Aqueous reduction of iodosteroids to deoxysteroids

Article abstract of DOI:10.3184/174751914X13968892307636

A new method for the reduction of iodosteroids to deoxysteroids has been developed using Zn, HCOOH and a catalytic amount of Aliquat 336 in water. In total, 13 iodosteroids were reduced in good to excellent yields. The higher solubilities of the substrates lead to the faster reactions, and the aqueous reaction was efficiently accelerated by granular polytetrafluoroethylene. The advantage of the aqueous system over eight organic solvents has also been demonstrated.

Full text of DOI:10.3184/174751914X13968892307636

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 MAY, 309–312
RESEARCH PAPER 309
Aqueous reduction of iodosteroids to deoxysteroids
Changsheng Liu, Lili Sun and Chunbao Li*
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P.R. China
A new method for the reduction of iodosteroids to deoxysteroids has been developed using Zn, HCOOH and a catalytic amount
of Aliquat 336 in water. In total, 13 iodosteroids were reduced in good to excellent yields. The higher solubilities of the substrates
lead to the faster reactions, and the aqueous reaction was efficiently accelerated by granular polytetrafluoroethylene. The
advantage of the aqueous system over eight organic solvents has also been demonstrated.
Keywords: reduction, steroids, deoxysteroids, aqueous reaction, granular polytetrafluoroethylene
One of the structural characteristics of steroids is the presence
of 3β‑hydroxyl groups. Reduction of the hydroxyl groups
leads to deoxysteroids examples of which inhibit the mouse
constitutive androstane receptor1 and aromatase in human
placental microsomes.2 In addition, they are effective reagents
for gastro‑intestinal diseases, obesity and metabolic disorders.3
The reduction of sulfonates, thiono esters and halo groups are
widely used methodologies for the preparation of deoxysteroids.
When the amount of Zn was reduced to 3 equiv., the conversion
was only 20% at 6 h (Table 1, entry 2). Increasing the amount of
Zn to 4 equiv. shortened the reaction time to 1 h and raised the
yield to 90% (Table 1, entry 3). When the amount of HCOOH
was reduced to 0.5 equiv., the reaction time was 1.25 h with a
91% yield (Table 1, entry 4). Further reducing the amount of
HCOOH to 0.2 equiv. caused a longer reaction time and a lower
yield (Table 1, entry 5). When the temperature was decreased
to 75 °C with 0.5 equiv. of HCOOH, the reaction became
sluggish (Table 1, entry 6). When the amount of Aliquat 336
was decreased to 0.04 equiv., the reaction time and yield
were 2.5 h and 86% respectively (Table 1, entry 7). In order
to further optimise the reaction conditions, AcOH, EtCO2H,
HCl, NH4Cl and H2SO4 were used to replace the HCOOH but
no better results were obtained (Table 1, entries 8–12). Using
tetrabutylammonium bromide and benzyltriethylammonium
chloride to replace Aliquat 336 also led to low conversions
(Table 1, entries 15 and 16). Therefore, the optimised reaction
conditions are Zn (4 equiv.), HCOOH (0.5 equiv.) and Aliquat
336 (0.08 equiv.) at 85 °C.
Sulfonates are usually reduced by LiAlH4 or LiEt3BH;5
4
steroidal thiono esters by organotins (Bu3SnH),6 organosilanes
7
8
((TMS)3SiH or Ph2SiH2 ), organoboranes (Me3B)9 or dialkyl
phosphites with hypophosphorous acid;10 and halosteroids
by organotins,11 organosilanes,12 organobornanes,13 SmI2,14
Na–K alloy,15 Raney Ni16 and Zn.17 However, there are several
drawbacks associated with these methods. For example, some
of the reagents like the tin compounds are costly, highly toxic
and difficult to remove from the products in the work‑up steps.
Furthermore, organic solvents such as THF,2 EtOAc18 and
toluene19 are often involved. Since organic solvents are volatile
and cause environmental problems, it would be ideal to carry
out the reduction in aqueous media. Steroids are very sparing
soluble high‑melting‑point (VSSHMP) compounds and there
have been no reports on the reduction of iodosteroids mediated
by water. In previous research, we have carried out a series
of aqueous organic reactions of VSSHMP compounds in the
presence of granular PTFE and a catalytic amount of Aliquat
336.20,21 We now report a methodology for the conversion of
iodosteroids to deoxysteroids mediated by water in the presence
of granular PTFE and a catalytic amount of Aliquat 336.
Table 1 Optimisation of the reduction conditions for iodosteroid 1a
O
O
Zn, Acid
PTC
granular PTFE (5 g)
H2O (5 mL)
I
1a
1b
Zn/
Acida/
Conversionc
(Yieldd)/%
Entry
PTCb/equiv. T/°C Time/h
equiv. equiv.
Results and discussion
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
6
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
1
1
1
0.08
0.08
0.08
0.08
0.08
0.08
0.04
0.08
0.08
0.08
0.08
0.08
0.08
–
85
85
85
85
85
75
85
85
85
85
85
85
85
85
85
85
0.67
6
1
1.25
3
6
2.5
2
2.75
2
3
10
18
18
1.25
100 (92)
20
100 (90)
100 (91)
100 (84)
6
100 (86)
100 (88)
100 (85)
100 (59)
100 (70)
100 (54)
79
Iodosteroids were prepared using the I2/PPh3/imidazole method
starting from the corresponding hydroxysteroids.22–25 The C‑3
configurations for 3‑iodo‑Δ5‑steroids were established by the
typical coupling constants of 3α‑H and 3β‑H. The 1H NMR data
for 3α‑H is ~4.05 ppm (ddd, J=16.4, 12.2, 4.1 Hz)26 and for
3β‑H ~4.05 ppm (tt, J=12.4, 4.3 Hz). The C‑3 configuration
for 3α‑iodo‑androstan‑17‑one (7a) was inconsistent with the
literature.27 The C‑17 configurations for 17‑iodo‑steroids
were established by the typical chemical shifts and coupling
0.5
0.2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
–
1
constants of 17α‑H and 17β‑H. The H NMR data for the
former is ~3.7 ppm (t, J=9.5 Hz) and for the latter ~4.3 ppm
(d, J=6.2 Hz).28 Initially 3α‑iodoandrost‑5‑en‑17‑one (1a) was
used as the model substrate to determine the best reaction
conditions. Amixtureof1a (0.2 g, Table1, entry1), Zn(6 equiv.),
HCOOH (1 equiv.), Aliquat 336 (0.08 equiv.), granular PTFE
(5 g, 70 pieces/g) and water (5 mL) was mechanically stirred
(400 rpm) at 85 °C to obtain 1b in 0.67 h with a 92% yield.
0.5
0.5
0.5
17
10
trace
0.08
0.08
1.25
aAll the acids were HCOOH, except for entries 8 (AcOH), 9 (EtCO2H) 10
(HCl), 11(NH4Cl), 12 (H2SO4) and 13 (no acid).
bPhase transfer catalyst, Aliquat 336 for entries 1–13, tetrabutylammonium
bromide for entry 15, benzyltriethylammonium chloride for entry 16.
cAll conversions are determined by 1H NMR.
dAll yields are isolated yields. Reaction conditions: iodosteroid 1a (0.2 g),
Zn, Acid, PTC, H2O (5 mL) and granular PTFE (5 g) at 75 °C or 85 °C.
* Correspondent. E‑mail: lichunbao@tju.edu.cn
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310 JOURNAL OF CHEMICAL RESEARCH 2014
In total, 13 VSSHMP iodosteroids were subjected to the
optimised reaction conditions and the results are shown in
Table 2. For 3α‑iodosteroids, the reduced steroids were obtained
in 72–96% yields and for 17α‑iodosteroids in 84–95% yields.
The melting points of the iodosteroids range from 75 to 188 °C
and had little effect on the reaction rates. For example, the
melting point of steroid 4a is 185–188 °C (Table 2, entry 4) and
its reaction time was 2.5 h. Steroid 5a has a much lower melting
point (109–112 °C) with a reaction rate of 3 h which is similar
to that of 4a. The solubilities of the 13 iodosteroids are also
shown in Table 2 and it is quite clear that solubility is a major
factor that affects reaction rate. For example, iodosteroid 2a has
the lowest solubility among the 3‑iodosteroids, and its reaction
rate is the slowest (4.5 h). Comparing the solubilities of steroid
10a versus 11a and 12a versus 13a also shows that the higher
the solubility, the faster the reaction rate. Finally it should be
noted that these reaction conditions are compatible with ester,
ether, ketone and alkene functional groups. To quantitatively
evaluate the effect of granular PTFE on the reaction rate,
a mixture of 1a, Zn, HCOOH, Aliquat 336, granular PTFE
and water was mechanically stirred at 85 °C for 1.25 h. The
conversions were determined by 1H NMR after extraction and
the results are listed in Table 3. When 1a (0.2 g) was stirred
in the presence of Zn (4 equiv.), HCOOH (0.5 equiv.), Aliquat
336 (0.08 equiv.), water (5 mL) and granular PTFE (0, 1, 3 or
5 g) at 85 °C, the conversions at 1.25 h were 26%, 31%, 41%
and 100% respectively (Table 3, entries 1–4). When the amount
of 1a was increased to 0.5 g, the corresponding conversions
were 39%, 43%, 66% and 100% at 1.25 h (Table 3, entries 5–8).
The accelerating effect of granular PTFE on the reduction is
obvious, and the accelerating effect becomes stronger as the
amount of substrate increases. The function of granular PTFE
is to smash the solid substrate which has a melting point above
the reaction temperature. In addition to its function as a PTC,
the Aliquat 336 acts to dissolve the smashed substrate. This is
also supported by the data in Table 1 (entries 15 and 16), where
Table 2 Reduction of VSSHMP iodosteroids using Zn, HCOOH and Aliquat 336 mediated by water
Zn (4 eq.), HCOOH (0.5 eq.),
Aliquat 336 (0.08 eq.)
Iodosteroid
Deoxysteroid
granular PTFE, water (5 mL), 85 °C
R4
R3
16
17
R2
R1
5
6
c
Entry
Substrate
S/mol L–1
M.p./°C
Product
C5–6
Time/h
Yield/%b
1a
1b
3.2×10–6
2.0×10–11
4.5×10–7
6.9×10–8
1.3×10–7
167–170
103–107
145–149
185–188
109–112
109–114
115–118
163–168
112–115
138–143
136–139
dd
d
d
d
d
d
se
d
s
1.25
4.5
3.6
2.5
3
91
95
89
72
92
96
93
84
89
78
86
1
2
(R1=H, R2=I, R3 +R4=O)
(R1, R2=H, R3 +R4=O)
2a
2b
(R1=H, R2=I, R3=C8H17, R4= H)
(R1, R2=H, R3=C8H17, R4=H)
3a
3b
3
(R1=H, R2=I, R3=Ac, R4=H)
(R1, R2= H, R3=Ac, R4=H)
4a
4b
4
(R1=H, R2=I, R3 +R4=Ac)
(R1, R2=H, R3 +R4=Ac)
5a
5b
5
(R1=H, R2=I, R3, R4=H)
(R1, R2, R3, R4=H)
6a
6b
1.16×10–8
2.4×10–7
1.5×10–7
1.1×10–7
7.5×10–7
2.7×10–9
2
6
(R1=H, R2=I, R3=C2H5, R4=H)
(R1, R2=H, R3=C2H5, R4=H)
7a
7b
4.6
2.5
1.8
1.5
5
7
(R1=H, R2=I, R3 +R4=O)
(R1, R2=H, R3 +R4=O)
8a
8b
8
(R1=AcO, R2=H, R3=H, R4=I)
(R1=AcO, R2=H, R3, R4=H)
9a
9b
9
(R1=AcO, R2=H, R3=H, R4=I)
(R1=AcO, R2=H, R3, R4=H)
10a
10b
d
d
10
11
(R1=MeO, R2=H, R3=H, R4=I)
(R1=MeO, R2= H, R3, R4=H)
11a
11b
(R1=BnO, R2=H, R3=H, R4=I)
(R1=BnO, R2=H, R3, R4=H)
12a
12b
3-Benzyloxy-17α-iodo-1,3,5(10)-
9.7×10–12
2.6×10–9
115–120
75–79
–
–
3.5
1
92
95
12
13
3-Benzyloxy-1,3,5(10)-estratriene
estratriene
13a
13b
3-Methoxy-17α-iodo-1,3,5(10)-
3-Methoxy-1,3,5(10)-estratriene
estratriene
aFor 4a and 4b, C16–17= double bond.
bAll conversions are 100%, all yields are isolated yields.
cSolubility; 1a–13a, data calculated using Software Wskow.
dDouble bond.
eSingle bond. Reaction conditions: iodosteroid (0.2 g), Zn (4 equiv.), HCOOH (0.5 equiv.), Aliquat 336 (0.08 equiv.), H2O (5 mL) and granular PTFE (5 g) at 85 °C.
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JOURNAL OF CHEMICAL RESEARCH 2014 311
Table 3 Effects of granular PTFE on the reaction rates
Experimental
Amount of granular
All reagents and solvents were of analytical grade and purchased
Entry
Amount of 1a/g
Conversion/%a
PTFE/g
1
from commercial sources. The H NMR (400 MHz) was recorded
1
on a Bruker AM‑400 spectrometer. The H NMR (600 MHz) and 13C
1
2
3
4
5
6
7
8
0.2
0.2
0.2
0.2
0.5
0.5
0.5
0.5
0
1
3
5
0
1
3
5
26
31
41
100
39
43
NMR (151 MHz) were recorded on a Bruker Avance III spectrometer,
using tetramethylsilane (TMS) as the internal standard (δ=0). IR
spectra were obtained using a BIO‑RAD FTS 3000 spectrometer,
using potassium bromide disks, and the spectra were scanned from 400
to 4000 cm−1. Melting points were recorded on an X‑4 Micro‑melting
Point Apparatus. Elemental analysis for C and H were performed on
a Vario Micro elemental analyser. granular PTFE was prepared as
following: A PTFE plate (~50×~50×~2 mm) was cut into wires
(~50×~2×~2 mm) and into granular form (70 pieces/g). The stirring
rod was modified by inserting a 25 cm PTFE wire into the blades,
which was used in all the following experiments unless specified. The
iodosteroids (1a,24 2a,22,23 3a,24 4a,24 5a–6a,22,23 7a,24 8a–13a25) were
prepared according to the literature procedures.
66
100
aDetermined by 1H NMR.
tetrabutylammonium bromide and benzyltriethylammonium
chloride did not catalyse the reductions because both of them are
water soluble and are not capable of dissolving the iodosteroids
to the extent that Aliquat 336 does.
Comparisons of organic solvent‑ and water‑mediated
reductions were made and the results are shown in Table 4.
In DMF and CH3CN (Table 4, entries 2 and 3), the reaction
yields were 76% and 88% respectively. In THF, dioxane and
ethyl acetate (Table 4, entries 4–6), the reaction was sluggish.
Complicated mixtures were produced in toluene and EtOH
(Table 4, entries 8 and 9), and no product was detected in
CHCl3 (Table 4, entry 7). The reaction times in DMF and
acetonitrile were 1.5 and 4.5 h respectively, and the reactions
in other organic solvents were stopped at 6 h. Only in the
reaction mediated by water (Table 4, entry 1) were the best
results achieved: 1.25 h (91%). This is a multiphasic system:
solid zinc, solid iodosteroid, liquid Aliquat 336 which dissolves
the iodosteroid and deoxysteroid, and water. Although other
VSSHMP substrates have been used in reactions mediated by
water, they are often bis‑ or triphasic and metal reagents have
not been used as the solid phase.20,21,29,30 In this aqueous system,
water and Aliquat 336 may facilitate the electron transfer
from the solid zinc to the iodosteroid. Therefore, the aqueous
reduction is faster and higher yielding than reductions mediated
by organic solvents.
Reduction of iodosteroids; general procedure
A mixture of iodosteroid (0.2 g), Zn (powder, 4 equiv.), HCOOH
(0.5 equiv.), Aliquat 336 (0.08 equiv.), granular PTFE (5 g) and
water (5 mL) was mechanically stirred at 85 °C. After TLC indicated
completion of the reaction, it was stopped, extracted with ethyl acetate
(5 mL×3), dried with Na2SO4 and concentrated to give the crude
product. The crude product was purified by a short silica gel pad.
Products 1b,31 2b,32 3b,33,34 4b,35,36 5b,37,38 6b,39,40 7b,41,42 8b,43 9b,44
10b,45,46 11b,47 and 13b48 are known. Product 12b is a new compound.
Androst-5-en-17-one (1b): White solid, m.p. 106–108 °C (lit.31
109–109.5 °C). IR (KBr): 2940, 2921, 2848, 1741, 1452 cm–1. 1H NMR
(400 MHz, CDCl3): δ 5.31 (d, J=5.0 Hz, 1H, 6‑H), 1.04 (s, 3H, 19‑Me),
0.90 (s, 3H, 18‑Me).
Cholest-5-ene (2b): White solid, m.p. 89–91 °C (lit.32 91–93 °C). IR
(KBr): 2933, 2862, 1463, 1377 cm–1. 1H NMR (400 MHz, CDCl3): δ 5.29
(d, J=5.0 Hz, 1H, 6‑H), 1.02 (s, 3H, 19‑Me), 0.94 (d, J=6.5 Hz, 3H,
21‑Me), 0.89 (dd, J=6.6, 4.8 Hz, 6H, 26‑Me and 27‑Me), 0.70 (s, 3H,
18‑Me).
Pregna-5-en-20-one (3b): White solid, m.p. 129–131 °C (lit.34
133–135 °C). IR (KBr): 2941, 2848, 1703, 1450, 1357 cm–1. H NMR
1
(400 MHz, CDCl3): δ 5.29 (d, J=5.0 Hz, 1H, 6‑H), 2.55 (m, 1H, 17‑H),
2.14 (s, 3H, 21‑Me), 1.01 (s, 3H, 19‑Me), 0.65 (s, 3H, 18‑Me).
Pregna-5,16-dien-20-one (4b): White solid, m.p. 127–130 °C (lit.35
In summary, an inexpensive and efficient methodology
for the dehalogenation of iodosteroids has been developed.
The reaction proceeds with good to excellent yields. The
accelerating effect of the granular PTFE on the reactions has
been demonstrated. The aqueous reactions have advantages of
faster reaction rates and better yields over the organic solvent‑
mediated reactions.
125–129 °C). IR (KBr): 2928, 2857, 1662, 1435, 1368 cm–1. H NMR
1
(400 MHz, CDCl3): δ 6.72 (s, 1H, 16‑H), 5.29 (d, J=4.5 Hz, 1H, 6‑H),
2.28 (s, 3H, 21‑Me), 1.05 (s, 3H, 19‑Me), 0.94 (s, 3H, 18‑Me).
Androst-5-ene (5b): White solid, m.p. 68–70 °C (lit.38 69–71 °C). IR
(KBr): 2937, 2846, 1451, 1378 cm–1. 1H NMR (600 MHz, CDCl3): δ 4.95
(s, 1H, 6‑H), 0.80 (s, 3H, 19‑Me), 0.69 (s, 3H, 18‑Me).
Pregna-5-ene (6b): White solid, m.p. 92–94 °C (lit.39 96–98 °C). IR
1
(KBr): 2930, 2862, 1453, 1375 cm–1. H NMR (600 MHz, CDCl3): δ
5.44–5.10 (m, 1H, 6‑H), 1.00 (s, 3H, 19‑Me), 0.88 (s, 3H, 21‑Me), 0.58
(s, 3H, 18‑Me).
Table 4 Comparisons for the reductions of 1a in different solvents
HCOOH
/equiv.
Conversiona
Entry Zn/equiv.
Solvent
T/°C
Time /h
Androstan-17-one (7b): White solid, m.p. 112–114 °C (lit.42
(yield) /%b
1
117–118 °C). IR (KBr): 2920, 2854, 1745, 1448, 1376, 1010 cm–1. H
1
2
3
4
5
6
7
4
4
4
4
4
4
4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Water
DMF
CH3CN
THF
Dioxane
AcOEt
CHCl3
85
85
82
66
85
77
61
1.25
1.5
4.5
6
6
6
100 (91)
100 (76)
100 (88)
32
NMR (600 MHz, CDCl3): δ 2.36 (dd, J=19.2, 8.7 Hz, 1H, 16‑H), 0.79
(s, H, 18‑Me), 0.74 (s, 3H, 19‑Me).
3β-Acetoxy-androst-5-ene (8b): White solid, m.p. 93–95 °C (lit.43
1
98 °C). IR (KBr): 2938, 2856, 1732, 1453, 1373, 1247, 1035 cm–1. H
34
45
NMR (600 MHz, CDCl3): δ 5.38 (d, J=4.6 Hz, 1H, 6‑H), 4.61 (m,
J=10.7, 5.5 Hz, 1H, 3‑H), 2.03 (s, 3H, CH3COO), 1.03 (s, 3H, 19‑Me),
0.72 (s, 3H, 18‑Me).
6
N.R.c
Complicated
8
4
0.5
PhMe
110
6
6
mixtured
3β-Acetoxy-androstane (9b): White solid, m.p. 86–89 °C (lit.44
85–86 °C). IR (KBr): 2932, 2853, 1736, 1447, 1368, 1242, 1027 cm–1. 1H
NMR (600 MHz, CDCl3): δ 4.62 (dd, J=10.8, 5.8 Hz, 1H, 3‑H), 1.95 (s,
3H, CH3COO), 0.75 (s, 3H, 19‑Me), 0.62 (s, 3H, 18‑Me).
Complicated
mixtured
9
4
0.5
EtOH
78
aAll conversions are determined by 1H NMR.
bAll yields are isolated yields.
3β-Methoxy-androst-5-ene (10b): White solid, m.p. 64–67 °C (lit.46
cNo reaction.
1
69–71 °C). IR (KBr): 2935, 2853, 1450, 1373, 1096 cm–1. H NMR
1
dDetermined by H NMR. Reaction conditions: iodosteroid 1a (0.2 g), Zn
(600 MHz, CDCl3) δ 5.36 (m, 1H, 6‑H), 3.35 (s, 3H, OCH3), 3.06 (s, 1H,
(4 equiv.), HCOOH (0.5 equiv.), Aliquat 336 (0.08 equiv.) and solvent (5 mL).
3‑H), 1.01 (s, 3H, 19‑Me), 0.72 (s, 3H, 18‑Me).
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312 JOURNAL OF CHEMICAL RESEARCH 2014
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3β-Benzyloxy-androst-5-ene (11b): White solid, m.p. 94–97 °C. IR
1
(KBr): 2926, 2854, 1456, 1374, 1104, 734 cm–1. H NMR (600 MHz,
CDCl3) δ 7.34 (m, 5H, C6H5CH2), 5.35 (m, 1H, 6‑H), 4.56 (s, 2H,
C6H5CH2), 3.28 (s, 1H, 3‑H), 1.02 (s, 3H, 19‑Me), 0.72 (s, 3H, 18‑Me).
3-Benzyloxy-1,3,5(10)-estratriene (12b): White solid, m.p.
1
103–108 °C. IR (KBr): 2925, 2858, 1604, 1500, 1254, 1041 cm–1. H
NMR (600 MHz, CDCl3) δ 7.36 (m, 5H, C6H5CH2), 7.20–7.24 (m, 1H,
1‑H), 6.77 (dd, J=8.6, 2.7 Hz, 1H, 2‑H), 6.71 (d, J=2.6 Hz, 1H, 4‑H),
5.02 (s, 2H, C6H5CH2), 2.96–2.75 (m, 2H), 2.36–2.15 (m, 2H), 0.74 (s,
3H, 18‑Me). 13C NMR (CDCl3, 151 MHz): δ 156.67, 138.18, 137.39,
133.42, 128.60, 127.90, 127.53, 126.44, 114.79, 112.22, 69.96, 53.56,
44.11, 41.13, 40.57, 39.18, 38.87, 30.04, 28.18, 26.81, 25.27, 20.65, 17.62.
Anal. calcd for C25H30O: C, 86.66; H, 8.37; found: C, 86.37; H, 8.52%.
3-Methoxy-1,3,5(10)-estratriene (13b): White solid, m.p. 76–78 °C
1
(lit.48 79 °C). IR (KBr): 2926, 2866, 1609, 1500, 1254, 1041 cm–1. H
NMR (600 MHz, CDCl3) δ 7.25–7.15 (m, 1H), 6.73 (dd, J=8.5, 2.5 Hz,
1H), 6.66 (d, J=2.3 Hz, 1H), 3.80 (s, 3H, OCH3), 0.77 (s, 3H, 18‑Me).
29 R.N. Butler, A.G. Coyne, W.J. Cunningham and E.M. Moloney, J. Org.
Chem., 2013, 78, 3276.
30 B.H. Lipshutz, N.A. Isley, J.C. Fennewald and E.D. Slack, Angew. Chem.
Int. Ed., 2013, 52, 10952.
Received 27 January 2014; accepted 13 March 2014
Paper 1402427 doi: 10.3184/174751914X13968892307636
Published online: 6 May 2014
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