained by filtration through drying columns (THF, CH2Cl2) or used as supplied (DMF,
1,2-dichloroethane). Flash column chromatography was performed using 230-400 mesh silica with the
indicated solvent system. Analytical thin-layer chromatography (TLC) was performed on precoated,
glass-backed silica gel plates. Visualization of the developed chromatogram was performed by UV
absorbance (254 nm), aqueous potassium permanganate stain, PMA (phosphomolybdic acid),
ninhydrin or vanillin. Infrared spectra (nmax, FTIR ATR) were recorded in reciprocal centimeters (cm-
1). Nuclear magnetic resonance spectra were recorded on either 400 MHz or 500 MHz spectrometers.
1
Chemical shifts for H NMR spectra are recorded in parts per million from tetramethylsilane with the
solvent resonance as the internal standard (chloroform: d = 7.27 ppm, DMSO: d = 2.50 ppm). Data is
reported as follows: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, quin = quintet, sep
13
= septet, m = multiplet and br = broad), coupling constant in Hz, integration, assignment]. C NMR
spectra were recorded with complete proton decoupling. Chemical shifts are reported in parts per
million from tetramethylsilane with the solvent resonance as the internal standard (13CDCl3: 77.0 ppm,
31
(13CD3)2SO: 39.5 ppm). P NMR spectra were recorded with complete proton decoupling. Chemical
shifts are reported in parts per million referenced to the standard 85% phosphoric acid: 0 ppm. J values
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are reported in Hz. Assignments of 1H/13C spectra were made by the analysis of d/J values, and COSY,
DEPT-135, HSQC, and HMBC experiments as appropriate. Melting points are uncorrected. Reagents:
Commercial reagents were used as supplied or purified by standard techniques where necessary. Diazo
transfer reagents (tosyl azide and p-ABSA) were prepared by reported procedures.27 Diazo compounds
1,28 8b,29 8c,30 8d,31 8e,32 and 8f,33 were prepared according to the referenced literature procedures. For
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all diazo compounds synthesized, the resonance for the fully substituted C=N=N carbon in the C
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NMR could not be seen due to quadrupole coupling to N, therefore the carbon resonance is not
reported. Although we have not experienced any problems in the handling of azides or diazo reagents,
extreme care should be taken when manipulating them due to their potentially explosive nature.
Substituted b-bromhydrins were prepared by reported procedures.18
Synthesis of 1,4-Dioxene 3
(±)-Ethyl 2-(2-bromoethoxy)-3-oxobutanoate (2) A microwave vial (0.5–2.0 mL volume) was
charged with 2-bromoethanol (125 mg, 1.0 mmol), 1,10-phenanthroline (1.7 mg, 0.01 mmol) and
tris(acetonitrile)cyclopentadienylruthenium (II) hexafluorophosphate (4.3 mg, 0.01 mmol). The
reaction vessel was flushed with argon and sealed with a cap. Diazo 1 (188 mg, 1.2 mmol) in 1,2-
dichloroethane (2.0 mL) was added to the sealed vial. The reaction mixture was heated in an oil bath at
60 °C for 1 h, then allowed to cool to rt. The reaction mixture was diluted with CH2Cl2 (10 mL) and
concentrated in vacuo. A mixture of Et2O/pentane (1:1, 80 mL) was added to the residue to precipitate
out metal salts, and filtered through a pad of celite. The filtrate was concentrated in vacuo. Purification
by flash chromatography (15% to 20% Et2O in pentane) afforded bromide 2 as a pale yellow oil
(217 mg, 86%); Rf = 0.14 (15% Et2O in pentane); IR (film) / cm-1 2982, 1747 (C=O), 1725 (C=O),
1412, 1357, 1339, 1258, 1183, 1130, 1063, 1014, 863, 807, 678, 620, 571; 1H NMR (400 MHz, CDCl3)
d 4.44 (s, 1 H, CH(CO2Et)(COMe)), 4.32–4.25 (m, 2 H, CO2CH2CH3), 4.04 (dt, J = 10.6, 5.7 Hz, 1 H,
OCHH), 3.80 (dt, J = 10.6, 6.4 Hz, 1 H, OCHH), 3.57–3.52 (m, 2 H, CH2Br), 2.32 (s, 3 H, COCH3),
1.31 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) d 201.4 (C=O ketone), 166.7
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(C=O ester), 85.5 (CH(CO2Et)(COMe)), 70.9 (OCH2), 62.1 (CO2CH2CH3), 29.5 (CH2Br), 26.5
(COCH3), 14.1 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for C8H13BrO4Na+ [M+Na]+: 274.9895,
Found: 274.9900.
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(±)-Ethyl 3-oxo-2-(2-(tosyloxy)ethoxy)butanoate (2a) A microwave vial (0.5–2.0 mL volume)
was charged with 2-hydroxyethyl 4-methylbenzenesulfonate (216 mg, 1.0 mmol), 1,10-phenanthroline
(1.7 mg, 0.01 mmol) and tris(acetonitrile)cyclopentadienylruthenium (II) hexafluorophosphate (4.3 mg,
0.01 mmol). The reaction vessel was flushed with argon and sealed with a cap. Diazo 1 (188 mg, 1.2
mmol) in 1,2-dichloroethane (2.0 mL) was added to the sealed vial. The reaction mixture was heated in
an oil bath at 60 °C for 15 h, then allowed to cool to rt. The reaction mixture was diluted with CH2Cl2
(10 mL) and concentrated in vacuo. A mixture of Et2O/pentane (1:1, 80 mL) was added to the residue
to precipitate out metal salts, and filtered through a pad of celite. The filtrate was concentrated in
vacuo. Purification by flash chromatography (50% Et2O in pentane) afforded tosylate 2a as a pale
yellow oil (315 mg, 92%); Rf = 0.13 (50% Et2O in pentane); IR (film) / cm-1 2985, 1748, 1726, 1356,
1189, 1174, 1143, 1096, 1017, 919, 816, 771, 662; Keto tautomer: 1H NMR (400 MHz, CDCl3) d 7.85–
7.72 (m, 2 H, 2 × Ar-H), 7.41–7.30 (m, 2 H, 2 × Ar-H), 4.37 (s, 1 H, CH(CO2Et)(COMe)), 4.29–4.17
(m, 4 H, CO2CH2CH3 and OCH2), 3.92–3.84 (m, 1 H, CHHOTs), 3.80 (ddd, J = 11.5, 6.5, 3.6 Hz, 1 H,
CHHOTs), 2.44 (s, 3 H, Ar-CH3), 2.21 (s, 3 H, COCH3), 1.29 (t, J = 7.1 Hz, 3 H, CO2CH2CH3);
13C{1H} NMR (101 MHz, CDCl3) d 201.1 (C=O ketone), 166.5 (C=O ester), 145.0 (Ar-Cq-Me), 132.7
(Ar-Cq-SO2), 129.9 (2 × Ar-CH), 127.9 (2 × Ar-CH), 85.5 (CH(CO2Et)(COMe)), 68.7 (OCH2), 68.4
(CH2OTs), 62.1 (CO2CH2CH3), 26.4 (COCH3), 21.6 (Ar-CH3), 14.1 (CO2CH2CH3); Enol tautomer: 1H
NMR (400 MHz, CDCl3) d 11.0 (s, 1 H, OH), 7.85–7.72 (m, 2 H, 2 × Ar-H), 7.41–7.30 (m, 2 H, 2 ×
Ar-H), 4.29–4.17 (m, 4 H, CO2CH2CH3 and OCH2), 3.92–3.84 (m, 2 H, CH2OTs), 2.44 (s, 3 H, Ar-
CH3), 1.99 (s, 3 H, COCH3), 1.30 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3)
d 167.0 (COH), 166.5 (C=O ester), 145.0 (Ar-Cq-Me), 132.7 (Ar-Cq-SO2), 129.8 (2 × Ar-CH), 127.9 (2
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× Ar-CH), 124.3 (Cq(CO2Et)(COH(Me))), 71.1 (OCH2), 68.6 (CH2OTs), 60.9 (CO2CH2CH3), 21.6 (Ar-
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CH3), 16.0 (COCH3), 14.2 (CO2CH2CH3). FTMS (+p NSI) m/z Calcd for C15H21O7S+ [M+H]+:
345.1003, Found: 345.0999.
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Ethyl 3-methyl-5,6-dihydro-1,4-dioxine-2-carboxylate (3) DMF (16 mL) was added to a
flask containing sodium hydride (60% in mineral oil, 25 mg, 0.6 mmol) which had been cooled to 0 °C.
Bromide 2 (127 mg, 0.5 mmol) in DMF (4 mL) was added dropwise to the stirred suspension of
sodium hydride in DMF at 0 °C over 8 min. The reaction mixture was stirred at 0 °C for 1 h. Saturated
aq. NH4Cl (20 mL) was added. The aqueous mixture was extracted with EtOAc (4 ´ 20 mL). The
organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. Purification by flash
chromatography (25% Et2O in pentane) afforded dioxene 3 as a white crystalline solid (73 mg, 85%);
Rf = 0.22 (25% Et2O in pentane); mp = 54–56 °C; IR (film) / cm-1 2989, 2945, 2906, 1708 (C=O), 1631
(C=C), 1468, 1454, 1381, 1369, 1312, 1283, 1260, 1244, 1163, 1099, 1026, 941, 922, 886, 766, 671;
1H NMR (400 MHz, CDCl3) d 4.26 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 4.16–4.12 (m, 2 H,
OCH2CH2O), 4.10–4.06 (m, 2 H, OCH2CH2O), 2.23 (s, 3 H, CH3), 1.33 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) d 163.9 (CO2), 147.4 ((Me)Cq=C), 125.1
((EtO2C)Cq=C), 65.1 (OCH2CH2O), 63.2 (OCH2CH2O), 60.5 (CO2CH2CH3), 17.8 (CH3), 14.4
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(CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for C8H13O4 [M+H]+: 173.0814, Found: 173.0813.
Synthesis of Trisubstituted 1,4-Dioxenes 6a–6j and oxetane 7
b
General Procedure A: Ru-Catalyzed O–H Insertion with -Halohydrins
A microwave vial (0.5–2.0 mL volume) was charged with the requisite b-halohydrin 4 (1.0
mmol, 1.0 equiv), 1,10-phenanthroline (1.8 mg, 0.01 mmol, 1.0 mol%) and tris(acetonitrile)-
cyclopentadienylruthenium (II) hexafluorophosphate (4.3 mg, 0.01 mmol, 1.0 mol%). The reaction
vessel was flushed with argon and sealed with a cap. The requisite diazo (1.2 mmol, 1.2 equiv) in 1,2-
dichloroethane (2.0 mL) was added to the sealed vial. The reaction mixture was heated in an oil bath at
60 °C for 15 h, then allowed to cool to rt. The reaction mixture was diluted with CH2Cl2 (10 mL) and
concentrated in vacuo. A mixture of Et2O/pentane (1:1; 80 mL) was added to the residue to precipitate
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out metal salts, and filtered through a pad of celite. The filtrate was concentrated in vacuo. Purification
by flash chromatography under the specified conditions afforded the desired bromide.
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General Procedure B: Cyclization
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DMF (16 mL) was added to a flask containing sodium hydride (60% in mineral oil, 25 mg,
0.6 mmol, 1.2 equiv) which had been cooled to 0 °C. The requisite bromide 5 (0.5 mmol, 1.0 equiv) in
DMF (4 mL) was added dropwise to the stirred suspension of sodium hydride in DMF at 0 °C over
5 min. The reaction mixture was stirred at 0 °C for 1 h then 25 °C for 30 min. Saturated aq. NH4Cl (20
mL) was added. The aqueous mixture was extracted with EtOAc (4 ´ 20 mL). The organic extracts
were combined, dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography under
the specified conditions afforded the desired dioxene.
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(±)-Ethyl 2-(2-bromo-1-phenylethoxy)-3-oxobutanoate (5a) Prepared according to General
Procedure A employing diazo 1 (187 mg, 1.2 mmol) and (±)-2-bromo-1-phenylethan-1-ol18a 4a (201
mg, 1.0 mmol). Purification by flash chromatography (75% CH2Cl2 in pentane) afforded bromide 5a as
a pale yellow oil (300 mg, 91%, d.r. 52:48); Rf = 0.29 (75% CH2Cl2 in pentane); IR (film) / cm-1 3032,
2982, 2903, 1745 (C=O), 1723 (C=O), 1494, 1455, 1417, 1357, 1257, 1204, 1158, 1110, 1029, 921,
860, 757, 701, 669, 602, 551; Diastereoisomer 1: 1H NMR (400 MHz, CDCl3) d 7.41–7.28 (m, 5 H, 5
´ Ph-H), 4.71 (dd, J = 7.2, 5.3 Hz, 1 H, OCH(Ph)), 4.35–4.22 (m, 3 H, CH(CO2Et)(COMe) and
CO2CH2CH3), 3.74 (dd, J = 10.6, 7.2 Hz, 1 H, CHHBr), 3.57 (dd, J = 10.6, 5.3 Hz, 1 H, CHHBr), 2.26
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(s, 3 H, COCH3), 1.32 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz, CDCl3) d 202.5
(C=O ketone), 166.9 (C=O ester), 137.5 (Ph-Cq), 129.4 (Ph-CH), 129.0 (2 ´ Ph-CH), 127.2 (2 ´ Ph-
CH), 82.8 (CH(CO2Et)(COMe)), 81.6 (OCH(Ph)), 62.0 (CO2CH2CH3), 35.0 (CH2Br), 26.58 (COCH3),
14.1 (CO2CH2CH3); Diastereoisomer 2: 1H NMR (400 MHz, CDCl3) d 7.41–7.28 (m, 5 H, 5 ´ Ph-H),
4.61 (dd, J = 8.8, 3.8 Hz, 1 H, OCH(Ph)), 4.31 (s, 1 H, CH(CO2Et)(COMe)), 4.04 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 3.73 (dd, J = 11.0, 8.8 Hz, 1 H, CHHBr), 3.52 (dd, J = 11.0, 3.8 Hz, 1 H, CHHBr), 2.42
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(s, 3 H, COCH3), 1.14 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz, CDCl3) d 201.1
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(C=O ketone), 166.6 (C=O ester), 137.1 (Ph-Cq), 129.2 (Ph-CH), 128.8 (2 ´ Ph-CH), 127.1 (2 ´ Ph-
CH), 84.2 (CH(CO2Et)(COMe)), 83.5 (OCH(Ph)), 61.8 (CO2CH2CH3), 35.3 (CH2Br), 26.63 (COCH3),
13.8 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for C14H17BrO4Na+ [M+Na]+: 351.0208, Found:
351.0194.
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Ethyl 2-[(1S)-2-bromo-1-phenylethoxy]-3-oxobutanoate ((S)-5a) Prepared according to
General Procedure A employing diazo 1 (187 mg, 1.2 mmol) and enantioenriched (1S)-2-bromo-1-
phenylethan-1-ol34 (S)-4a) (201 mg, 1.0 mmol, 93% ee). Purification by flash chromatography (75%
CH2Cl2 in pentane) afforded bromide (S)-5a as a pale yellow oil (297 mg, 90%, d.r. 50:50); ꢀ ꢂꢃ +66.0
ꢁ
(c. 0.67, CHCl3).
(±)-Ethyl 3-methyl-6-phenyl-5,6-dihydro-1,4-dioxine-2-carboxylate (6a) Prepared according
to General Procedure B employing bromide (±)-5a (165 mg, 0.5 mmol). Purification by flash
chromatography (10% Et2O in pentane) afforded dioxene 6a as a white solid (113 mg, 91%); Rf = 0.23
(10% Et2O in pentane); mp = 25–27 °C; IR (film) / cm-1 2981, 2929, 1709 (C=O), 1634 (C=C), 1497,
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1455, 1370, 1315, 1297, 1281, 1243, 1156, 1101, 1070, 1043, 924, 881, 757, 698, 610, 593; H NMR
(400 MHz, CDCl3) d 7.43–7.34 (m, 5 H, 5 ´ Ph-H), 4.86 (dd, J = 8.3, 2.3 Hz, 1 H, OCH(Ph)), 4.32–
4.25 (m, 3 H, OCHH and CO2CH2CH3), 3.92 (dd, J = 11.2, 8.3 Hz, 1 H, OCHH), 2.29 (s, 3 H, CH3),
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1.34 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz, CDCl3) d 164.1 (CO2), 146.7
((Me)Cq=C), 136.3 (Ph-Cq), 128.6 (2 ´ Ph-CH), 128.5 (Ph-CH), 126.5 (2 ´ Ph-CH), 125.6
((EtO2C)Cq=C), 73.7 (OCH(Ph)), 69.9 (OCH2), 60.5 (CO2CH2CH3), 17.6 (CH3), 14.4 (CO2CH2CH3);
+
HRMS (ESI-TOF) m/z Calcd for C14H17O4 [M+H]+: 249.1127, Found: 249.1134.
Ethyl (6S)-3-methyl-6-phenyl-5,6-dihydro-1,4-dioxine-2-carboxylate ((S)-6a) Prepared
according to General Procedure B employing enantioenriched bromide (S)-5a (164 mg, 0.5 mmol,
93% ee). Purification by flash chromatography (10% Et2O in pentane) afforded dioxene (S)-6a as a
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ꢄꢅ
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white solid (105 mg, 85%, 92% ee); ꢀ
+157 (c. 0.98, CHCl3); HPLC, Chiralpak ID column,
ꢁ
99.3:0.7 nhexane/IPA, flow 1.0 mLmin-1, UV detection at 254 nm, 13.6 min ((S)-6a), 15.6 min ((R)-
6a).
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(±)-Ethyl 2-[2-bromo-1-(3-methoxyphenyl)ethoxy]-3-oxobutanoate (5b) Prepared according
to General Procedure A employing diazo 1 (187 mg, 1.2 mmol) and (±)-2-bromo-1-(3-
methoxyphenyl)ethan-1-ol18a,35 4b (231 mg, 1.0 mmol). Purification by flash chromatography (50% to
60% to 70% CH2Cl2 in pentane) afforded bromide 5b as a pale yellow oil (292 mg, 81%, dr 50:50); Rf
= 0.32 (60% CH2Cl2 in pentane); IR (film) / cm-1 2981, 2939, 2839, 1745 (C=O), 1723 (C=O), 1587,
1489, 1456, 1436, 1357, 1322, 1283, 1257, 1156, 1111, 1035, 862, 788, 754, 704, 671, 564;
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Diastereoisomer 1: H NMR (400 MHz, CDCl3) d 7.34–7.26 (m, 1 H, Ar-H), 6.98–6.89 (m, 2 H, 2 ´
Ar-H), 6.89–6.83 (m, 1 H, Ar-H), 4.69 (dd, J = 7.4, 5.2 Hz, 1 H, OCH(Ar)), 4.36–4.22 (m, 3 H,
CH(CO2Et)(COMe) and CO2CH2CH3), 3.82 (s, 3 H, OCH3), 3.72 (dd, J = 10.7, 7.4 Hz, 1 H, CHHBr),
3.56 (dd, J = 10.7, 5.2 Hz, 1 H, CHHBr), 2.27 (s, 3 H, COCH3), 1.32 (t, J = 7.1 Hz, 3 H, CO2CH2CH3);
13C{1H} NMR (101 MHz, CDCl3) d 202.5 (C=O ketone), 166.6 (C=O ester), 160.03 (Ar-Cq-OMe),
138.7 (Ar-Cq-CH(O)), 130.1 (Ar-CH), 119.5 (Ar-CH), 114.9 (Ar-CH), 112.9 (Ar-CH), 82.8
(CH(CO2Et)(COMe)), 81.5 (OCH(Ar)), 62.0 (CO2CH2CH3), 55.3 (OCH3), 34.9 (CH2Br), 26.59
1
(COCH3), 14.1 (CO2CH2CH3); Diastereoisomer 2: H NMR (400 MHz, CDCl3) d 7.34–7.26 (m, 1 H,
Ar-H), 6.98–6.89 (m, 2 H, 2 ´ Ar-H), 6.89–6.83 (m, 1 H, Ar-H), 4.59 (dd, J = 8.9, 3.7 Hz, 1 H,
OCH(Ar)), 4.31 (s, 1 H, CH(CO2Et)(COMe)), 4.11–4.03 (m, 2 H, CO2CH2CH3), 3.82 (s, 3 H, OCH3),
3.71 (dd, J = 11.0, 8.9 Hz, 1 H, CHHBr), 3.52 (dd, J = 11.0, 3.7 Hz, 1 H, CHHBr), 2.42 (s, 3 H,
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COCH3), 1.16 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz, CDCl3) d 201.0 (C=O
ketone), 166.9 (C=O ester), 159.95 (Ar-Cq-OMe), 139.0 (Ar-Cq-CH(O)), 129.9 (Ar-CH), 119.4 (Ar-
CH), 114.6 (Ar-CH), 112.3 (Ar-CH), 84.2 (CH(CO2Et)(COMe)), 83.4 (OCH(Ar)), 61.8 (CO2CH2CH3),
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55.3 (OCH3), 35.2 (CH2Br), 26.61 (COCH3), 13.8 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for
C15H19BrO5Na+ [M+Na]+: 381.0314, Found: 381.0318.
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(±)-Ethyl
6-(3-methoxyphenyl)-3-methyl-5,6-dihydro-1,4-dioxine-2-carboxylate
(6b)
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Prepared according to General Procedure B employing bromide 5b (180 mg, 0.5 mmol). Purification
by flash chromatography (20% Et2O in pentane) afforded dioxene 6b as a white solid (131 mg, 94%);
Rf = 0.32 (20% Et2O in pentane); mp = 53–55 °C; IR (film) / cm-1 2980, 2932, 2838, 1708 (C=O), 1635
(C=C), 1604, 1490, 1456, 1437, 1370, 1302, 1288, 1254, 1152, 1103, 1069, 1038, 927, 864, 782, 767,
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696, 585; H NMR (400 MHz, CDCl3) d 7.33–7.29 (m, 1 H, Ar-H), 6.98–6.92 (m, 2 H, 2 ´ Ar-H),
6.91–6.86 (m, 1 H, Ar-H), 4.83 (dd, J = 8.3, 2.3 Hz, 1 H, OCH(Ar)), 4.34–4.21 (m, 3 H, OCHH and
CO2CH2CH3), 3.91 (dd, J = 11.1, 8.3 Hz, 1 H, OCHH), 3.82 (s, 3 H, OCH3), 2.28 (s, 3 H, CH3), 1.33 (t,
J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) d 164.0 (CO2), 159.8 (Ar-Cq-OMe),
146.7 ((Me)Cq=C), 137.9 (Ar-Cq-CH(O)), 129.7 (Ar-CH), 125.5 ((EtO2C)Cq=C), 118.7 (Ar-CH), 113.9
(Ar-CH), 112.1 (Ar-CH), 73.5 (OCH(Ar)), 69.8 (OCH2), 60.5 (CO2CH2CH3), 55.3 (OCH3), 17.6
+
(CH3), 14.4 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for C15H19O5 [M+H]+: 279.1132, Found:
279.1125.
(±)-2-Bromo-1-(3,4-dichlorophenyl)ethan-1-ol (4c) Sodium borohydride (158 mg, 4.2 mmol)
was added portionwise to a solution of 2-bromo-3’,4’-dichloroacetophenone (1.61 g, 6.0 mmol) in
MeOH (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h 30 min. The reaction mixture
was concentrated in vacuo and water (20 mL) was added. The aqueous mixture was extracted with
Et2O (3 ´ 30 mL). The organic extracts were combined, washed with saturated aq. NH4Cl (15 mL),
brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography (20%
Et2O in pentane) afforded alcohol 4c as a white crystalline solid (1.33 g, 82%); Rf = 0.27 (20% Et2O in
pentane); mp = 49–51 °C (lit.36 mp = 59–50 °C (petroleum ether)); IR (film) / cm-1 3412 (br O-H),
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2961, 2899, 1565, 1471, 1421, 1392, 1196, 1133, 1070, 1031, 993, 885, 823, 743, 675, 640, 581; H
NMR (400 MHz, CDCl3) d 7.52 (d, J = 2.0 Hz, 1 H, Ar-H), 7.46 (d, J = 8.3 Hz, 1 H, Ar-H), 7.22 (dd, J
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= 8.3, 2.0 Hz, 1 H, Ar-H), 4.94–4.86 (m, 1 H, CH(OH)), 3.63 (dd, J = 10.6, 3.4 Hz, 1 H, CHHBr), 3.49
(dd, J = 10.6, 8.6 Hz, 1 H, CHHBr), 2.73 (d, J = 3.1 Hz, 1 H, OH); 13C{1H} NMR (101 MHz, CDCl3) d
140.4 (Ar-Cq-CH(OH)), 132.9 (Ar-Cq-Cl), 132.4 (Ar-Cq-Cl), 130.6 (Ar-CH), 128.0 (Ar-CH), 125.3
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(Ar-CH), 72.5 (CH(OH)), 39.6 (CH2Br). Observed data (1H and C NMR) was consistent with that
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previously reported.34 The reaction was performed on a larger scale (10 mmol acetophenone), which
afforded an isolated yield of alcohol (2.28 g, 84%).
(±)-Ethyl
2-[2-bromo-1-(3,4-dichlorophenyl)ethoxy]-3-oxobutanoate
(5c)
Prepared
according to General Procedure A employing diazo 1 (188 mg, 1.2 mmol) and 4c (269 mg, 1.0
mmol). Purification by flash chromatography (40% to 50% to 60% CH2Cl2 in pentane) afforded
bromide 5c as a colorless oil (302 mg, 76%, d.r. 52:48); Rf = 0.23 (50% CH2Cl2 in pentane); IR (film) /
cm-1 2984, 2939, 2912, 1746 (C=O), 1724 (C=O), 1565, 1470, 1403, 1357, 1258, 1202, 1158, 1110,
1062, 1031, 883, 824, 754, 710, 676, 644, 573, 541; Diastereoisomer 1: 1H NMR (400 MHz, CDCl3) d
7.51–7.45 (m, 2 H, 2 ´ Ar-H), 7.22 (dd, J = 8.3, 2.0 Hz, 1 H, Ar-H), 4.58 (dd, J = 8.2, 4.3 Hz, 1 H,
OCH(Ar)), 4.34 (s, 1 H, CH(CO2Et)(COMe)), 4.11 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.66 (dd, J =
11.0, 8.2 Hz, 1 H, CHHBr), 3.49 (dd, J = 11.0, 4.3 Hz, 1 H, CHHBr), 2.40 (s, 3 H, COCH3), 1.19 (t, J =
13
7.1 Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz, CDCl3) d 200.1 (C=O ketone), 166.5 (C=O
ester), 137.9 (Ar-Cq-CH(O)), 133.3 (Ar-Cq-Cl), 133.2 (Ar-Cq-Cl), 130.8 (Ar-CH), 129.0 (Ar-CH),
126.3 (Ar-CH), 84.4 (CH(CO2Et)(COMe)), 81.9 (OCH(Ar)), 62.1 (CO2CH2CH3), 34.6 (CH2Br), 26.6
1
(COCH3), 13.8 (CO2CH2CH3); Diastereoisomer 2: H NMR (400 MHz, CDCl3) d 7.51–7.45 (m, 1 H,
Ar-H), 7.42 (d, J = 2.0 Hz, 1 H, Ar-H), 7.18 (dd, J = 8.3, 2.0 Hz, 1 H, Ar-H), 4.68 (t, J = 6.2 Hz, 1 H,
OCH(Ar)), 4.32–4.23 (m, 3 H, CH(CO2Et)(COMe) and CO2CH2CH3), 3.71 (dd, J = 10.6, 6.4 Hz, 1 H,
CHHBr), 3.54 (dd, J = 10.6, 6.0 Hz, 1 H, CHHBr), 2.27 (s, 3 H, COCH3), 1.32 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) d 201.6 (C=O ketone), 166.3 (C=O ester), 137.4 (Ar-
Cq-CH(O)), 133.5 (Ar-Cq-Cl), 133.0 (Ar-Cq-Cl), 131.0 (Ar-CH), 129.2 (Ar-CH), 126.4 (Ar-CH), 82.9
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(CH(CO2Et)(COMe)), 80.1 (OCH(Ar)), 62.2 (CO2CH2CH3), 34.4 (CH2Br), 26.5 (COCH3), 14.1
(CO2CH2CH3); HRMS (FTMS +pNSI) m/z Calcd for C14H15BrCl2O4Na+ [M+Na]+: 418.9423, Found:
418.9422. The reaction was performed on a larger scale (8.0 mmol alcohol 4c) using a microwave vial
(10–20 mL volume) equipped with an Ar balloon, which afforded an improved isolated yield of
bromide 5c (2.91 g, 91%).
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(±)-Ethyl 6-(3,4-dichlorophenyl)-3-methyl-5,6-dihydro-1,4-dioxine-2-carboxylate (6c)
Prepared according to General Procedure B employing bromide 5c (199 mg, 0.5 mmol). Purification
by flash chromatography (15% Et2O in pentane) afforded dioxene 6c as a white crystalline solid
(133 mg, 84%); Rf = 0.29 (15% Et2O in pentane); mp = 84–86 °C; IR (film) / cm-1 2982, 2928, 2875,
1709 (C=O), 1636 (C=C), 1565, 1473, 1385, 1371, 1343, 1318, 1297, 1252, 1162, 1132, 1103, 1071,
1
1032, 930, 822, 767, 707, 681, 660, 582; H NMR (400 MHz, CDCl3) d 7.49 (d, J = 2.0 Hz, 1 H, Ar-
H), 7.47 (d, J = 8.3 Hz, 1 H, Ar-H), 7.22 (dd, J = 8.3, 2.0 Hz, 1 H, Ar-H), 4.83 (dd, J = 8.0, 2.3 Hz,
1 H, OCH(Ar)), 4.33–4.23 (m, 3 H, OCHH and CO2CH2CH3), 3.88 (dd, J = 11.2, 8.0 Hz, 1 H, OCHH),
2.27 (s, 3 H, CH3), 1.34 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) d 163.7
(CO2), 146.9 ((Me)Cq=C), 136.5 (Ar-Cq-CH(O)), 133.0 (Ar-Cq-Cl), 132.7 (Ar-Cq-Cl), 130.7 (Ar-CH),
128.5 (Ar-CH), 125.7 (Ar-CH), 125.6 ((EtO2C)Cq=C), 72.4 (OCH(Ar)), 69.2 (OCH2), 60.7
+
(CO2CH2CH3), 17.5 (CH3), 14.4 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for C14H15Cl2O4
[M+H]+: 317.0347, Found: 317.0356. The reaction was performed on a larger scale (5.0 mmol bromide
5c) which afforded an isolated yield of dioxene 6c (1.28 g, 80%).
(±)-2-Bromo-1-cyclohexylethan-1-ol (4d) and (±)-2-bromo-2-cyclohexylethan-1-ol (4g)
Using conditions developed by Ward,37 N-bromosuccinimide (3.56 g, 20.0 mmol) was added to a
solution of vinylcyclohexane (1.37 mL, 10.0 mmol) in DMSO (12.5 mL) and water (0.4 mL) at 10 ºC.
The reaction mixture was warmed to 25 ºC and stirred for 1 h 15 min. Saturated aq. NaHCO3 (20 mL)
was then added, followed by EtOAc (30 mL). The layers were separated and the aqueous layer was
extracted with EtOAc (2 ´ 30 mL). The organic extracts were combined, dried (Na2SO4) and
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concentrated in vacuo. Purification by flash chromatography (10% Et2O in pentane) afforded alcohol
4d as a pale yellow oil (601 mg, 29%) followed by alcohol 4g as a pale yellow oil (784 mg, 38%);
Alcohol 4d: Rf = 0.37 (10% EtOAc in hexanes); IR (film) / cm-1 3385 (br O-H), 2923, 2852, 1449,
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1096, 1039, 986, 893, 659; H NMR (400 MHz, CDCl3) d 3.62 (dd, J = 9.5, 1.9 Hz, 1 H, CHHBr),
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3.58–3.40 (m, 2 H, CHOH and CHHBr), 2.08 (d, J = 4.6 Hz, 1 H, OH), 1.99–1.86 (m, 1 H, Cy-CH),
1.84–1.72 (m, 2 H, 2 × Cy-CH), 1.72–1.63 (m, 2 H, 2 × Cy-CH), 1.56–1.46 (m, 1 H, Cy-CH), 1.35–
13
0.98 (m, 5 H, 5 × Cy-CH); C{1H} NMR (101 MHz, CDCl3) d 75.2 (CHOH), 42.1 (Cy-CH2), 39.5
(CH2Br), 29.0 (Cy-CH), 28.3 (Cy-CH2), 26.2 (Cy-CH2), 26.0 (Cy-CH2), 25.9 (Cy-CH2); HRMS (EI-
TOF) m/z Calcd for C8H13Br+ [M-H2O]+: 188.0201, Found: 188.0201. Alcohol 4g: Rf = 0.21 (10%
EtOAc in hexanes); IR (film) / cm-1 3349 (br O-H), 2925, 2853, 1449, 1068, 1015, 891, 658; 1H NMR
(400 MHz, CDCl3) d 4.09 (q, J = 5.7 Hz, 1 H, CHBr), 3.86 (dd, J = 6.6, 5.7 Hz, 2 H, CH2OH), 2.00 (t,
J = 6.6 Hz, 1 H, OH), 1.95–1.84 (m, 1 H, Cy-CH), 1.84–1.62 (m, 5 H, 5 × Cy-CH), 1.39–1.04 (m, 5 H,
13
5 × Cy-CH); C{1H} NMR (101 MHz, CDCl3) d 67.4 (CHBr), 65.3 (CH2OH), 41.3 (Cy-CH), 30.9
1
(Cy-CH2), 30.3 (Cy-CH2), 26.1 (Cy-CH2), 26.0 (Cy-CH2), 25.9 (Cy-CH2). Observed data (IR, H and
13C NMR) for alcohol 4g was consistent with that previously reported.38
(±)-Ethyl 2-(2-bromo-1-cyclohexylethoxy)-3-oxobutanoate (5d) Prepared according to
General Procedure A employing diazo 1 (188 mg, 1.2 mmol) and 4d (209 mg, 1.0 mmol).
Purification by flash chromatography (15% Et2O in pentane) afforded bromide 5d as a pale yellow oil
as a mixture of keto and enol tautomers (283 mg, 84%; 67% keto; d.r. 64:36); Rf = 0.26 (15% Et2O in
pentane); IR (film) / cm-1 2926, 2854, 1748 (C=O), 1726 (C=O), 1655, 1449, 1255, 1180, 1112, 1035,
1015; Diastereomer 1 (keto tautomer): 1H NMR (400 MHz, CDCl3) d 4.51 (s, 1 H,
CH(CO2Et)(COMe)), 4.46–4.40 (m, 2 H, CO2CH2CH3), 3.75–3.37 (m, 3 H, CH2Br and OCH(Cy)),
2.35 (s, 3 H, COCH3), 2.04–1.53 (m, 6 H, 6 ´ Cy-CH), 1.44–0.98 (m, 8 H, CO2CH2CH3 and 5 ´ Cy-
CH); 13C{1H} NMR (101 MHz, CDCl3) d 202.7 (C=O ketone), 167.4 (C=O ester), 84.7
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(CH(CO2Et)(COMe)), 84.4 (OCH(Cy)), 61.9 (CO2CH2CH3), 40.8 (Cy-CH), 32.4 (CH2Br), 29.0 (Cy-
CH2), 28.4 (2 × Cy-CH2), 26.6 (Cy-CH2), 26.3 (Cy-CH2), 26.03 (COCH3), 25.98 (Cy-CH2), 14.1
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(CO2CH2CH3); Diastereomer 2 (keto tautomer): H NMR (400 MHz, CDCl3) d 4.44 (s, 1 H,
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CH(CO2Et)(COMe)), 4.46–4.40 (m, 2 H, CO2CH2CH3), 3.75–3.37 (m, 3 H, CH2Br and OCH(Cy)),
2.30 (s, 3 H, COCH3), 2.04–1.53 (m, 6 H, 6 ´ Cy-CH), 1.44–0.98 (m, 8 H, CO2CH2CH3 and 5 ´ Cy-
CH); 13C{1H} NMR (101 MHz, CDCl3) d 202.0 (C=O ketone), 167.6 (C=O ester), 86.0
(CH(CO2Et)(COMe)), 85.6 (OCH(Cy)), 62.0 (CO2CH2CH3), 42.1 (Cy-CH2), 40.5 (Cy-CH2), 39.5 (Cy-
CH), 32.5 (CH2Br) 28.3 (Cy-CH2), 27.7 (Cy-CH2), 26.6 (COCH3), 25.9 (Cy-CH2), 14.1 (CO2CH2CH3);
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Enol tautomer: H NMR (400 MHz, CDCl3) d 11.3 (s, 1 H, OH), 4.46–4.40 (m, 2 H, CO2CH2CH3),
3.75–3.37 (m, 3 H, CH2Br and OCH(Cy)), 2.11 (s, 3 H, COCH3), 2.04–1.53 (m, 6 H, 6 ´ Cy-CH),
1.44–0.98 (m, 8 H, CO2CH2CH3 and 5 ´ Cy-CH); HRMS (ESI-TOF) m/z Calcd for C14H23O4BrNa+
[M+Na]+: 357.0677, Found: 357.0683. Signals for enol tautomer were very weak by 13C NMR.
(±)-Ethyl 6-cyclohexyl-3-methyl-5,6-dihydro-1,4-dioxine-2-carboxylate (6d) Prepared
according to General Procedure B employing bromide 5d (168 mg, 0.5 mmol). Purification by flash
chromatography (10% Et2O in pentane) afforded dioxene 6d as a white crystalline solid (100 mg,
78%); Rf = 0.28 (10% Et2O in pentane); mp = 32–33 °C; IR (film) / cm-1 2988, 2924, 2855, 1709
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(C=O), 1639 (C=C), 1210, 1297, 1247, 1176, 1126, 1081, 1053, 1027, 922, 767; H NMR (400 MHz,
CDCl3) d 4.25 (dq, J = 7.1, 1.5 Hz, 2 H, CO2CH2CH3), 4.19 (dd, J = 11.0, 2.1 Hz, 1 H, OCHH), 3.87
(dd, J = 11.0, 7.3 Hz, 1 H, OCHH), 3.57 (td, J = 7.3, 2.1 Hz, 1 H, OCH(Cy)), 2.23 (s, 3 H, CH3), 2.10–
1.97 (m, 1 H, Cy-CH), 1.85–1.54 (m, 5 H, 5 ´ Cy-CH), 1.34 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.31–
0.97 (m, 5 H, 5 ´ Cy-CH); 13C{1H} NMR (101 MHz, CDCl3) d 164.3 (CO2), 146.7 ((Me)Cq=C), 124.8
((EtO2C)Cq=C), 75.9 (OCH(Cy)), 67.0 (OCH2), 60.3 (CO2CH2CH3), 38.3 (Cy-CH), 28.9 (Cy-CH2),
28.3 (Cy-CH2), 26.3 (Cy-CH2), 25.8 (Cy-CH2), 25.7 (Cy-CH2), 17.5 (CH3), 14.4 (CO2CH2CH3);
+
HRMS (ESI-TOF) m/z Calcd for C14H23O4 [M+H]+: 255.1596, Found: 255.1606.
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(±)-Ethyl
2-({1-[(tert-butyldimethylsilyl)oxy]-3-chloropropan-2-yl}oxy)-3-oxobutanoate
(5e) Prepared according to General Procedure A employing diazo 1 (187 mg, 1.2 mmol) and (±)-1-
[(tert-butyldimethylsilyl)oxy]-3-chloropropan-2-ol18a,39 4e (225 mg, 1.0 mmol). Purification by flash
chromatography (5% EtOAc in pentane) afforded chloride 5e as a colorless oil (251 mg, 71%, d.r.
52:48); Rf = 0.28 (5% EtOAc in pentane); IR (film) / cm-1 2956, 2931, 2858, 1749 (C=O), 1729 (C=O),
1472, 1359, 1339, 1253, 1183, 1114, 1062, 1008, 974, 939, 900, 835, 777, 669, 555; Diastereoisomer
1: 1H NMR (400 MHz, CDCl3) d 4.69 (s, 1 H, CH(CO2Et)(COMe)), 4.31–4.24 (m, 2 H, CO2CH2CH3),
3.88–3.78 (m, 2 H, CHHOTBS and CHHCl), 3.76–3.67 (m, 3 H, OCH(CH2OTBS) and CHHOTBS and
CHHCl), 2.32 (s, 3 H, COCH3), 1.307 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 0.89 (s, 9 H, C(CH3)3), 0.07
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(s, 6 H, OSi(CH3)2(tBu)); C{1H} NMR (101 MHz, CDCl3) d 201.8 (C=O ketone), 167.23 (C=O
ester), 85.1 (CH(CO2Et)(COMe)), 81.0 (OCH(CH2OTBS)), 62.9 (CH2OTBS), 61.96 (CO2CH2CH3),
44.0 (CH2Cl), 26.6 (COCH3), 25.8 (C(CH3)3), 18.2 (Cq(CH3)3), 14.1 (CO2CH2CH3), –5.5
(OSi(CH3)(C’H3)(tBu), –5.6 (OSi(CH3)(C’H3)(tBu); Diastereoisomer 2: 1H NMR (400 MHz, CDCl3) d
4.72 (s, 1 H, CH(CO2Et)(COMe)), 4.31–4.24 (m, 2 H, CO2CH2CH3), 3.88–3.78 (m, 2 H, CHHOTBS
and CHHCl), 3.76–3.67 (m, 3 H, OCH(CH2OTBS) and CHHOTBS and CHHCl), 2.30 (s, 3 H,
COCH3), 1.310 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 0.89 (s, 9 H, C(CH3)3), 0.08 (s, 6 H,
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OSi(CH3)2(tBu)); C{1H} NMR (101 MHz, CDCl3) d 201.7 (C=O ketone), 167.22 (C=O ester), 85.2
(CH(CO2Et)(COMe)), 80.8 (OCH(CH2OTBS)), 63.0 (CH2OTBS), 61.99 (CO2CH2CH3), 43.2 (CH2Cl),
26.4 (COCH3), 25.8 (C(CH3)3), 18.2 (Cq(CH3)3), 14.1 (CO2CH2CH3), –5.5 (OSi(CH3)(C’H3)(tBu), –5.6
(OSi(CH3)(C’H3)(tBu); HRMS (ESI-TOF) m/z Calcd for C15H30ClO5Si+ [M+H]+: 353.1551, Found:
353.1548.
(±)-Ethyl
6-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-5,6-dihydro-1,4-dioxine-2-
carboxylate (6e) Prepared according to General Procedure B employing chloride 5e (177 mg, 0.5
mmol). Purification by flash chromatography (10% Et2O in pentane) afforded dioxene 6e as a white
solid (143 mg, 90%); Rf = 0.26 (10% Et2O in pentane); mp = 20–21 °C; IR (film) / cm-1 2954, 2931,
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2886, 2858, 1714 (C=O), 1638 (C=C), 1464, 1370, 1300, 1253, 1175, 1139, 1107, 1052, 973, 919, 837,
779, 668; 1H NMR (400 MHz, CDCl3) d 4.29–4.19 (m, 3 H, OCHH and CO2CH2CH3), 4.01–3.85 (m, 3
H, OCH(CH2OTBS) and OCHH and CHHOTBS), 3.70 (dd, J = 10.5, 7.0 Hz, 1 H, CHHOTBS), 2.22
(s, 3 H, CH3), 1.32 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 0.89 (s, 9 H, C(CH3)3), 0.080 (s, 3 H,
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OSi(CH3)(C’H3)(tBu)), 0.076 (s, 3 H, OSi(CH3)(C’H3)(tBu)); C{1H} NMR (101 MHz, CDCl3) d
164.0 (CO2), 146.9 ((Me)Cq=C), 124.6 ((EtO2C)Cq=C), 71.8 (OCH(CH2OTBS)), 66.3 (OCH2), 61.5
(CH2OTBS), 60.5 (CO2CH2CH3), 25.8 (C(CH3)3), 18.2 (Cq(CH3)3), 17.7 (CH3), 14.3 (CO2CH2CH3),
–5.44 (OSi(CH3)(C’H3)(tBu), –5.46 (OSi(CH3)(C’H3)(tBu); HRMS (ESI-TOF) m/z Calcd for
C15H29O5Si+ [M+H]+: 317.1784, Found: 317.1783.
(±)-Ethyl 2-[(1,3-dichloropropan-2-yl)oxy]-3-oxobutanoate (5f) Prepared according to
General Procedure A employing diazo 1 (189 mg, 1.2 mmol) and 1,3-dichloropropan-2-ol18a,40 4f
(129 mg, 1.0 mmol). Purification by flash chromatography (5% to 10% EtOAc in pentane) afforded
chloride 5f as a colorless oil (171 mg, 67%); Rf = 0.31 (10% EtOAc in pentane); IR (film) / cm-1 2984,
2905, 1747 (C=O), 1726 (C=O), 1427, 1358, 1340, 1257, 1211, 1182, 1157, 1121, 1016, 860, 837, 757,
1
704, 613, 560; H NMR (400 MHz, CDCl3) d 4.64 (s, 1 H, CH(CO2Et)(COMe)), 4.33–4.24 (m, 2 H,
CO2CH2CH3), 3.92–3.86 (m, 1 H, OCH(CH2Cl)2), 3.82–3.78 (m, 2 H, CH2Cl), 3.77–3.70 (m, 2 H,
C’H2Cl), 2.32 (s, 3 H, COCH3), 1.32 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz,
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CDCl3) d 200.8 (C=O ketone), 166.8 (C=O ester), 85.1 (CH(CO2Et)(COMe)), 79.9 (OCH(CH2Cl)2),
62.3 (CO2CH2CH3), 43.4 (CH2Cl), 43.2 (C’H2Cl), 26.6 (COCH3), 14.1 (CO2CH2CH3); HRMS (CI) m/z
Calcd for C9H18Cl2NO4 [M+NH4]+: 274.0613, Found: 274.0619.
+
(±)-Ethyl 6-(chloromethyl)-3-methyl-5,6-dihydro-1,4-dioxine-2-carboxylate (6f) Prepared
according to General Procedure B employing chloride 5f (129 mg, 0.5 mmol). Purification by flash
chromatography (15% to 20% Et2O in pentane) afforded dioxene 6f as a colorless oil (100 mg, 90%);
Rf = 0.33 (20% Et2O in pentane); IR (film) / cm-1 2981, 2932, 1708 (C=O), 1635 (C=C), 1446, 1371,
1307, 1249, 1164, 1123, 1075, 961, 931, 852, 767, 728, 692, 588, 579; 1H NMR (400 MHz, CDCl3) d
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4.32–4.24 (m, 3 H, OCHH and CO2CH2CH3), 4.24–4.17 (m, 1 H, OCH(CH2Cl)), 4.07 (dd, J = 11.1,
5.7 Hz, 1 H, OCHH), 3.76 (dd, J = 11.3, 4.6 Hz, 1 H, CHHCl), 3.61 (dd, J = 11.3, 8.2 Hz, 1 H,
CHHCl), 2.25 (s, 3 H, CH3), 1.35 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3)
d 163.6 (CO2), 147.0 ((Me)Cq=C), 124.3 ((EtO2C)Cq=C), 71.0 (OCH(CH2Cl)), 65.6 (OCH2), 60.7
(CO2CH2CH3), 40.8 (CH2Cl) 17.6 (CH3), 14.3 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for
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C9H14ClO4 [M+H]+: 221.0581, Found: 221.0580.
(±)-Ethyl 2-(2-bromo-2-cyclohexylethoxy)-3-oxobutanoate (5g) Prepared according to
General Procedure A employing diazo 1 (188 mg, 1.2 mmol) and 4g (209 mg, 1.0 mmol). Purification
by flash chromatography (15% Et2O in pentane) afforded bromide 5g as a pale yellow oil as a mixture
of keto and enol tautomers (291 mg, 87%; 71% keto; d.r. 56:44); Rf = 0.26 (15% Et2O in pentane); IR
(film) / cm-1 2928, 2854, 1747 (C=O), 1728 (C=O), 1449, 1369, 1258, 1149, 1128, 1016; Diastereomer
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1 (keto tautomer): H NMR (400 MHz, CDCl3) d 4.41 (s, 1 H, CH(CO2Et)(COMe)), 4.37–4.21 (m, 2
H, CO2CH2CH3), 4.19–3.61 (m, 3 H, CH(Cy)Br and OCH2), 2.32 (s, 3 H, COCH3), 1.96–1.61 (m, 6 H,
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6 × Cy-CH), 1.46–1.08 (m, 8 H, CO2CH2CH3 and 5 ´ Cy-CH); C{1H} NMR (101 MHz, CDCl3) d
201.6 (C=O ketone), 166.9 (C=O ester), 85.7 (CH(CO2Et)(COMe)), 73.5 (OCH2), 62.0 (CO2CH2CH3),
59.9 (CH(Cy)Br), 40.9 (Cy-CH), 30.96 (Cy-CH2), 29.1 (Cy-CH2), 28.7 (Cy-CH2), 26.6 (Cy-CH2),
26.11 (Cy-CH2), 26.08 (COCH3), 25.86 (Cy-CH2), 14.1 (CO2CH2CH3); Diastereomer 2 (keto
1
tautomer): H NMR (400 MHz, CDCl3) d 4.40 (s, 1 H, CH(CO2Et)(COMe)), 4.37–4.21 (m, 2 H,
CO2CH2CH3), 4.19–3.61 (m, 3 H, CH(Cy)Br and OCH2), 2.31 (s, 3 H, COCH3), 1.96–1.61 (m, 6 H, 6 ´
Cy-CH), 1.46–1.08 (m, 8 H, CO2CH2CH3 and 5 ´ Cy-CH); 13C{1H} NMR (101 MHz, CDCl3) d 201.6
(C=O ketone), 166.8 (C=O ester), 85.6 (CH(CO2Et)(COMe)), 72.8 (OCH2), 62.0 (CO2CH2CH3), 59.3
(CH(Cy)Br), 40.6 (Cy-CH), 30.93 (Cy-CH2), 29.1 (Cy-CH2), 26.5 (Cy-CH2), 26.13 (Cy-CH2), 26.08
(COCH3), 25.87 (Cy-CH2), 14.1 (CO2CH2CH3); Enol tautomer: 1H NMR (400 MHz, CDCl3) d 11.1 (s,
1 H, OH), 4.37–4.21 (m, 2 H, CO2CH2CH3), 4.19–3.61 (m, 3 H, CH(Cy)Br and OCH2), 2.11 (s, 3 H,
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COCH3), 1.96–1.61 (m, 6 H, 6 ´ Cy-CH), 1.46–1.08 (m, 8 H, CO2CH2CH3 and 5 ´ Cy-CH); HRMS
(ESI-TOF) m/z Calcd for C14H23O4BrNa+ [M+Na]+: 357.0677, Found: 357.0669. Signals for enol
tautomer were very weak by 13C NMR.
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(±)-Ethyl 5-cyclohexyl-3-methyl-5,6-dihydro-1,4-dioxine-2-carboxylate (6g) Prepared
according to General Procedure B employing bromide 5g (168 mg, 0.5 mmol). Purification by flash
chromatography (10% Et2O in pentane) afforded dioxene 6g as a white crystalline solid (113 mg,
89%); Rf = 0.16 (10% Et2O in pentane); mp = 35–37 °C; IR (film) / cm-1 2982, 2930, 2857, 1706
(C=O), 1633 (C=C), 1446, 1372, 1306, 1287, 1270, 1241, 1166, 1123, 1082, 1066, 1015, 976, 964,
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769; H NMR (400 MHz, CDCl3) d 4.33–4.21 (m, 2 H, CO2CH2CH3), 4.19–4.11 (m, 1 H, OCHH),
3.79–3.71 (m, 2 H, OCHH and OCH(Cy)), 2.24 (CH3), 1.95–1.88 (m, 1 H, Cy-CH), 1.76 (m, 2 H, 2 ×
Cy-CH), 1.73–1.64 (m, 2 H, 2 ´ Cy-CH), 1.64–1.58 (m, 1 H, Cy-CH), 1.34 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 1.30–1.02 (m, 5 H, 5 ´ Cy-CH); 13C{1H} NMR (101 MHz, CDCl3) d 164.0 (CO2), 147.5
((Me)Cq=C), 124.7 ((EtO2C)Cq=C), 78.3 (OCH(Cy)), 65.2 (OCH2), 60.4 (CO2CH2CH3), 38.6 (Cy-CH),
28.4 (Cy-CH2), 28.3 (Cy-CH2), 26.2 (Cy-CH2), 25.8 (Cy-CH2), 25.7 (Cy-CH2), 17.8 (CH3), 14.4
+
(CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for C14H23O4 [M+H]+: 255.1596, Found: 255.1601.
(±)-trans-Ethyl 2-[(2-bromocyclopentyl)oxy]-3-oxobutanoate (5h) Prepared according to
General Procedure A employing diazo 1 (187 mg, 1.2 mmol) and (±)-trans-2-bromocyclopentan-1-
ol18a,41 4h (165 mg, 1.0 mmol). Purification by flash chromatography (5% to 10% Et2O in pentane)
afforded bromide 5h as a colorless oil (213 mg, 73%, d.r. 50:50); Rf = 0.13 (5% Et2O in pentane); IR
(film) / cm-1 2980, 2876, 1747 (C=O), 1726 (C=O), 1436, 1411, 1356, 1335, 1256, 1182, 1159, 1114,
1
1070, 1031, 960, 848, 810, 618, 537; Diastereoisomer 1: H NMR (400 MHz, CDCl3) d 4.52 (s, 1 H,
CH(CO2Et)(COMe)), 4.33–4.21 (m, 3 H, CHBr and CO2CH2CH3), 4.20–4.13 (m, 1 H, OCH), 2.45–
2.32 (m, 1 H, CHH), 2.29 (s, 3 H, COCH3), 2.23–2.14 (m, 1 H, CHH), 2.04–1.97 (m, 1 H, CHH), 1.91–
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1.76 (m, 3 H, CHH and CH2), 1.32 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz,
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CDCl3) d 201.8 (C=O ketone), 167.2 (C=O ester), 89.3 (OCH), 84.4 (CH(CO2Et)(COMe)), 62.1
(CO2CH2CH3), 53.5 (CHBr), 34.64 (CH2), 29.9 (CH2), 26.4 (COCH3), 21.5 (CH2), 14.1 (CO2CH2CH3);
Diastereoisomer 2: 1H NMR (400 MHz, CDCl3) d 4.47 (s, 1 H, CH(CO2Et)(COMe)), 4.33–4.21 (m, 3
H, CHBr and CO2CH2CH3), 4.20–4.13 (m, 1 H, OCH), 2.45–2.32 (m, 1 H, CHH), 2.25 (s, 3 H,
COCH3), 2.23–2.14 (m, 1 H, CHH), 2.04–1.97 (m, 1 H, CHH), 1.91–1.76 (m, 3 H, CHH and CH2),
1.31 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) d 201.7 (C=O ketone), 167.2
(C=O ester), 89.1 (OCH), 84.5 (CH(CO2Et)(COMe)), 62.0 (CO2CH2CH3), 52.9 (CHBr), 34.57 (CH2),
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29.8 (CH2), 26.3 (COCH3), 21.6 (CH2), 14.1 (CO2CH2CH3); HRMS (CI) m/z Calcd for C11H21BrNO4
[M+NH4]+: 310.0654, Found: 310.0650.
(±)-cis-Ethyl 3-methyl-4aH,5H,6H,7H,7aH-cyclopenta[b][1,4]dioxine-2-carboxylate (6h)
Prepared according to General Procedure B employing bromide 5h (147 mg, 0.5 mmol). Purification
by flash chromatography (20% Et2O in pentane) afforded dioxene 6h as a colorless oil (97 mg, 91%);
Rf = 0.30 (20% Et2O in pentane); IR (film) / cm-1 2978, 2945, 2878, 1707 (C=O), 1635 (C=C), 1447,
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1370, 1347, 1303, 1252, 1157, 1127, 1082, 1041, 1021, 936, 886, 861, 768, 739; H NMR (400 MHz,
CDCl3) d 4.33–4.21 (m, 3 H, OCH and CO2CH2CH3), 4.19–4.14 (td, J = 5.2, 3.4 Hz, 1 H, OC’H), 2.24
(s, 3 H, CH3), 1.96–1.85 (m, 4 H, 2 ´ CHH and CH2), 1.82–1.72 (m, 1 H, CHH), 1.68–1.58 (m, 1 H,
CHH), 1.33 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) d 164.3 (CO2), 146.0
((Me)Cq=C), 122.5 ((EtO2C)Cq=C), 76.7 (OCH), 74.0 (OC’H), 60.5 (CO2CH2CH3), 28.0 (CH2), 27.2
+
(CH2), 18.8 (CH2), 17.9 (CH3), 14.4 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for C11H17O4
[M+H]+: 213.1127, Found: 213.1127.
(±)-trans-Ethyl 2-[(2-bromo-2,3-dihydro-1H-inden-1-yl)oxy]-3-oxobutanoate (5i) Prepared
according to General Procedure A employing diazo 1 (188 mg, 1.2 mmol) and (±)-trans-2-bromo-1-
indanol 4i (213 mg, 1.0 mmol). Purification by flash chromatography (10% Et2O in pentane) afforded
bromide 5i as a yellow oil as a mixture of keto and enol tautomers (298 mg, 87%; 58% keto; d.r.
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62:38); Rf = 0.20 (10% Et2O in pentane); IR (film) / cm-1 2983, 1728 (C=O), 1656 (C=O), 1621, 1478,
1464, 1409, 1337, 1254, 1216, 1179, 1123, 1061, 1019, 961, 936, 915, 861, 820, 755, 734, 615, 545;
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Diastereoisomer 1 (keto tautomer): H NMR (400 MHz, CDCl3) d 7.63–7.58 (m, 1 H, Ar-CH), 7.47–
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7.20 (m, 3 H, 3 ´ Ar-H), 5.23 (d, J = 5.2 Hz, 1 H, OCH(Ar)), 5.00 (s, 1 H, CH(CO2Et)(COMe)), 4.51–
4.44 (m, 1 H, CHBr), 4.41–4.24 (m, 2 H, CO2CH2CH3), 3.65 (d, J = 16.4, 7.3 Hz, 1 H, CHH(Ar)),
3.31–3.19 (m, 1 H, CHH(Ar)), 2.34 (s, 3 H, COCH3), 1.33 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H}
NMR (101 MHz, CDCl3) d 201.1 (C=O ketone), 167.2 (C=O ester), 140.0 (Ar-Cq), 139.2 (Ar-Cq),
129.5 (Ar-CH), 127.6 (Ar-CH), 125.4 (Ar-CH), 124.4 (Ar-CH), 90.8 (OCH(Ar)), 84.6
(CH(CO2Et)(COMe)), 62.1 (CO2CH2CH3), 51.0 (CHBr), 41.2 (CH2(Ar)), 26.7 (COCH3), 14.1
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(CO2CH2CH3); Diastereoisomer 2 (keto tautomer): H NMR (400 MHz, CDCl3) d 7.47–7.20 (m, 4 H,
4 ´ Ar-H), 5.21 (d, J = 3.5 Hz, 1 H, OCH(Ar)), 4.74 (s, 1 H, CH(CO2Et)(COMe)), 4.64–4.60 (m, 1 H,
CHBr), 4.41–4.24 (m, 2 H, CO2CH2CH3), 3.75 (d, J = 16.9, 6.5 Hz, 1 H, CHH(Ar)), 3.31–3.19 (m, 1 H,
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CHH(Ar)), 2.24 (s, 3 H, COCH3), 1.35 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz,
CDCl3) d 201.5 (C=O ketone), 167.0 (C=O ester), 141.0 (Ar-Cq), 138.4 (Ar-Cq), 129.8 (Ar-CH), 127.4
(Ar-CH), 125.5 (Ar-CH), 125.0 (Ar-CH), 91.2 (OCH(Ar)), 84.0 (CH(CO2Et)(COMe)), 62.2
1
(CO2CH2CH3), 51.2 (CHBr), 41.6 (CH2(Ar)), 26.4 (COCH3), 14.1 (CO2CH2CH3); Enol tautomer: H
NMR (400 MHz, CDCl3) d 11.25 (br s, 1 H, C=C(OH)), 7.47–7.20 (m, 4 H, 4 ´ Ar-H), 5.32 (d, J = 2.6
Hz, 1 H, OCH(Ar)), 4.68–4.64 (m, 1 H, CHBr), 4.41–4.24 (m, 2 H, CO2CH2CH3), 3.80 (dd, J = 17.1,
6.3 Hz, 1 H, CHH(Ar)), 3.31–3.19 (m, 1 H, CHH(Ar)), 1.80 (d, J = 0.7 Hz, 3 H, CH3), 1.39 (t, J = 7.1
13
Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz, CDCl3) d 169.5 ((EtO2C)Cq=C(OH)), 167.3 (CO2),
141.3 (Ar-Cq), 138.8 (Ar-Cq), 129.7 (Ar-CH), 127.2 (Ar-CH), 126.0 (Ar-CH), 124.9 (Ar-CH), 123.1
((EtO2C)C=Cq(OH)), 92.0 (OCH(Ar)), 61.1 (CO2CH2CH3), 51.1 (CHBr), 41.7 (CH2(Ar)), 16.5 (CH3),
14.3 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for C17H20BrNO4Na+ [M+CH3CN+Na]+: 404.0473,
Found: 404.0490.
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(±)-cis-Ethyl 2-methyl-4aH,9H,9aH-indeno[1,2-b][1,4]dioxine-3-carboxylate (6i) Prepared
according to General Procedure B employing bromide 5i (171 mg, 0.5 mmol). Purification by flash
chromatography (20% Et2O in pentane) afforded dioxene 6i as a pale yellow oil (125 mg, 96%); Rf =
0.29 (20% Et2O in pentane); IR (film) / cm-1 2979, 2954, 1708 (C=O), 1640 (C=C), 1462, 1444, 1370,
1305, 1250, 1160, 1149, 1084, 1010, 960, 933, 888, 862, 834, 751, 668, 627, 602; 1H NMR (400 MHz,
CDCl3) d 7.48–7.44 (m, 1 H, Ar-H), 7.33–7.23 (m, 3 H, 3 ´ Ar-H), 5.36 (d, J = 3.9 Hz, 1 H, OCH(Ar)),
4.74 (q, J = 3.9 Hz, 1 H, OCH(CH2Ar)), 4.28 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.14–3.08 (m, 2 H,
CH2Ar), 2.15 (s, 3 H, CH3), 1.35 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3)
d 164.1 (CO2), 147.6 ((Me)Cq=C), 139.6 (Ar-Cq), 139.3 (Ar-Cq), 129.1 (Ar-CH), 127.2 (Ar-CH), 125.7
(Ar-CH), 124.7 (Ar-CH), 122.9 ((EtO2C)Cq=C), 76.6 (OCH(Ar)), 75.9 (OCH(CH2Ar)), 60.4
(CO2CH2CH3), 36.7 (CH2Ar), 17.9 (CH3), 14.4 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for
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C15H17O4 [M+H]+: 261.1127, Found: 261.1130.
(±)-Ethyl 2-[(1-chloro-2-methylpropan-2-yl)oxy]-3-oxobutanoate (5j) Prepared according to
General Procedure A employing diazo 1 (188 mg, 1.2 mmol) and 1-chloro-2-methyl-2-propanol 4j
(109 mg, 1.0 mmol). Purification by flash chromatography (15% to 20% Et2O in pentane) afforded
chloride 5j as a pale yellow oil (111 mg, 47%); Rf = 0.22 (20% Et2O in pentane); IR (film) / cm-1 2983,
2941, 1745 (C=O), 1723 (C=O), 1467, 1423, 1387, 1370, 1356, 1337, 1257, 1208, 1158, 1123, 1107,
1033, 901, 856, 784, 735, 554; 1H NMR (400 MHz, CDCl3) d 4.51 (s, 1 H, CH(CO2Et)(COMe)), 4.28–
4.22 (m, 2 H, CO2CH2CH3), 3.54 (s, 2 H, CH2Cl), 2.30 (s, 3 H, COCH3), 1.333 (s, 3 H, CH3), 1.326 (s,
13
3 H, CH3), 1.32 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); C{1H} NMR (101 MHz, CDCl3) d 203.4 (C=O
ketone), 168.4 (C=O ester), 79.0 (CH(CO2Et)(COMe)), 77.9 (OCq(CH3)2), 61.9 (CO2CH2CH3), 51.8
(CH2Cl), 26.2 (COCH3), 24.1 (CH3), 23.4 (CH3), 14.0 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for
C10H17ClO4Na+ [M+Na]+: 259.0713, Found: 259.0707.
Ethyl 3,6,6-trimethyl-5,6-dihydro-1,4-dioxine-2-carboxylate (6j) and (±)-ethyl 2-acetyl-4,4-
dimethyloxetane-2-carboxylate (7) Prepared according to a scaled down General Procedure B
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employing chloride 5j (71 mg, 0.3 mmol). Purification by flash chromatography (10% to 20% Et2O in
pentane) afforded dioxene 6j as a colorless oil which solidified upon storage at –25 °C (20 mg, 34%)
followed by oxetane 7 as a pale yellow oil (12 mg, 20%). Dioxene 6j: Rf = 0.31 (20% Et2O in pentane);
mp = 18–20 °C; IR (film) / cm-1 2981, 2934, 2880, 1709 (C=O), 1634 (C=C), 1461, 1382, 1367, 1311,
1286, 1273, 1238, 1156, 1078, 1027, 985, 940, 923, 897, 865, 835, 770, 721, 598; 1H NMR (400 MHz,
CDCl3) d 4.25 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 3.74 (s, 2 H, OCH2), 2.23 (s, 3 H, CH3), 1.32 (t, J =
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7.1 Hz, 3 H, CO2CH2CH3), 1.28 (s, 6 H, OC(CH3)2); 13C{1H} NMR (101 MHz, CDCl3) d 164.5 (CO2),
145.0 ((Me)Cq=C), 123.4 ((EtO2C)Cq=C), 72.4 (OCH2), 70.2 (OCq(CH3)2), 60.5 (CO2CH2CH3), 22.7
+
(Cq(CH3)2), 17.5 (CH3), 14.4 (CO2CH2CH3); HRMS (FTMS +pAPCI) m/z Calcd for C10H17O4
[M+H]+: 201.1121, Found: 201.1123. Oxetane 7: Rf = 0.20 (20% Et2O in pentane); IR (film) / cm-1
2973, 2933, 2875, 1745 (C=O), 1727 (C=O), 1448, 1372, 1355, 1283, 1215, 1158, 1123, 1060, 1015,
971, 843, 771, 744, 580; 1H NMR (400 MHz, CDCl3) d 4.31–4.24 (m, 2 H, CO2CH2CH3), 2.82 (d, J =
11.8 Hz, 1 H, CHH), 2.74 (d, J = 11.8 Hz, 1 H, CHH), 2.29 (s, 3 H, COCH3), 1.51 (s, 3 H, CH3), 1.39
(s, 3 H, CH3), 1.30 (t, J = 7.1 Hz, 3 H, CO2CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) d 204.8 (C=O
ketone), 169.9 (C=O ester), 82.0 (Cq(CO2Et)(COMe)), 81.6 (OCq(CH3)2), 62.1 (CO2CH2CH3), 39.5
(CH2Cl), 29.3 (CH3), 29.0 (CH3), 24.5 (COCH3), 14.0 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for
+
C10H17O4 [M+H]+: 201.1127, Found: 201.1136.
Synthesis of Diazo Compound 8a
Ethyl 2-diazo-4-methyl-3-oxopentanoate (8a) Cesium carbonate (1.63 g, 5 mmol) was added
portionwise to a stirring solution of tosyl azide (986 mg, 5 mmol) and ethyl isobutyrylacetate (0.81 mL,
5 mmol) in THF (50 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 3 h. The reaction
mixture was filtered through celite, and the precipitate washed with Et2O (100 mL). The filtrate was
concentrated in vacuo. Pentane (100 mL) was added to the residue to precipitate out the sulphonamide
by-product. The mixture was filtered through celite and the filtrate concentrated in vacuo. Purification
by flash chromatography (30% to 50% to 70% CH2Cl2 in pentane) afforded diazo 8a as a yellow liquid
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The Journal of Organic Chemistry
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(801 mg, 87%); Rf = 0.26 (50% CH2Cl2 in pentane); IR (film) / cm-1 2979, 2938, 2875, 2131 (C=N=N
out-of-phase), 1713 (C=O), 1655, 1467, 1383, 1372 (C=N=N in-phase),1355, 1292, 1207, 1173, 1128,
1101, 1017, 987, 873, 829, 753, 724, 672, 536; 1H NMR (400 MHz, CDCl3) d 4.29 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 3.57 (sep, J = 6.8 Hz, 1 H, COCH(CH3)2), 1.33 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.12
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(d, J = 6.8 Hz, 6 H, 2 ´ CH3); C{1H} NMR (101 MHz, CDCl3) d 197.1 (C=O ketone), 161.2 (C=O
ester), 61.3 (CO2CH2CH3), 36.8 (COCH(CH3)2), 18.5 (2 ´ CH3), 14.3 (CO2CH2CH3); HRMS (ESI-
+
TOF) m/z Calcd for C8H13N2O3 [M+H]+: 185.0926, Found: 185.0927.
Synthesis of dioxenes 10a-e
(±)-Ethyl 2-(2-bromoethoxy)-4-methyl-3-oxopentanoate (9a) Prepared according to General
Procedure A employing diazo 8a (221 mg, 1.2 mmol) and 2-bromoethanol (124 mg, 1.0 mmol).
Purification by flash chromatography (15% Et2O in pentane) afforded bromide 9a as a pale yellow oil
(234 mg, 84%); Rf = 0.19 (15% Et2O in pentane); IR (film) / cm-1 2975, 2937, 2876, 1747 (C=O), 1721
(C=O), 1467, 1385, 1369, 1334, 1259, 1204, 1180, 1139, 1022, 859, 806, 738, 679, 582; 1H NMR (400
MHz, CDCl3) d 4.57 (s, 1 H, CH(CO2Et)(COMe)), 4.32–4.21 (m, 2 H, CO2CH2CH3), 4.04 (dt, J =
10.6, 5.5 Hz, 1 H, OCHH), 3.78 (dt, J = 10.6, 6.4 Hz, 1 H, OCHH), 3.58–3.51 (m, 2 H, CH2Br), 3.15
(sep, J = 6.9 Hz, 1 H, COCH(CH3)2), 1.30 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 1.14 (d, J = 6.9 Hz, 3 H,
CH3), 1.11 (d, J = 6.9 Hz, 3 H, CH3); 13C{1H} NMR (101 MHz, CDCl3) d 206.9 (C=O ketone), 167.1
(C=O ester), 84.1 (CH(CO2Et)(COMe)), 70.9 (OCH2), 61.9 (CO2CH2CH3), 37.2 (COCH(CH3)2), 29.6
(CH2Br), 17.99 (CH3), 17.96 (CH3), 14.1 (CO2CH2CH3); HRMS (ESI-TOF) m/z Calcd for
C12H20BrNO4Na+ [M+CH3CN+Na]+: 344.0473, Found: 344.0463.
Ethyl 3-(propan-2-yl)-5,6-dihydro-1,4-dioxine-2-carboxylate (10a) Prepared according to a
scaled down General Procedure B employing bromide 9a (112 mg, 0.4 mmol). Purification by flash
chromatography (25% Et2O in pentane) afforded dioxene 10a a colorless oil (71 mg, 89%); Rf = 0.31
(25% Et2O in pentane); IR (film) / cm-1 2972, 2936, 2874, 1708 (C=O), 1619 (C=C), 1459, 1370, 1337,
1
1303, 1276, 1260, 1236, 1174, 1133, 1101, 1086, 1028, 974, 901, 863, 811, 770; H NMR (400 MHz,
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