Regiodivergent Iodocyclizations for the Highly Diastereoselective Synthesis of syn - And anti -Hydroxyl-Isochromanones and -Isobenzofuranones: Concise Synthesis of the Isochromanone Core of the Ajudazols

Article abstract of DOI:10.1055/s-0035-1561278

An efficient synthetic strategy to access hydroxyl-isochromanone and -isobenzofurans from readily available joint alkene precursors by a regiodivergent one-pot iodocyclization-substitution tandem process is reported. The cyclizations proceed with excellen

Full text of DOI:10.1055/s-0035-1561278

SYNTHESIS
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1
1
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-
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1
0
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 697–709
paper
697
S. Thiede et al.
Paper
Synthesis
Regiodivergent Iodocyclizations for the Highly Diastereoselective
Synthesis of syn- and anti-Hydroxyl-Isochromanones and -Isoben-
zofuranones: Concise Synthesis of the Isochromanone Core of the
Ajudazols
Sebastian Thiedea
Peter Maria Winterscheida
Jan Hartmannb
Gregor Schnakenburgc
Sebastian Essigb,1
Dirk Menche*a
OH
light, r.t.
75%
commercial substrate
75%
(A/B 1.2:1)
dr > 20:1
O
A
B
OMe
O
I2 (5 equiv)
THF/H2O (5:1)
O
HO
a Kekulé-Institut für Organische Chemie und Biochemie
der Universität Bonn, Gerhard-Domagk-Str. 1, 53121
Bonn, Germany
OMe NEt2
dark, ΔT
72%
(B/A 15:1)
dr > 20:1
O
regiodivergent
3-step tandem process
dirk.menche@uni-bonn.de
b Universität Heidelberg, Institut für Organische Chemie,
INF 270, 69120 Heidelberg, Germany
O
OMe
c Institut für Anorganische Chemie, Universität Bonn,
Gerhard-Domagk-Straße 1, 53121 Bonn, Germany
Received: 30.09.2015
Accepted after revision: 12.11.2015
Published online: 29.12.2015
been reported,10 and these rely mainly on intramolecular
Diels–Alder reactions (IMDA),11 rearrangement reactions,12
gold catalysis,13 asymmetric oxylactonization reactions,14
or asymmetric ortholithiation strategies.4,15
DOI: 10.1055/s-0035-1561278; Art ID: ss-2015-t0575-op
Abstract An efficient synthetic strategy to access hydroxyl-isochroma-
none and -isobenzofurans from readily available joint alkene precursors
by a regiodivergent one-pot iodocyclization–substitution tandem pro-
cess is reported. The cyclizations proceed with excellent diastereoselec-
tivities, with E-alkenes giving syn-configured products and Z-alkenes
giving anti-products. A strong influence of light on the regioselectivity
of the reaction was observed. High yields were also observed under rad-
ical conditions. The protective-group-free method enables a highly
concise synthesis of the authentic isochromanone core of the ajudazols,
which are highly potent inhibitors of the mitochondrial respiratory
chain.
As exemplified by the paecilomycins/aigialomycin
group of natural products (5, 7)9b,d hydroxyl-isochroma-
nones often co-occur with their corresponding hydroxyl-
isobenzofuranone isomers. These heterocycles likewise
constitute an important structural element in various bio-
active natural products and medicinal compounds,9,16 such
as pestaphthalide A and B (6, 8),16c with variable relative
configurations. In addition, hydroxyl-isochromanones may
also easily form the corresponding benzofuranones under
basic conditions by translactonizations,2,14c and analogues
of type 3 and 4 have also been postulated as more stable
isomerization products for the ajudazols.4 This renders the
development of a flexible approach to access hydroxyl-
isochromanone and –isobenzofuranone isomers by a mod-
ular synthetic route an attractive research goal.
As part of our efforts to develop novel one-pot proce-
dures to generate complex polyketides,17 we report herein a
concise synthetic strategy to access all possible syn- and
anti-hydroxyl-isochromanones and -isobenzofuranones.
The approach involves a diversification strategy from readi-
ly available alkene precursors through a regiodivergent
one-pot iodocyclization tandem process. The cyclizations
proceed with excellent diastereoselectivity and enable an
extremely short synthesis of the isochromanone and iso-
benzofuranone cores of the ajudazols and isoajudazols.
Key words natural products, asymmetric synthesis, iodocyclisation,
tandem reaction, diastereoselectivity
The ajudazols, which are structurally unique
polyketides from the myxobacterium Chondromyces croca-
tus,2–4 demonstrate extremely potent and selective inhibi-
tory activities of the mitochondrial respiratory chain,5 a key
regulatory pathway for aerobic energy production that has
been associated with various diseases,6 including neuronal
disorders.7 As shown in Figure 1, a densely functionalized
hydroxyl-isochromanone core constitutes one of the key
structural elements of natural ajudazols A (1) and B (2), as
well as a range of further bioactive natural products,8,9 in-
cluding the paecilomycins (5).8b However, only a few gener-
al synthetic methods to access this structural feature have
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 697–709

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Synthesis
As shown in detail in Scheme 1, our modular synthetic
strategy to access the target lactones of type 9 and 10 was
based on iodocyclization of the same benzoic acid derived
alkene 11. After formation of an iodonium intermediate 14,
the amide or an analogous nucleophilic benzoic acid deriva-
tive may then undergo a formal 6-endo- or 5-exo-cycliza-
tion to access either 12 or 13, which may then be substitut-
ed and hydrolyzed to the desired target heterocycles 9 or
10.18 We expected that a suitable choice of reaction condi-
tions would lead to the desired regioisomeric product,
whereas the double bond configuration may be used to
control the diastereoselectivity. Reported precedence sug-
gested that such a formal endo-pathway may indeed be
possible for certain aromatic benzoic esters with E-
alkenes,14a,c and related 5-exo-iodocyclizations without hy-
drolysis of the iodide have also been reported.19,20
HO
OH
R2
R2
regiodivergent
3-step
*
*
*
O
*
tandem process
O
R1
R1
O
O
10
9
R2
(3)
(3)
O
H2O
R1
I
I
NR2
R2
H2O
R2
11
(1)
*
*
*
O
*
I2/H2O
O
R1
R1
+ NHR2
(2)
+NR2
I+
13
12
R2
(2)
b)
O
a)
To examine the feasibility of such a tandem process, we
first studied the iodocyclization of various E-alkenes of
type 19 to access hydroxyl-isochromanone 20 (Scheme 2).
We envisioned that the functionalization of the benzoic
acid derivative would have a critical influence on the reac-
tion pathway. We were particularly interested in evaluating
amides because they can be axially chiral,4,21 which may
R1
6-endo-
cyclisation
5-exo-
cyclisation
NEt2
14
Scheme 1 Proposed mechanism for a modular tandem process for the
regiodivergent synthesis of hydroxyl-isochromanones and -isobenzofu-
ranones
N
O
O
OH
N
R
OMe
O
R:
R:
CH2
ajudazol A (1)
ajudazol B (2)
OH
O
O
CH3
O
N
O
O
HO
N
R
OMe
OH
R:
R:
CH2
CH3
iso-ajudazol A (3)
iso-ajudazol B (4)
HO
OH
OH
MeO
HO
O
O
OH OH
OH
O
OH
O
OH
paecilomycin C (5)
pestaphthalide A (6)
HO
O
O
OH
HO
HO
O
OH OH OH
OH
O
OH
MeO
aigialomycin F (7)
pestaphthalide B (8)
Figure 1 The ajudazols and related hydroxyl-isochromanone and hydroxyl-isobenzofuranone natural products
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 697–709

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Synthesis
potentially be of use for asymmetric induction of the tan-
dem process. Consequently, three different amides 17b–d
with variable steric demand were prepared together with
ester 17a. As shown in Scheme 2, their synthesis was ac-
complished by a diversification strategy from commercial
iodobenzoic acid 15. Synthesis of methyl ester 17a was ef-
fected by acid-catalyzed esterification,22 whereas dimethyl,
diethyl, and diisopropyl amides 17b–d were obtained by
treatment of the acid chloride with the corresponding
amines.23 Suzuki coupling24 of these iodides with E-boro-
nate 1825 then gave access to the desired E-alkenes 19a–d in
high yields.26
the corresponding configuration of the hydroxyl-lac-
tone.17,18
Having established the principal adaptability and the
usefulness of ethyl amides, we then turned our attention to
the authentic substitution pattern of the ajduzols and pre-
pared the ortho-substituted Z- and E-alkenes 25 and 26. As
shown in Scheme 3, a joint synthesis was achieved by a di-
versification strategy involving iodo-compound 23, which
was coupled with either Z- or E-boronate 2430 and 18 to
give the target compounds 25 and 26 in high yields. Iodo-
compound 23 was readily available from commercial ben-
zoic acid 21 by methylation,11b conversion into amide 22 via
the acid chloride (not shown), and a high-yielding introduc-
tion of the iodide by an ortho-metalation strategy.
I
I
SOCl2, DMF
O
1. K2CO3, Me2SO4
acetone, heat; KOH
MeOH
O
CH2Cl2, ΔT
OH
Cl
89%
NEt2
16
15
COOH
2. SOCl2; Et2NH
CH2Cl2
96%
HNMe2 or
HNEt2 or
HNi-Pr2
MeOH
H2SO4
heat
OH
OMe
O
I
21
22
CH2Cl2
O
s-BuLi,
TMEDA; I2
THF
86% (17b) 0 °C to r.t.
92% (17c)
70% (17d)
I
96% (17a)
R
17a–d
NEt2
–78 °C
91%
OMe
O
O
a R = OMe
b R = NMe2
c R = NEt2
d R = Ni-Pr2
[Pd(PPh3)4]
NaOH
dioxane, heat
23
B
O
O
O
B
B
[Pd(PPh3)4]
NaOH
dioxane, heat
O
O
18
24
18
OH
92%
96%
I
2 (5 equiv)
THF/H2O (5:1)
R
O
r.t., 72 h
NEt2
NEt2
O
O
19a–d
20
OMe
O
OMe
O
substrate yield (%) dr (20)
substrate yield (%)
25
26
19a
19b
19c
19d
36%
27%
43%
-
>20:1
>20:1
>20:1
-
17a
17b
17c
17d
66%
68%
95%
94%
Scheme 3 Concise synthesis of E- and Z-alkenes by a diversification
strategy from joint intermediate 23
Scheme 2 Concise synthesis of simplified hydroxyl-isochromanone 20
by one-pot iodocyclization-hydrolysis: evaluation of benzoic amides
With both 25 and 26 in hand, we studied our concept of
a regiodivergent cyclization. We thus analyzed the tandem
iodocyclization-hydrolysis of 26 to access both isochroma-
none 27 and isobenzofuranone 28. As shown in Table 1, we
first evaluated various solvent conditions. Gratifyingly, it
quickly became apparent that both products could indeed
be obtained in a regiodivergent fashion, proving our initial
concept.31 In agreement with our first study (Scheme 2),
the syn-configured isochromanone was obtained, which
was assigned from the small vicinal coupling constant be-
tween the two oxygen-bearing substituents (J = 1.8 Hz),
whereas the configuration of the isobenzofurane was un-
ambiguously determined by X-ray crystallographic analysis
(see Figure 2). In contrast to the reaction of the unsubstitut-
ed alkenes 19 (Scheme 2), the observed yields were only
These substrates were then submitted to various modi-
fications of an iodocyclization protocol that was reported
for a related cyclization.27 Gratifyingly, using iodine (5
equiv) in a mixture of THF and water (5:1), the desired
transformation into 20 could indeed be observed.28,29 High-
er yields were obtained for diethyl amide 19c compared
with dimethyl amide 19b and methyl ester 19a. In contrast,
no product formation was observed for diisopropylamide
19d, presumably for steric reasons. Importantly, in all cases,
excellent syn-diastereoselectivities were observed, which
suggests that this reaction proceeds by a highly conserved
stereochemical transfer of the double bond configuration to
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Table 1 Evaluation of Solvents for the Regiodivergent Cyclization of E-
alkene 26 to syn-Products 27 and 28a
low. Among the solvents evaluated, best yields were ob-
tained for THF, acetone, and DMSO (entries 1, 3, and 5). We
then studied the influence of the THF/water ratios (entries
15–21). As expected, no product was formed in the absence
of water (entry 16). Increasing the water ratio was accom-
panied by a slight increase in the isochromanone/isobenzo-
furan ratio (entry 15), whereas the use of stoichiometric
amounts of water lead to exclusive formation of the five-
membered product, albeit in very low yields (entries 20
and 21). The low yield could not be further improved by in-
creasing the concentration (entry 19), and dilution lead to
decreased conversion (entry 18). In general, the degree of
selectivity for product formation was affected by both the
nature and the amount of solvent.
OH
O
OMe
O
27
+
I
2 (5 equiv)
solvent
O
HO
OMe NEt2
26
O
O
OMe
28
Entry
Solvent
Yield/rsm (%)a
27
28
26
1b
2b
THF
13
17
0
0
dioxane
acetone
DMF
5
2
9
37
6
3b
22
2
4b
9
Figure 2 X-ray crystal structure analysis of isobenzofuranone 28
5b
DMSO
pyridine
Et2O
18
0
13
0
29
28
33
73
50
26
43
32
23
18
15
100
23
100
0
6b
As shown in Table 2, we then evaluated alternative reac-
tion parameters. Essentially no effect was observed by ul-
trasonicating the mixture (entries 1 and 2). However, the
use of microwave irradiation accelerated the cyclization sig-
nificantly, leading to useful levels of conversion (entry 4).
Furthermore, irradiation with a 300 W Osram daylight
lamp speeded up the reaction (entry 5). Importantly, a dif-
ferent preference for one of the regioisomers was observed
under these conditions. Whereas microwave activation led
to preferential formation of the five-membered lactone 28,
the six-membered ring 27 was obtained as the main prod-
uct by irradiation with a daylight lamp.32 During irradiation,
a significant warming of the reaction to approximately
65 °C was observed. To analyze the thermal effect, we heat-
ed the reaction to this temperature, but excluded light (en-
try 6).33 Again, higher yields were observed compared with
those obtained by conducting the reaction at room tem-
perature (Table 1, entry 1). However, the selectivity was
switched and isobenzofuranone 28 was obtained as the
main product. In contrast, only low levels of conversions
were obtained upon irradiation and cooling (Table 2, entry
7) or upon lowering the reflux temperature (entry 8),
demonstrating the important thermal effect. Carrying out
the same reaction in the absence of light (entry 9) also led
to a decreased yield, which again documents the impor-
tance of light for activation of the reaction. Importantly, no
loss in the diastereoselectivity of the reaction was observed
during irradiation (entries 5, 7, and 8).
7b
1
6
8b
toluene
CH2Cl2
EtOAc
0
0
9b
12
2
6
10b
11b
12b
13
14b
15c
16d
17
18e
19f
20g
21h
11
2
cyclohexane
0
EtOH
H2O
MeCN
THF
THF
H2O
THF
THF
THF
THF
4
4
0
2
0
11
12
0
13
0
0
2
0
0
8
21
5
0
61
70
0
11
a Reaction conditions (concn: 0.02 M): I2 (5.0 equiv), r.t., 72 h; yield was de-
termined by qNMR analysis of the crude product: see experimental part;
rsm = recovered starting material.
b Solvent–H2O, 5:1.
c Solvent–H2O, 1:1.
d No water added.
e Concn: 0.002 M.
f Concn: 0.2 M.
g H2O (1.0 equiv) used.
h H2O (2.0 equiv) used.
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Table 2 Evaluation of Microwave Conditions, Temperature, and Irradi-
ation on the Regiodivergent Cyclization of E-Alkene 26 to syn-Products
27 and 28a
Table 3 Evaluation of Iodine Reagents and Additives on the Regiodi-
vergent Cyclization of E-Alkene 26 to syn-Products 27 and 28a
OH
OH
O
O
OMe
O
OMe
O
27
27
reagent
O
I2 (5 equiv)
+
O
THF/H2O
(5:1)
+
HO
OMe NEt2
THF/H2O
(5:1)
HO
OMe NEt2
26
26
O
O
O
OMe
O
OMe
28
28
Entry Conditionsa
Yield/rsm (%)b
27 28
Entry
Conditionsa
Yield/rsm (%)b
27 28
26
47
26
47
1
2
3
4
5
6
7
8
9
I2 (1.1 equiv)
2
3
1
2
3
4
5
6
7
8
9
ultrasound, r.t., 4 h
ultrasound, r.t., 15 h
MW, 100 °C, 1 h
2
5
I2 (20 equiv)
16
10
12
2
19
23
15
8
0
31
49
30
14
15
0
5
7
14
24
40
29
42
5
0
43
0
NIS (5 equiv)
ICl (5 equiv)
MW, 100 °C, 4 h
12
34
22
2
I2 (5 equiv), HCl (5%)
I2 (5 equiv), H2SO4 (5%)
I2 (5 equiv), KOH (5%)
I2 (5 eq), AIBN
300 W irradiation, reflux, 72 h
dark, 65 °C, 72 h
5
13
6
16
17
49
48
6
300 W irradiation, 10 °C, cooling, 72 h
300 W irradiation, reflux, CH2Cl2, 72 h
dark, r.t., 72 h
49
40
27
17
25
14
9
15
12
I2 (5 equiv), AIBN, irradiation (300 W)
0
a Reaction conditions (concn: 0.02 M): stirring at r.t. for 72 h, THF–H2O
(5:1).
a Reaction conditions (concn: 0.02 M): I2 (5.0 equiv), THF–H2O, 5:1.
b Yield was determined by qNMR analysis of the crude product: see experi-
mental part; rsm = recovered starting material.
b Yield was determined by qNMR analysis of the crude product: see experi-
mental part; rsm = recovered starting material.
As shown in Table 3, we then studied the influence of
the number of equivalents and the source of iodine, as well
as alternative additives. Increasing the iodine concentration
lead to a slight increase in yield (entry 2), whereas only
very low yields were obtained with 1.1 equivalent of the
halogen (entry 1). The use of either NIS or iodine chloride
led to very similar yields (entries 3 and 4). Addition of acids
or bases did not have a beneficial effect on the reaction (en-
tries 5–7). As shown in Table 3, entries 8 and 9 this reaction
can be carried out under radical conditions. In the presence
of the radical initiator AIBN an increase of the conversion
was observed (entries 8 and 9). In agreement with a slight
decrease of diastereoselectivity (28: dr 7:1; entry 8) the re-
action presumably proceeds through a radical pathway.
Having established useful conditions to access both the
syn-isochromanone 27 and -isobenzofuranone 28, with ex-
cellent diastereoselectivities and useful regioselectivities
(e.g., Table 2, entries 4–6), we then evaluated whether these
results may also be applied to the corresponding Z-alkene
25 and evaluated the most efficient conditions for conver-
sion of 25. As shown in Table 4, both isochromanone 29 and
isobenzofuranone 30 were obtained, which confirms the
general proof of our divergent synthetic concept. Impor-
tantly, these two products were again observed as single
isomers, but now with an anti-configuration. This demon-
strates that the configuration of the double bond is reliably
transferred to the relative configuration of the two new vic-
inal chiral centers. Consistent with the results obtained
above, irradiation with light resulted in preparatively useful
yields (entry 3), with the six-membered heterocycle
formed as the main product. Heating the reaction led to
dramatically improved yields (entry 2) and, consistent with
the results obtained above, the regioselectivity was again
switched in favor of the isobenzofuranone, and high re-
gioselectivities (15:1) were obtained.
Importantly, the most effective conditions reported
above were readily reproducible. As shown in Scheme 4 this
enables rapid access to all syn- and anti-configured aju-
dazol type isochromanones and isobenzofuranones 27–30
in only two steps from iodo compound 23, which, in turn,
can be easily synthesized from commercial benzoic acid 21.
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Table 4 Regiodivergent Cyclization of Z-Alkene 25 to anti-Products 29
and 30a
OH
O
300 W, reflux
63%
(27/28 1.25:1)
dr > 20:1
OH
O
OMe
OMe
OMe
OMe
27
I2 (5 equiv)
THF/H2O (5:1)
O
O
HO
OMe NEt2
OMe
O
29
+
26
dark, 65 °C
64%
(28/27 2.1:1)
dr > 20:1
I2 (5 equiv)
O
O
18
92%
THF/H2O
(5:1)
OMe NEt2
HO
I
O
28
25
21
O
78%
O
OH
O
daylight, r.t.
75%
(29/30 1.8:1)
dr > 20:1
OMe NEt2
96%
23
24
O
OMe
O
30
29
I2 (5 equiv)
THF/H2O (5:1)
Entry
Conditionsa
Yield/rsm (%)b
O
HO
29
48
30
27
25
OMe NEt2
25
1
2
3
4
daylight, r.t.
dark, 65 °C
0
0
0
0
dark, 65 °C
77%
(30/29 15:1)
dr > 20:1
O
5
34
33
72
28
26
300 W irradiation, reflux
MW, 100 °C, 4 h
O
30
Scheme 4 Concise synthesis of all ajudazol type syn- and anti-hydrox-
yl-isochromanones and -isobenzofuranones by a diversification strategy
from joint intermediate 23
a Reaction conditions (concn: 0.02 M): I2 (5.0 equiv), THF–H2O (5:1), stirring
for 72 h.
b Yield was determined by qNMR analysis of the crude product: see experi-
mental part; rsm = recovered starting material.
All regio- and diastereomeric products can be obtained se-
lectively in the tandem cyclization depending on the choice
of reaction conditions. In all cases, high diastereoselectivi-
ties were obtained, with the anti-configured products be-
ing obtained from Z-alkenes and the syn-products deriving
from E-alkenes.
To further understand the mechanism of this reaction,
we then tried to isolate iodinated intermediates. This was
successful in the cyclization of simplified Z-alkene 31,
which was readily obtained by coupling of iodide 17c with
Z-boronate 24 (Scheme 5). Both the anti-isochromanone 32
and the iodinated compound 33 could be obtained, and the
structures of both heterocycles were unambiguously prov-
en by X-ray crystallographic analysis.
Based on these results, a mechanism may be proposed
for this iodocyclization/substitution reaction. As shown in
Scheme 6 for the conversion of Z-alkene 34, it is expected
that the excellent diastereoselectivities are derived from
two nucleophilic substitution reactions. Presumably, the
reaction proceeds via iodonium intermediate 35. Based on
the isolation of iodolactone 33, we assume that formation
of isobenzofuranone 41 is initiated by a 5-exo-trig cycliza-
tion of the amide oxygen of 35 and subsequent substitution
of intermediate 39. This pathway should be favored over an
alternative that would first involve intermolecular attack of
water and subsequent 5-exo-cyclization of 38. Presumably,
Scheme 5 Synthesis and X-ray crystal structures of simplified anti-iso-
chromanone 32 and iodo-isobenzofuranone 33
formation of isochromanone 40 should proceed by a differ-
ent sequence, involving direct intramolecular substitution
of the reactive benzylic position as compared to a 6-endo-
cyclization of 35 towards 36.34 Cyclization of the resulting
benzylic alcohol 37 would then proceed in a much more fa-
vorable exo-fashion. This proposal is consistent with a pre-
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vious proposal for a related conversion14a as well as with
our own experimental results demonstrating that a de-
crease of the water concentration disfavors the six-mem-
bered-ring formation.
thentic isochromanone and isobenzofurane fragments of
the ajudazols and isoajudazols in only four steps from com-
mercially available starting materials. The developed proto-
cols may enable general applicable modular joint synthetic
routes to hydroxyl-isochromanone and isobenzofuranone
natural products and derived bioactive agents. Efforts will
now be applied to develop an enantioselective variant of
this reaction36 and to further analyze the influence of light
on this reaction. Furthermore, strategies will be pursued for
further SAR studies of the ajudazols.
H2O
H2O
I+
b)
d)
c)
R2
R2
I2
a)
O
O
R1
R1
b)
NEt2
NEt2
34
35
a) 6-endo-
cyclization
d) 5-exo-
cyclization
c)
H2O
All reactions in anhydrous solvents were performed under an atmo-
sphere of argon in flame-dried glassware. All flasks were equipped
with rubber septa and reactants were handled by using standard
Schlenk techniques. Reactions were monitored by TLC on silica gel 60
F254 precoated plates (0.2 mm SiO2, Machery–Nagel) and visualized
using UV light and/or staining with a solution of KMnO4 (1.5 g
KMnO4, 10 g K2CO3, 1.25 mL 10% NaOH in 200 mL H2O) and subse-
quent heating. For column chromatography, silica gel (pore size 60 Å,
40–63 μm) was used. 1H and 13C NMR spectra were recorded with
Bruker AC-300, DRX-300, DPX-300, DPX-400, and DRX-500 spec-
trometers. Chemical shifts (δ) are reported in ppm, coupling con-
stants (J) in hertz (Hz). Abbreviations are as follows: s (singlet), d
(doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br.
(broad). High-resolution mass spectra (HRMS) were recorded with
Bruker ICR APEX-QE, Vacuum Generators ZAB-2F, Finnigan MAT TSQ
700, JEOL JMS-700, Bruker Daltonics micrOTOF-Q and a Thermo
Finnigan MAT 95 XL. The X-ray crystallographic data collection of 28
was performed with a Bruker X8 KappaApex-II diffractometer (CCD)
at 100(2) K; those of 32 and 33 were obtained with a STOE IPDS-2T
diffractometer at 123(2) K. The diffractometers were equipped with a
low-temperature device (Kryoflex I, Bruker AXS GmbH or Cryostream
700er series, Oxford Cryosystems) and used graphite monochromat-
ed Mo-Kα radiation (λ = 0.71073 Å). Details of the X-ray structure de-
terminations are given in the Supporting Information. The structures
have been deposited with the Cambridge Crystallographic Data Cen-
tre as CCDC-1428336 (28), CCDC-1428337 (32), and CCDC-1428338
(33), and can be obtained free of charge via www.ccdc.cam.ac.uk.
I
H2O
R2
H2O
I
OH
I
I+
OH
O
R2
R2
R2
O
O
O
R1
R1
R1
R1
+NEt2
+NEt2
NEt2
NEt2
36
37
38
39
6-exo
5-exo-
H2O
H2O
R2
cyclization cyclization
R2
HO
OH
O
O
O
R1
R1
O
41
40
Scheme 6 Proposed mechanism for the one-pot iodocyclization-sub-
stitution sequence: divergent pathway for isochromanone and isoben-
zofuranone synthesis
In summary, we have developed an efficient synthetic
strategy with which to access all syn- and anti-configured
hydroxyl-isochromanone and -isobenzofuranones with an
ajudazol type substitution pattern from readily available
joint alkene precursors. The protective-group-free35 pro-
cess is based on a one-pot iodocyclization–substitution tan-
dem reaction and proceeds with excellent diastereoselec-
tivities. Conversion of E-alkenes leads to stereoselective
formation of syn-configured isochromanones and -iso-
benzofuranones, whereas Z-alkenes give rise to the anti-
configured products. Depending on the reaction conditions,
either six- or five-membered products may be obtained
with good to preparatively useful selectivity. Both products
are easily separable by column chromatography. Irradiation
was shown to have a beneficial effect towards six-mem-
bered-ring formation, whereas carrying out the reaction
under microwave or thermal conditions led to selective iso-
benzofurane lactones. An iodo-intermediate could be iso-
lated for a related conversion, which further underlines a
mechanistic proposal that suggests a different pathway for
isochromanone and isobenzofuranone formation. The de-
scribed method allows a highly concise synthesis of the au-
Methyl 2-Iodobenzoate (17a)37
2-Iodobenzoic acid (7.50 g, 30.2 mmol, 1 equiv) was dissolved in
MeOH (150 mL), then concentrated sulfuric acid (20 mL) was added
slowly. The mixture was stirred and heated at reflux for 3 h. After
cooling to r.t., the reaction mixture was diluted with Et2O (150 mL),
the layers were separated, and the organic phase was washed with
H2O (2 × 150 mL), sat. aq NaHCO3 (200 mL) and sat. aq NaCl (200 mL).
After drying over MgSO4, the solvent was removed in vacuo to give
the product.
Yield: 7.59 g (29.0 mmol, 96%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 3.93 (s, 3 H), 7.14 (ddd, J = 8.0, 7.5,
1.7 Hz, 1 H), 7.39 (ddd, J = 7.7, 7.5, 1.2 Hz, 1 H), 7.79 (dd, J = 7.7,
1.7 Hz, 1 H), 7.99 (dd, J = 8.0, 1.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 52.5, 94.0, 127.9, 130.9, 132.6, 135.1,
141.3, 166.9.
HRMS (EI): m/z [M – H]·+ calcd for C8H6IO2: 260.9412; found:
260.9407.
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Amides 17b–d; General Procedure 1 (GP1)
1H NMR (400 MHz, CDCl3): δ = 1.06 (d, J = 6.7 Hz, 3 H), 1.27 (d,
J = 6.7 Hz, 3 H), 1.56 (d, J = 6.7 Hz, 3 H), 1.60 (d, J = 6.7 Hz, 3 H), 3.55
(d.sept, J = 25.6, 6.7 Hz, 2 H), 7.02 (ddd, J = 7.9, 7.6, 1.6 Hz, 1 H), 7.13
(dd, J = 7.5, 1.6 Hz, 1 H), 7.35 (ddd, J = 7.6, 7.5, 1.1 Hz, 1 H), 7.81 (dd,
J = 7.9, 1.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.0 (2C), 20.6, 20.7, 46.0, 51.2, 92.3,
125.8, 128.2, 129.4, 139.3, 144.2, 169.8.
Freshly distilled thionyl chloride (5 equiv) and DMF (0.1 mL, cat.)
were added to a solution of 2-iodobenzoic acid (15; 1 equiv) in CH2Cl2
(75 mL) under an argon atmosphere. The resulting mixture was
stirred and heated at reflux for 5 h. Excess thionyl chloride was re-
moved in vacuo and the residue was dissolved in CH2Cl2 (50 mL) and
cooled to 0 °C. The amine (5 equiv) was slowly added to the solution.
The mixture was stirred overnight at r.t. and then diluted with EtOAc
(150 mL) and washed with sat. aq NH4Cl (100 mL). The phases were
separated and the aqueous phase was extracted with EtOAc (2 × 75
mL). The combined organic layers were washed with sat. aq NaCl (100
mL) and dried over MgSO4. After removing the solvent in vacuo, flash
chromatography (silica gel) afforded the product.
HRMS (ESI+): m/z [M + H]+ calcd for C13H18INOH: 332.0506; found:
332.0507.
Suzuki Coupling Reaction for the Synthesis of 19a–d; General Pro-
cedure 2 (GP2)
Substituted 2-iodobenzamide or methyl 2-iodobenzoate (1 equiv)
was dissolved in dioxane (30 mL), then boronic acid pinacol ester
(1 equiv), tetrakis(triphenylphosphine)palladium(0) (5 mol%) and
NaOH (2 N in H2O, 2 equiv) were added successively. The reaction
mixture was stirred and heated at reflux for 3 h, then the reaction
was quenched with H2O (50 mL) and the mixture was extracted with
Et2O (3 × 50 mL). The combined organic phases were washed with sat.
aq NaCl (50 mL) and dried over MgSO4. After removing the solvent in
vacuo, flash chromatography (silica gel) afforded the product.
2-Iodo-N,N-dimethylbenzamide (17b)38
Thionyl chloride (12.0 g, 101 mmol, 5 equiv) and DMF (0.1 mL, cat.)
were added to a solution of 2-iodobenzoic acid (5.00 g, 20.2 mmol, 1
equiv). Dimethylamine hydrochloride (1.81 g, 22.2 mmol, 5 equiv)
was added after 5 h, as described in GP1 for the preparation of 2-io-
dobenzamides. After work-up of the crude product, flash chromatog-
raphy (silica gel; cyclohexane–Et2O, 3:1) afforded the product.
Yield: 4.74 g (17.3 mmol, 86%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 2.84 (s, 3 H), 3.13 (s, 3 H), 7.06 (ddd,
J = 8.0, 7.5, 1.6 Hz, 1 H), 7.20 (dd, J = 7.5, 1.6 Hz, 1 H), 7.38 (ddd, J = 7.5,
7.5, 1.1 Hz, 1 H), 7.81 (dd, J = 8.0, 1.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 34.7, 38.4, 92.4, 127.0, 128.4, 130.0,
139.0, 142.8, 170.1.
(E)-Methyl 2-(Pent-1-enyl)benzoate (19a)
(E)-4,4,5,5-Tetramethyl-2-(pent-1-enyl)-1,3,2-dioxaborolane
(18;
1.10 g, 5.60 mmol, equiv), palladium(0) catalyst (324 mg,
1
0.28 mmol, 5 mol%), and NaOH (2 N solution, 5.60 mL, 11.20 mmol, 2
equiv) were added to methyl 2-iodobenzoate (17a; 1.47 g, 5.60 mmol,
1 equiv) in dioxane by following GP2. Flash chromatography (silica
gel; cyclohexane–Et2O, 50:1) gave the product.
HRMS (ESI+): m/z [M + Na]+ calcd for C9H10INONa: 297.9705; found:
297.9711.
Yield: 0.76 g (3.71 mmol, 66%); pale-yellow liquid.
N,N-Diethyl-2-iodobenzamide (17c)39
1H NMR (400 MHz, CDCl3): δ = 0.97 (t, J = 7.3 Hz, 3 H), 1.52 (sext,
J = 7.3 Hz, 2 H), 2.23 (dq, J = 7.3, 1.6 Hz, 2 H), 3.90 (s, 3 H), 6.14 (dt,
J = 15.7, 7.3 Hz, 1 H), 7.13 (dt, J = 15.7, 1.6 Hz, 1 H), 7.25 (ddd, J = 7.8,
7.5, 1.2 Hz, 1 H), 7.43 (ddd, J = 7.9, 7.5, 1.5 Hz, 1 H), 7.52–7.56 (m,
1 H), 7.84 (ddd, J = 7.8, 1.5, 0.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.7, 22.4, 35.2, 52.0, 126.4, 127.2,
128.1, 128.5, 130.2, 131.9, 133.8, 139.7, 168.1.
Thionyl chloride (30.5 g, 256 mmol, 5 equiv), DMF (0.1 mL, cat.) and
2-iodobenzoic acid (12.7 g, 51.2 mmol, 1 equiv) were reacted with di-
ethylamine (18.7 g, 256 mmol, 5 equiv) by following GP1 for the
preparation of 2-iodobenzamides. Purification of the crude product
by flash chromatography (silica gel; cyclohexane–Et2O, 2:1) afforded
the product.
HRMS (ESI+): m/z [M]·+ calcd for C13H16O2: 204.1150; found:
Yield: 14.29 g (47.13 mmol, 92%); light-yellow oil.
1H NMR (400 MHz, CDCl3): δ = 1.06 (t, J = 7.1 Hz, 3 H), 1.28 (t,
J = 7.1 Hz, 3 H), 3.02–3.22 (m, 2 H), 3.22–3.39 (m, 1 H), 3.78–3.93 (m,
1 H), 7.04 (ddd, J = 8.0, 7.5, 1.7 Hz, 1 H), 7.19 (ddd, J = 7.5, 1.7, 0.4 Hz,
1 H), 7.36 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H), 7.80 (ddd, J = 8.0, 1.1, 0.4 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 12.4, 13.9, 38.9, 42.7, 92.7, 126.8,
128.2, 129.8, 139.1, 142.8, 170.0.
204.1151.
(E)-N,N-Dimethyl-2-(pent-1-enyl)benzamide (19b)
2-Iodo-N,N-dimethylbenzamide (17b; 2.27 g, 8.24 mmol, 1 equiv)
was reacted with (E)-4,4,5,5-tetramethyl-2-(pent-1-enyl)-1,3,2-diox-
aborolane (18; 1.61 g, 8.24 mmol, 1 equiv), tetrakis(triphenylphos-
phine)palladium(0) (476 mg, 0.41 mmol, 5 mol%) and NaOH (2 N
solution, 8.24 mL, 16.5 mmol, 2 equiv) according to GP2. Flash chro-
matography (silica gel; cyclohexane–Et2O, 4:1 and 5 vol% Et3N) gave
the product.
HRMS (ESI+): m/z [M + Na]+ calcd for C11H14INONa: 326.0012; found:
326.0012.
Yield: 1.22 g (5.63 mmol, 68%); yellow oil.
2-Iodo-N,N-diisopropylbenzamide (17d)
1H NMR (400 MHz, CDCl3): δ = 0.93 (t, J = 7.4 Hz, 3 H), 1.47 (sext,
J = 7.4 Hz, 2 H), 2.12–2.21 (m, 2 H), 2.77 (br. s, 3 H), 3.13 (br. s, 3 H),
6.21 (dt, J = 15.8, 6.8 Hz, 1 H), 6.34 (dt, J = 15.8, 1.4 Hz, 1 H), 7.17 (ddd,
J = 7.5, 1.7, 0.6 Hz, 1 H), 7.21 (ddd, J = 7.5, 7.4, 1.5 Hz, 1 H), 7.29 (ddd,
J = 7.8, 1.5, 0.6 Hz, 1 H), 7.47–7.51 (m, 1 H).
The reaction was carried out as described in GP1. Thionyl chloride
(18.0 g, 151 mmol, 5 equiv) and DMF (0.1 mL, cat.) were added to 2-
iodobenzoic acid (7.50 g, 30.2 mmol, 1 equiv). After 5 h, diisopropyl-
amine (15.3 g, 151 mmol, 5 equiv) was added slowly. The crude prod-
uct was purified by flash chromatography (silica gel; cyclohexane–
13C NMR (100 MHz, CDCl3): δ = 13.7, 22.4, 34.7, 35.2, 38.4, 125.5,
Et2O, 3:1) to afford
a pale-yellow solid. Recrystallization from
CH2Cl2/n-hexane (dissolved at 40 °C, then cooled to –28 °C) gave the
126.3, 126.5, 126.9, 128.8, 133.7, 134.4, 135.0, 171.3.
product.
HRMS (ESI+): m/z [M + Na]+ calcd for C14H19NONa: 240.1359; found:
Yield: 7.04 g (21.3 mmol, 70%); colorless crystals.
240.1357.
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(E)-N,N-Diethyl-2-(pent-1-enyl)benzamide (19c)
1H NMR (400 MHz, CDCl3): δ = 1.00 (t, J = 7.4 Hz, 3 H), 1.45–1.56 (m,
1 H), 1.58–1.69 (m, 1 H), 1.78–1.90 (m, 1 H), 1.93–2.06 (m, 1 H), 2.14–
2.46 (br. m, 1 H), 4.47 (ddd, J = 8.1, 5.5, 2.1 Hz, 1 H), 4.62 (d, J = 2.1 Hz,
1 H), 7.46 (dd, J = 7.6, 1.1 Hz, 1 H), 7.48–7.54 (m, 1 H), 7.64 (ddd,
J = 7.6, 7.5, 1.1 Hz, 1 H), 8.09 (dd, J = 7.6, 1.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.9, 18.3, 32.3, 66.6, 80.9, 124.2,
127.8, 129.8, 130.4, 134.3, 140.3, 165.0.
N,N-Diethyl-2-iodobenzamide (17c; 2.70 g, 8.91 mmol, 1 equiv) was
dissolved in dioxane as described in the GP2. (E)-4,4,5,5-Tetramethyl-
2-(pent-1-enyl)-1,3,2-dioxaborolane (18; 1.75 g, 8.91 mmol, 1 equiv),
tetrakis(triphenylphosphine)palladium(0) (515 mg, 0.45 mmol,
5
mol%) and NaOH (2 N solution, 8.91 mL, 17.8 mmol, 2 equiv) were
added and the reaction is allowed to run. After work-up, the crude
product was purified by flash chromatography (silica gel; cyclohex-
ane–Et2O, 4:1).
HRMS (ESI+): m/z [M + Na]+ calcd for C12H14O3Na: 229.0835; found:
229.0842.
Yield: 2.07 g (8.46 mmol, 95%); brown oil.
1H NMR (400 MHz, CDCl3): δ = 0.93 (t, J = 7.4 Hz, 3 H), 0.99 (t,
J = 7.1 Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.47 (sext, J = 7.4 Hz, 2 H),
2.11–2.20 (m, 2 H), 3.08 (q, J = 7.1 Hz, 2 H), 3.29–3.89 (m, 2 H), 6.21
(dt, J = 15.8, 6.8 Hz, 1 H), 6.37 (dt, J = 15.8, 1.4 Hz, 1 H), 7.14–7.24 (m,
2 H), 7.27–7.32 (m, 1 H), 7.45–7.53 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.8, 13.7, 13.9, 22.3, 35.2, 38.7, 42.7,
125.3, 125.9, 126.5, 126.7, 128.5, 133.4, 134.2, 135.5, 170.6.
N,N-Diethyl-2-methoxy-3-methylbenzamide (22)
To a solution of 2-methoxy-3-methylbenzoic acid (5 g, 30 mmol, 1.0
equiv) in anhydrous CH2Cl2 (300 mL), freshly distilled thionyl chloride
(11.0 mL, 150 mmol, 5.0 equiv) was added. The reaction mixture was
heated at reflux vigorously (oil bath temperature 100 °C) for 5 h. After
cooling to r.t., all volatiles were removed in vacuo, the residue was
dissolved in anhydrous CH2Cl2 (150 mL) under an atmosphere of ar-
gon and cooled to 0 °C. Maintaining the internal temperature below
5 °C a solution of diethylamine (15.5 mL, 150 mmol, 5.0 equiv) in an-
hydrous CH2Cl2 (50 mL) was added dropwise. When the addition was
complete, the reaction mixture was slowly warmed to r.t., and stirred
overnight to complete the reaction. H2O (100 mL) was added, the or-
ganic phase was separated and the aqueous phase was extracted with
Et2O (3 × 150 mL). The combined organic phases were washed with
HCl (2 N, 2 × 25 mL), aq NaOH (2 N, 2 × 25 mL), H2O (25 mL), and sat.
aq NaCl (25 mL). After drying over MgSO4 the solvent was removed
under reduced pressure and the crude product was purified by flash
chromatography (silica gel; cyclohexane–EtOAc, 3:1) to give 22.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H23NONa: 268.1672; found:
268.1672.
(E)-N,N-Diisopropyl-2-(pent-1-enyl)benzamide (19d)
2-Iodo-N,N-diisopropylbenzamide (17d; 1.88 g, 5.69 mmol, 1 equiv)
was dissolved in dioxane. (E)-4,4,5,5-Tetramethyl-2-(pent-1-enyl)-
1,3,2-dioxaborolane (18; 1.12 g, 5.69 mmol, 1 equiv), the palladi-
um(0) catalyst (324 mg, 0.28 mmol, 5 mol%) and NaOH (2 N solution,
5.69 mL, 11.4 mmol, 2 equiv) were added in accordance with GP2.
Flash chromatography (silica gel; cyclohexane–Et2O, 8:1) gave the
product.
Yield: 6.4 g (29 mmol, 96%); colorless oil.
Yield: 1.45 g (5.37 mmol, 94%); orange oil.
1H NMR (500 MHz, CDCl3): δ = 1.02 (t, J = 7.1 Hz, 3 H), 1.26 (t, J =
7.1 Hz, 3 H), 2.29 (s, 3 H), 3.05–3.23 (m, 2 H), 3.27–3.44 (m, 2 H), 3.79
(s, 3 H), 7.00–7.08 (m, 2 H), 7.15–7.21 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.9, 14.1, 16.1, 39.0, 43.1, 61.5, 124.2,
125.4, 131.5, 131.6, 131.8, 154.2, 169.3.
1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.4 Hz, 3 H), 1.04 (d,
J = 6.7 Hz, 3 H), 1.08 (d, J = 6.7 Hz, 3 H), 1.48 (sext, J = 7.4 Hz, 2 H),
1.58 (d, J = 6.8 Hz, 3 H), 1.59 (d, J = 6.8 Hz, 3 H), 2.16 (ddt, J = 7.4, 6.6,
1.4 Hz, 2 H), 3.50 (sept, J = 6.8 Hz, 1 H), 3.60 (sept, J = 6.7 Hz, 1 H),
6.23 (dt, J = 15.8, 6.6 Hz, 1 H), 6.43 (dt, J = 15.8, 1.4 Hz, 1 H), 7.10 (dd,
J = 7.5, 1.4 Hz, 1 H), 7.19 (ddd, J = 7.5, 7.5, 1.3 Hz, 1 H), 7.27 (ddd,
J = 7.7, 7.5, 1.4 Hz, 1 H), 7.50 (dd, J = 7.7, 1.3 Hz, 1 H).
HRMS (ESI+): m/z [M + 2H]+ calcd for C13H21NO2: 223.1522; found:
223.1524.
13C NMR (100 MHz, CDCl3): δ = –13.8, 20.3, 20.5, 20.7, 20.7, 22.3, 35.3,
45.8, 50.9, 125.1, 125.3, 126.6, 126.8, 128.2, 133.0, 133.9, 136.8, 170.6.
N,N-Diethyl-6-Iodo-2-methoxy-3-methylbenzamide (23)
N,N-Diethyl-2-methoxy-3-methylbenzamide (22; 2.6 g, 12 mmol, 1.0
equiv) and tetramethylethylenediamine (1.6 g, 14 mmol, 1.2 equiv)
were dissolved in anhydrous THF and cooled to –78 °C. s-BuLi (1.4 M
in hexanes; 10 mL, 14 mmol) was added dropwise and the reaction
mixture was stirred for 30 min at –78 °C. A solution of iodine (3.5 g,
14 mmol, 1.2 equiv) in THF (30 mL) was added dropwise by using a
dropping funnel, keeping the internal temperature below –70 °C. The
reaction mixture was stirred for 1 h at –78 °C then warmed slowly to
r.t. The reaction was quenched by adding sat. aq sodium thiosulfate
(50 mL), the organic phase was separated, and the aqueous phase was
extracted with Et2O (3 × 100 mL). The combined organic phases were
washed with H2O (50 mL) and sat. aq NaCl (50 mL). After drying over
MgSO4, the solvent was removed under reduced pressure and the
crude product was purified by flash chromatography (silica gel; cy-
clohexane–EtOAc, 4:1) to give 23.
HRMS (ESI+): m/z [M + Na]+ calcd for C18H27NONa: 296.1985; found:
296.1982.
Iodolactonization; General Procedure 3 (GP3)
2-Alkenylbenzamide or 2-alkenylmethyl benzoate was dissolved in
THF–H2O (5:1, 5 mL), then I2 (5 equiv) was added and the reaction
mixture was protected from light and stirred at r.t. for three days. The
reaction was then quenched by addition of sat. aq sodium thiosulfate
(10 mL) and the aqueous phase was extracted with Et2O (3 × 5 mL).
The combined organic layers were washed with sat. aq NaCl (10 mL)
and dried over MgSO4. The product was obtained by flash chromatog-
raphy after removing the solvent in vacuo.
syn-4-Hydroxy-3-propylisochroman-1-one (20) from 19c
(E)-N,N-Diethyl-2-(pent-1-enyl)benzamide (19c; 0.23 g, 1.12 mmol,
1 equiv) was reacted with I2 (1.43 g, 5.62 mmol, 5 equiv) according to
GP3, except the reaction was exposed to light while stirring. Flash
chromatography (silica gel; cyclohexane–Et2O, 4:1) afforded the
product.
Yield: 3.7 g (11 mmol, 91%); pale-yellow oil.
1H NMR (500 MHz, CDCl3): δ = 1.09 (t, J = 7.2 Hz, 3 H), 1.28 (t, J =
7.2 Hz, 3 H), 2.23 (s, 3 H), 2.99–3.19 (m, 2 H), 3.43–3.72 (m, 2 H), 3.76
(s, 3 H), 6.87 (d, J = 7.9 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.4, 13.7, 15.7, 38.9, 42.9, 61.7, 89.7,
131.8, 132.5, 134.5, 137.3, 154.9, 168.0.
Yield: 0.13 g (0.65 mmol, 58%, dr > 20:1); pale milky oil.
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Synthesis
HRMS (ESI+): m/z [M + H]+ calcd for C13H19INO2: 348.0455; found:
348.0457.
mmol, 0.06 equiv) was added. The reaction mixture was heated at re-
flux (oil bath temperature 105 °C) for 3 h under argon atmosphere
then the reaction was quenched with H2O (25 mL) and the mixture
was extracted with Et2O (3 × 50 mL). The combined organic phases
were washed with sat. aq NaCl (25 mL) and dried over MgSO4. The
solvent was removed under reduced pressure and the crude product
was purified by flash chromatography (silica gel; cyclohexane–EtOAc,
3:1) to give 26.
(Z)-4,4,5,5-Tetramethyl-2-(pent-1-enyl)-1,3,2-dioxaborolane (24)
The reaction was carried out under argon atmosphere. The reaction
vessel was charged with chloro(1,5-cyclooctadiene)rhodium(I) dimer
(280 mg, 0.06 mmol, 3 mol%), then cyclohexane (100 mL), triisopro-
pylphosphine (384 mg, 2.40 mmol, 6 mol%), Et3N (4.05 g, 40.0 mmol,
1.0 equiv) and catecholborane (4.80 g, 40.0 mmol, 1.0 equiv) were
added consecutively. The resulting reaction mixture was stirred at r.t.
for 2 h, then a solution of pinacol (7.09 g, 60 mmol, 1.5 equiv) in cy-
clohexane (60 mL) was added and the mixture was stirred under ar-
gon atmosphere at r.t. overnight. The solvent was removed in vacuo
and the residue was purified by flash chromatography (silica gel; cy-
clohexane–Et2O, 40:1) to give 24.
Yield: 1.00 g (3.5 mmol, 96%); brown oil.
1H NMR (500 MHz, CDCl3): δ = 0.91 (t, J = 7.4 Hz, 3 H), 0.99 (t, J =
7.2 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.45 (sext, J = 7.3 Hz, 2 H), 2.07–
2.18 (m, 2 H), 2.26 (s, 3 H), 2.97–3.15 (m, 2 H), 3.49–3.70 (m, 2 H),
3.77 (s, 3 H), 6.16 (dt, J = 15.8, 6.8 Hz, 1 H), 6.28 (d, J = 15.8 Hz, 1 H),
7.08 (d, J = 7.9 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.7, 13.7 (2 C), 15.7, 22.4, 35.2, 38.8,
42.9, 61.5, 120.8, 126.3, 129.5, 130.0, 131.1, 132.7, 133.8, 154.2, 168.2.
Yield: 4.42 g (22.5 mmol, 56%); yellowish brown liquid.
1H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 7.4 Hz, 3 H), 1.26 (s, 12 H),
1.41 (sext, J = 7.4 Hz, 2 H), 2.37 (qd, J = 7.4, 1.3 Hz, 2 H), 5.34 (dt,
J = 14.0, 1.3 Hz, 1 H), 6.42 (dt, J = 14.0, 7.4 Hz, 1 H).
HRMS (ESI+): m/z [M]·+ calcd for C18H27NO2: 289.2042; found:
289.2041.
13C NMR (100 MHz, CDCl3): δ = 13.6, 24.8 (4C), 26.9, 34.2, 82.8 (2C),
General Procedure for qNMR Studies
154.9 (the olefinic C next to boron was not detected).
HRMS (EI): m/z [M]+ calcd for C11H21BO2: 196.1744; found:
196.17242.
The crude product that was obtained after the iodolactonization reac-
tion was dissolved in CDCl3 (0.5 mL) and transferred into an NMR
tube. An accurately measured amount (0.1 mL) of a precisely prepared
stock solution of dimethyl terephthalate in CDCl3 was added and the
mixture was homogenized. The amount of each product was deter-
mined by relating the proton integral of the ester functions of di-
methyl terephthalate (3.9 ppm, 6 H) to the signals of the products.40
(Z)-N,N-Diethyl-2-methoxy-3-methyl-6-(pent-1-en-1-yl)benz-
amide (25)
N,N-Diethyl-6-iodo-2-methoxy-3-methylbenzamide (23; 0.95 g, 2.73
mmol, 1.00 equiv), (Z)-4,4,5,5-tetramethyl-2-(pent-1-en-1-yl)-1,3,2-
dioxaborolane (24; 0.64 g, 3.28 mmol, 1.20 equiv) and aq NaOH (2 N,
2.7 mL, 5.40 mmol, 2.00 equiv) were dissolved in 1,4-dioxane (15 mL).
The mixture was degassed by bubbling argon gas through the solvent
for 15 min, then tetrakis(triphenylphosphine)palladium(0) (0.19 g,
0.16 mmol, 0.06 equiv) was added. The reaction mixture was heated
at reflux (oil bath temperature 105 °C) for 3 h under argon atmo-
sphere, then the reaction was quenched with H2O (20 mL) and ex-
tracted with Et2O (3 × 50 mL). The combined organic phases were
washed with sat. aq NaCl (25 mL) and dried over MgSO4. The solvent
was removed under reduced pressure and the crude product was pu-
rified by flash chromatography (silica gel; cyclohexane–EtOAc, 3:1) to
give 25.
syn-4-Hydroxy-8-methoxy-7-methyl-3-propylisochroman-1-one
(27)
(E)-N,N-Diethyl-2-methoxy-3-methyl-6-(pent-1-en-1-yl)benzamide
(26; 39 mg, 135 μmol, 1.0 equiv), was dissolved in THF (5 mL) then
H2O (1 mL) and I2 (170 mg, 675 μmol, 5.0 equiv) were added. The re-
action mixture was irradiated with a 300 W daylight lamp held ap-
proximately 10 cm from the reaction vessel. A cooling finger was at-
tached to the reaction flask and the mixture was stirred for three
days. The reaction was quenched by addition of sat. aq sodium thio-
sulfate solution (5 mL), the organic phase was separated, and the
aqueous phase was extracted with Et2O (3 × 5 mL). The combined or-
ganic layers were washed with sat. aq NaCl (5 mL) and dried over
MgSO4. The solvent was removed under reduced pressure and the
crude product was purified by flash chromatography (silica gel; cyclo-
hexane–EtOAc, 5:1) to give 27 (12 mg, 47 μmol, 34%; mp 93 °C) as a
white solid as well as 28 (9.7 mg, 42.3 μmol, 29%).
1H NMR (300 MHz, CDCl3): δ = 1.00 (t, J = 7.3 Hz, 3 H), 1.44–1.69 (m,
2 H), 1.72–2.03 (br. s m, 3 H), 2.33 (s, 3 H), 3.88 (s, 3 H), 4.38 (ddd, J =
8.1, 6.0, 1.8 Hz, 1 H), 4.60 (d, J = 1.7 Hz, 1 H), 7.10 (d, J = 7.7 Hz, 1 H),
7.43 (d, J = 7.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 13.9, 16.2, 18.3, 32.2, 61.5, 67.3, 80.0,
116.8, 122.8, 134.6, 136.5, 140.2, 160.5, 162.0.
Yield: 0.73 g (2.5 mmol, 92%); green-brown oil.
1H NMR (500 MHz, CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3 H), 0.98 (t, J =
7.3 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.36–1.50 (m, 2 H), 2.14–2.27 (m,
2 H), 2.28 (s, 3 H), 2.99–3.09 (m, 2 H), 3.46–3.66 (m, 2 H), 3.77 (s, 3 H),
5.65 (dt, J = 11.7, 7.3 Hz, 1 H), 6.31 (d, J = 11.7 Hz, 1 H), 7.00 (d, J =
7.9 Hz, 1 H), 7.11 (d, J = 7.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.6, 13.7, 13.9, 15.8, 23.1, 30.8, 38.6,
42.9, 61.5, 124.9, 125.5, 129.6, 130.5, 131.2, 133.3, 133.9, 154.1, 168.1.
HRMS (ESI+): m/z [M + H]+ calcd for C18H28NO2: 290.2115; found:
290.2113.
HRMS (ESI+): m/z [M + Na]+ calcd for C14H18O4Na: 273.1097; found:
273.1095.
(E)-N,N-Diethyl-2-methoxy-3-methyl-6-(pent-1-en-1-yl)benz-
amide (26)
syn-(1-Hydroxybutyl)-7-methoxy-6-methylisobenzofuran-1(3H)-
one (28)
N,N-Diethyl-6-iodo-2-methoxy-3-methylbenzamide (23; 1.25 g, 3.6
mmol, 1.00 equiv), (E)-4,4,5,5-tetramethyl-2-(pent-1-en-1-yl)-1,3,2-
dioxaborolane (0.85 g, 4.3 mmol, 1.20 equiv) and aq NaOH (2 N, 3.6
mL, 7.2 mmol, 2.00 equiv) were dissolved in 1,4-dioxane (20 mL). The
mixture was degassed by bubbling argon gas through the solvent for
15 min before tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.2
(E)-N,N-Diethyl-2-methoxy-3-methyl-6-(pent-1-en-1-yl)benzamide
(26; 33 mg, 114 μmol, 1.0 equiv), was dissolved in THF (5 mL), then
H2O (1 mL) and I2 (145 mg, 570 μmol, 5.0 equiv) were added. The re-
action mixture was heated at reflux for three days protected from
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 697–709

707
S. Thiede et al.
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Synthesis
light. The reaction was quenched by addition of sat. aq sodium thio-
sulfate (5 mL), the organic phase was separated, and the aqueous
phase was extracted with Et2O (3 × 5 mL). The combined organic lay-
ers were washed with sat. aq NaCl (5 mL) and dried over MgSO4. The
solvent was removed under reduced pressure and the crude product
was purified by flash chromatography (silica gel; cyclohexane–EtOAc,
5:1) to give 28 (12 mg, 48 μmol, 42%; mp 103 °C) as an off-white solid,
as well as 27 (5.7 mg, 22.9 μmol, 20%).
(Z)-N,N-Diethyl-2-(pent-1-enyl)benzamide (31)
By following GP2, N,N-diethyl-2-iodobenzamide (17c; 1.70 g,
5.61 mmol, 1 equiv) was reacted with (Z)-4,4,5,5-tetramethyl-2-
(pent-1-enyl)-1,3,2-dioxaborolane (24; 1.10 g, 5.61 mmol, 1 equiv),
palladium(0) catalyst (324 mg, 0.28 mmol, 5 mol%), and NaOH (2 N,
5.61 mL, 11.22 mmol, 2 equiv). After work-up of the reaction, flash
chromatography (silica gel; cyclohexene–Et2O, 4:1) afforded the
product.
1H NMR (300 MHz, CDCl3): δ = 0.98 (t, J = 7.2 Hz, 1 H), 1.44–1.72 (m,
5 H), 2.33 (s, 3 H), 3.89–4.00 (m, 1 H), 4.09 (s, 3 H), 5.29 (d, J = 3.5 Hz,
1 H), 7.09 (d, J = 7.7 Hz, 1 H), 7.48 (d, J = 7.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 13.9, 15.6, 18.8, 35.1, 62.2, 72.3, 82.1,
116.6, 117.6, 132.1, 137.6, 147.3, 157.6, 168.2.
Yield: 1.36 g (5.53 mmol, 99%); orange oil.
1H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.5 Hz, 3 H), 0.99 (t,
J = 7.1 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.45 (sext, J = 7.5 Hz, 2 H),
2.19–2.28 (m, 2 H), 3.06 (q, J = 7.1 Hz, 2 H), 3.24–3.87 (m, 2 H), 5.71
(dt, J = 11.6, 7.3 Hz, 1 H), 6.39 (dt, J = 11.6, 1.8 Hz, 1 H), 7.15–7.34 (m,
4 H).
HRMS (ESI+): m/z [M + Na]+ calcd for C14H18O4Na: 273.1097; found:
13C NMR (100 MHz, CDCl3): δ = 12.8, 13.9, 14.0, 23.0, 30.7, 38.6, 42.6,
273.1102.
125.7, 125.8, 126.7, 128.0, 129.3, 134.0, 134.4, 136.9, 170.4.
anti-4-Hydroxy-8-methoxy-7-methyl-3-propylisochroman-1-one
(29)
HRMS (ESI+): m/z [M]·+ calcd for C16H23NO: 245.1780; found:
245.1783.
(Z)-N,N-Diethyl-2-methoxy-3-methyl-6-(pent-1-en-1-yl)benzamide
(25; 29.0 mg, 100 μmol, 1.0 equiv), was dissolved in THF (4.2 mL),
then H2O (0.8 mL) and I2 (125 mg, 500 μmol, 5.0 equiv) were added.
The reaction mixture was stirred at r.t. for three days, then the reac-
tion was quenched by addition of sat. aq sodium thiosulfate (5 mL).
The organic phase was separated and the aqueous phase was extract-
ed with Et2O (3 × 5 mL). The combined organic layers were washed
with sat. aq NaCl (5 mL) and dried over MgSO4. The solvent was re-
moved under reduced pressure and the crude product was purified
by flash chromatography (silica gel; cyclohexane–EtOAc, 5:1) to give
29.
anti-4-Hydroxy-3-propylisochroman-1-one (32) and syn-(1-Io-
dobutyl)isobenzofuran-1(3H)-one (33)
(Z)-N,N-Diethyl-2-(pent-1-en-1-yl)benzamide (51 mg, 0.21 mmol, 1.0
equiv), was dissolved in THF (5 mL), then H2O (1 mL) and I2 (264 mg,
1.05 mmol, 5.0 equiv) were added. The reaction mixture was irradiat-
ed with a 300 W daylight lamp held approximately 10 cm from the
reaction vessel. A cooling finger was attached to the reaction flask
and the mixture was stirred for 60 min. The reaction was quenched
by addition of sat. aq sodium thiosulfate (5 mL), the organic phase
was separated, and the aqueous phase was extracted with Et2O (3 × 5
mL). The combined organic layers were washed with sat. aq NaCl (5
mL) and dried over MgSO4. The solvent was removed under reduced
pressure and the crude product was purified by flash chromatogra-
phy (silica gel; cyclohexane–EtOAc, 4:1) to give 32 (8.1 mg, 40.6 μmol,
20%) as a colorless oil and 33 (9.0 mg, 32.9 μmol, 14%) as a yellow oil.
Yield: 12.1 mg (48 μmol, 48%); white solid; mp 129 °C.
1H NMR (300 MHz, CDCl3): δ = 0.96 (t, J = 7.2 Hz, 3 H),1.42–1.86 (m,
5 H), 2.30 (s, 3 H), 3.86 (s, 3 H), 4.29 (td, J = 8.0, 3.6 Hz, 1 H), 4.57–4.63
(m, 1 H), 7.22 (d, J = 7.7 Hz, 1 H), 7.43 (d, J = 7.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 13.8, 16.0, 18.1, 33.6, 61.5, 68.2, 81.8,
116.3, 120.4, 133.3, 136.6, 141.4, 160.1, 161.6.
HRMS (ESI+): m/z [M + Na]+ calcd for C14H18O4Na: 273.1097; found:
273.1095.
anti-4-Hydroxy-3-propylisochroman-1-one (32)
1H NMR (400 MHz, CDCl3): δ = 0.96 (t, J = 7.3 Hz, 3 H), 1.43–1.55 (m,
1 H), 1.60–1.77 (m, 2 H), 1.77–1.89 (m, 1 H), 2.20–2.91 (br. s, 1 H),
4.42 (ddd, J = 8.5, 7.6, 3.6 Hz, 1 H), 4.73 (d, J = 7.6 Hz, 1 H), 7.47 (ddd,
J = 7.6, 7.5, 1.3 Hz, 1 H), 7.58 (d, J = 7.6 Hz, 1 H), 7.65 (ddd, J = 7.6, 7.5,
1.4 Hz, 1 H), 8.06 (dd, J = 7.6, 1.3 Hz, 1 H).
anti-(1-Hydroxybutyl)-7-methoxy-6-methylisobenzofuran-1(3H)-
one (30)
(Z)-N,N-Diethyl-2-methoxy-3-methyl-6-(pent-1-en-1-yl)benzamide
(25; 37 mg, 128 μmol, 1.0 equiv), was dissolved in THF (5 mL), then
H2O (1 mL) and I2 (162 mg, 640 μmol, 5.0 equiv) were added. The re-
action mixture was heated at reflux for three days protected from
light. The reaction was quenched by addition of sat. aq sodium thio-
sulfate (5 mL), the organic phase was separated, and the aqueous
phase was extracted with Et2O (3 × 5 mL). The combined organic lay-
ers were washed with sat. aq NaCl (5 mL) and dried over MgSO4. The
solvent was removed under reduced pressure and the crude product
was purified by flash chromatography (silica gel; cyclohexane–EtOAc,
5:1) to give 30 (23.0 mg, 92.0 μmol, 72%) as a colorless oil, and 29 (1.6
mg, 6.40 μmol, 5%).
1H NMR (300 MHz, CDCl3): δ = 0.87–1.03 (m, 3 H), 1.38–1.70 (m, 5 H),
2.31 (s, 3 H), 3.84–4.01 (m, 1 H), 4.06 (s, 3 H), 5.29 (d, J = 4.4 Hz, 1 H),
7.13 (d, J = 7.7 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 13.8, 15.5, 18.7, 34.0, 62.2, 72.7, 82.5,
116.6, 117.4, 132.1, 137.4, 147.0, 157.3, 168.2.
13C (100 MHz, CDCl3): δ = 13.8, 18.1, 33.9, 67.9, 82.6, 123.7, 125.5,
128.8, 130.2, 134.3, 141.4, 164.4.
HRMS (ESI+): m/z [M]·+ calcd for C12H14O3: 206.0943; found:
206.0942.
syn-(1-Iodobutyl)isobenzofuran-1(3H)-one (33)
1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.3 Hz, 3 H), 1.39–1.54 (m,
1 H), 1.58–1.72 (m, 1 H), 1.72–1.81 (m, 1 H), 1.82–1.94 (m, 1 H), 4.49
(ddd, J = 9.9, 4.7, 2.5 Hz, 1 H), 5.32 (d, J = 2.5 Hz, 1 H), 7.58 (ddd,
J = 7.7, 7.6, 1.3 Hz, 1 H), 7.64 (dd, J = 7.7, 1.0 Hz, 1 H), 7.70 (ddd, J = 7.6,
7.6, 1.0 Hz, 1 H), 7.92 (dd, J = 7.6, 1.3 Hz, 1 H).
13C (100 MHz, CDCl3): δ = 13.1, 22.9, 35.3, 38.0, 82.3, 122.2, 125.7,
126.9, 129.8, 134.2, 148.3, 169.6.
HRMS (ESI+): m/z [M]•+ calcd for C12H14O3: 315.9960; found:
315.9961.
HRMS (ESI+): m/z [M + Na]+ calcd for C14H18O4Na: 273.1097; found:
273.1095.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 697–709

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Acknowledgment
(12) (a) Hobson, S. J.; Parkin, A.; Marquez, R. Org. Lett. 2008, 10,
2813. (b) Egan, B. A.; Paradowski, M.; Thomas, L. H.; Marquez, R.
Org. Lett. 2011, 13, 2086. (c) Egan, B. A.; Paradowski, M.;
Thomas, L. H.; Marquez, R. Tetrahedron 2011, 67, 9700.
(13) Hashmi, A. S. K.; Bechem, B.; Loos, A.; Hamzic, M.; Rominger, F.;
Rabaa, H. Aust. J. Chem. 2014, 67, 481.
(14) (a) Fujita, M.; Yoshida, Y.; Miyata, K.; Wakisaka, A.; Sugimura, T.
Angew. Chem. Int. Ed. 2010, 49, 7068. (b) Fujita, M.; Wakita, M.;
Sugimura, T. Chem. Commun. 2011, 47, 3983. (c) Fujita, M.;
Mori, K.; Shimogaki, M.; Sugimura, T. Org. Lett. 2012, 14, 1294.
(15) In contrast to this work, the group of Fujita has only studied for-
mation of syn-hydroxyl protected isochromanones from E-
alkenes of type 17a. Z-Configured alkenes and were not studied
and also isobenzofuranones were only obtained in low yields:
see ref. 14.
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (SFB 813) and the Fonds der chemischen Industrie
(scholarship to S.E.). We thank Andreas J. Schneider (University of
Bonn) for excellent HPLC support. G.S. thanks Prof. Dr. A. C. Filippou
for providing X-ray infrastructure.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561278.
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(20) For selected enantioselective iodocyclizations, see ref. 14 as
well as: (a) Veitch, G. E.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2010, 49, 7332. (b) Denmark, S. E.; Kuester, W. E.; Burk, M. T.
Angew. Chem. Int. Ed. 2012, 51, 10938. (c) Hennecke, U. Chem.
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(21) Clayden, J.; Mitjans, D.; Youssef, L. H. J. Am. Chem. Soc. 2002, 124,
5266.
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129, 15122. (b) Jithunsa, M.; Ueda, M.; Miyata, O. Org. Lett.
2011, 13, 518.
(24) The procedure was adapted from: Noguchi, H.; Shioda, T.; Chou,
C.-M.; Suginome, M. Org. Lett. 2008, 10, 377.
(25) Fairlamb, I. J.; Marrison, L. R.; Dickinson, J. M.; Lu, F.-J.; Schmidt,
J. P. Bioorg. Med. Chem. 2004, 12, 4285.
(11) (a) Donner, C.; Gill, M.; Tewierik, L. Molecules 2004, 9, 498.
(b) Birkett, S.; Ganame, D.; Hawkins, B. C.; Meiries, S.; Quach, T.;
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(26) Presumably, the decreased yield for 19a was due to partial ester
cleavage under these basic conditions.
(27) Smith, A. B.; Zheng, J. Tetrahedron 2002, 58, 6455.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 697–709

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Synthesis
(28) Besides 20, also unreacted starting material and anti-(1-
iodobutyl)isobenzofuran-1(3H)-one (anti-33) were isolated.
(29) Studies with the corresponding free carboxylic acid proved vari-
able and inconclusive.
(33) Translactonizations under these neutral conditions have not
been observed.
(34) Very recently, an unfavorable 6-endo-iodocyclization has been
observed for
a sterically highly hindered substrate, see:
(30) Boronate 24 was obtained by hydroboration of the correspond-
ing terminal alkyne, according to a procedure of Miyaura, see:
Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000,
122, 4990.
Schmalzbauer, B.; Menche, D. Org. Lett. 2015, 17, 2956.
(35) In contrast to this method, all other methods for isochroma-
none systems require initial protection of the hydroxyls (refs. 4
and 10–13) or result in the formation of hydroxyl-protected
products (ref. 14).
(36) For reviews on chiral hypervalent iodine reagents, see:
(a) Liang, H.; CiufoliniM, A. Angew. Chem. Int. Ed. 2011, 50,
11849. (b) Parra, A.; Reboredo, S. Chem. Eur. J. 2013, 19, 17244.
(c) Singh, F. V.; Wirth, T. Chem. Asian J. 2014, 9, 950.
(37) (a) Crawford, L. A.; McNab, H.; Mount, A. R.; Wharton, S. I. J. Org.
Chem. 2008, 73, 6642. (b) Heller, S. T.; Sarpong, R. Org. Lett.
2010, 12, 4572.
(38) Jithunsa, M.; Ueda, M.; Okiko, M. Org. Lett. 2011, 13, 518.
(39) Zhang, L.; Su, S.; Wu, H.; Wang, S. Tetrahedron 2009, 65, 10022.
(40) Pauli, G. F.; Jaki, B. U.; Lankin, D. C. J. Nat. Prod. 2005, 68, 133.
(31) A detailed analysis of further side products to explain the mass
balance in the reaction of 25 and 26 (Table 1, Table 2, Table 3,
and Table 4) was not carried out. NMR analyses of crude prod-
ucts suggested decomposition of the labile styrene double bond
without cyclization and/or aromatic substitution reactions.
Intermediate iodinated products could not be isolated, in con-
trast to the reactions of 19 and 31. The reason for the different
stability of the iodinated intermediates remains unclear.
(32) A reason for the strong influence of light is not clear. Possibly,
light leads to a spin-activation.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 697–709