Synthesis of Polysubstituted Meta-Halophenols by Anion-Accelerated 2π-Electrocyclic Ring Opening

Article abstract of DOI:10.1002/chem.202100939

Disrotatory – thermally allowed – 2π-electrocyclic ring-opening reactions require high temperatures to proceed. Herein, we report the first anion-accelerated 2π-electrocyclic ring opening of 6,6-dihalobicyclo[3.1.0]hexan-2-ones at low temperature to give the corresponding meta-halophenols in good to high yields (18 examples, 29–92 % yield, average: 65 %). Many of the phenols have unconventional substitution patterns and are reported here for the first time. Furthermore, the strength of the methodology was shown by the total synthesis of the densely functionalized phenolic natural product caramboxin (isolated as the lactam dehydrate). The reaction mechanism underlying the anion-acceleration was investigated in an ab initio study, which concluded that base-mediated proton abstraction anti to the concurrently departing endo-bromine was the initiating step in an overall concerted reaction mechanism leading directly to the meta-halophenol.

Full text of DOI:10.1002/chem.202100939

Full Paper
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Chemistry—A European Journal
Synthesis of Polysubstituted Meta-Halophenols by Anion-
Accelerated 2π-Electrocyclic Ring Opening
Markus Staudt,[a] Theis Sølling,[b] and Lennart Bunch*[a]
Abstract: Disrotatory – thermally allowed – 2π-electrocyclic
ring-opening reactions require high temperatures to proceed.
Herein, we report the first anion-accelerated 2π-electrocyclic
ring opening of 6,6-dihalobicyclo[3.1.0]hexan-2-ones at low
temperature to give the corresponding meta-halophenols in
good to high yields (18 examples, 29–92% yield, average:
65%). Many of the phenols have unconventional substitution
patterns and are reported here for the first time. Furthermore,
the strength of the methodology was shown by the total
synthesis of the densely functionalized phenolic natural
product caramboxin (isolated as the lactam dehydrate). The
reaction mechanism underlying the anion-acceleration was
investigated in an ab initio study, which concluded that base-
mediated proton abstraction anti to the concurrently depart-
ing endo-bromine was the initiating step in an overall
concerted reaction mechanism leading directly to the meta-
halophenol.
Introduction
Phenols are frequent motifs in pharmaceutical agents as well as
in agrochemicals,[1] thus, their halo-functionalized analogues are
highly valuable building blocks in the synthesis thereof. For
electron-rich aromatic rings, such as phenols, the electronic
distribution directs electrophiles to the ortho/para positions
when undergoing electrophilic aromatic substitution reactions.
However, only few methods have been reported for direct
synthesis of meta-halophenols from their aromatic precursors,
all of which require harsh conditions or expensive transition-
metal catalysts.[2]
As an alternative strategy for the synthesis of phenols,
electrocyclic ring opening of bicyclo[3.1.0]hex-3-en-2-ones
under thermal conditions to give the corresponding phenols 1
has been studied (Scheme 1a).[3] However, the difficult access to
these bicyclic systems limits the practical use of this overall
strategy. Recently, Magauer and co-workers reported the syn-
thesis of a series of meta-(methoxycarbonyl)phenols by the 1,4-
addition of methyl dichloroacetate to cyclopent-2-en-1-ones to
isolate the corresponding 6-halo-6-methoxycarbonyl-bicyclo
[3.1.0]hexan-2-ones 2 in 2–65% yield (Scheme 1a). Subsequent
Scheme 1. a) High-temperature thermal electrocyclic ring opening of bicyclo
[3.1.0]hex-3-en-2-ones 1 to the corresponding phenols. b) Synthesis of meta-
halo-phenols 6 from the corresponding cyclopentenones 3 by anion-
accelerated electrocyclic ring opening.
[a] Dr. M. Staudt, Prof. L. Bunch
Department of Drug Design and Pharmacology
Faculty of Health and Medical Sciences
University of Copenhagen
°
heating to high-temperature (190 C) facilitated electrocyclic
ring opening to the corresponding phenols 3.[4]
2100 Copenhagen Ø (Denmark)
E-mail: lebu@sund.ku.dk
Results and Discussion
[b] Prof. T. Sølling
Center for Integrative Petroleum Research
College of Petroleum & Geosciences
King Fahd University of Petroleum & Minerals
Dhahran 31261 (Saudi Arabia)
We envisaged that synthetically versatile meta-halophenols 6
could be derived from 6,6-dihalobicyclo[3.1.0]hexan-2-ones 5.
However, the synthesis of dibromocyclopropane 5 has only
been reported as an intermediate in the total synthesis of (�)-γ-
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202100939
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lycorane (Scheme 2a).[5] Thus, an efficient method to access
dibromocyclopropanes 5 was required, which ideally would
also allow a direct in situ transformation to their corresponding
phenols.
respectively) were at equilibrium. Most satisfying, further
warming of the reaction mixture to room temperature led to
partial formation of the desired dibromocyclopropane product
5a (3:2 ratio of 4a:5a determined by 1H NMR) after 30 minutes
(Scheme 2b). However, continued stirring at room temperature
did not lead to the identification of phenol 6a (Scheme 3).
Anion-assisted rate acceleration are an often-observed
effect in many sigmatropic reactions like the anionic oxy-Cope
or the Ireland-Claisen rearrangements.[8] On the other hand,
reports on utilizing this effect in electrocyclic reactions are less
common.[9] We hypothesized that running the reaction with
three equivalents of LiHMDS could promote the departure of
the bromide in an electron-push mechanistic way. As the
developing cation would be energetically counterbalanced by
the already present anion, this would open up an anion-
accelerated pathway towards neutral ketone 9a and eventually
phenoxide 10 after proton abstraction (Scheme 3, pathway B).
This strategy also alleviates the stability problem with cation 8
being in conjugation with the electron-withdrawing carbonyl
group. As an alternative mechanism (pathway C), anionic
fragmentation of 5a could lead to enolate 9b, which upon
elimination of bromide also gives rise to neutral ketone 9a.
To our delight, performing the reaction with 3.1 equivalents
The findings by Krebs et al. that bromoform undergoes 1,2-
°
and 1,4-addition to 2-cyclopentenone 3a at À 95 C in a 2:3
ratio (Scheme 2b),[7] served as the starting point for us to further
explore if 1,4-adduct 4a could undergo in situ ring-closure to
form the corresponding 6,6-dibromobicyclo[3.1.0]hexan-2-one
5a upon temperature increase (Scheme 2). In fact, warming the
°
reaction to À 20 C resulted in full conversion to the thermody-
namically more stable 1,4-adduct 4a in 92% yield (Scheme 2b),
demonstrating that the 1,2- and 1,4-adducts (7 and 4a,
°
of LiHMDS at À 78 C to room temperature led to clean
conversion to give the corresponding meta-bromophenol 6a, in
68% isolated yield. With this breakthrough secured, we turned
to investigate and determine the optimal reaction conditions
for this new transformation. Due to observed issues with the
volatility of meta-bromophenol 6a, we decided to use the
tetramethylated analog 6d for the further detailed investigation
of reaction conditions. First, we decided to explore the
influence of the metal counter ion by employing NaHMDS and
KHMDS (Table 1, entries 2 and 3). In both cases several side
products were formed, along with a clear decline in product
formation (57 and 11%, respectively). It remains unclear how
the Lewis acid character of the metal counter ion plays such a
decisive role in this transformation. To our surprise, the use of
the stronger base LDA (Table 1, entry 4) led to several side
products with only a trace amount of product 6d (<1%). This
demonstrates that also the pKa value of the base is important
for the reaction to proceed.
Scheme 2. a) Synthesis of 6,6-dibromobicyclo[3.1.0]hexan-2-one in a three-
step carbene/hydrolysis/oxidation procedure. 1) CHBr3, NaOH, nBu4NCl; 2)
KOH, MeOH; 3) pyridinium chlorochromate.[6] b) Bromoform undergoes 1,2-
°
and 1,4-addition to cyclopent-2-eneone 3a at À 95 C in a 2:3 ratio. 4) CHBr3
[7]
°
°
(1.0 equiv.), BuLi (1.0 equiv), À 95 C or LiHMDS (1.0 equiv.), À 20 C and RT,
THF.
Table 1. Screening of bases.
Base
Equivalents
Isolated yield [%]
qNMR yield [%][a]
1
2
3
4
LiHMDS
NaHMDS
KHMDS
LDA
3.1
3.1
3.1
3.1
89
–
–
92
57
11
traces
–
Scheme 3. Ring opening of intermediate 5a to afford meta-bromophenol 6a
is only observed upon addition of a total of 3.1 equiv. of LiHMDS to 3a at
[a] Yield determined by quantitative 1H NMR of the crude product using
1,3,5-trimethoxybenzene as internal standard.
°
À 78 C to RT (pathway B).
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Next, we ran a reaction with a 1:1 mixture of 3-methyl
cyclopentenone 3b and cyclopentene 11 to address if
dibromocarbene formation (through the reaction of bromoform
with strong base) is involved in the reaction mechanism
(Scheme 4a). From this experiment, only the corresponding
meta-bromophenol 6b was observed, which rules out dibromo-
carbene formation being involved in the reaction mechanism.
To further address endo-cyclic enolate formation playing a
key part in the mechanism, we employed non-α’-enolizable
substrate 5,5-dimethylcyclopent-2-en-1-one 13 and non-α-eno-
lizable substrate methyl 1-cyclopentene-1-carboxylate 15 (Sche-
me 4b). The reactions were carried out with only 2.1 equivalents
of base as aromatization cannot take place in these two
transformations. For dimethyl analog 13, the outcome was a
complex reaction mixture with no indication of the desired
product 15, presumably due to the instability of the gem-
dibromocyclopropane intermediate 14 as previously seen for
the unsubstituted analog. The exo-cyclic ester 16 led to
formation of dibromocyclopropane 17 in 52% yield as the only
product, underlining the necessity for endo-cyclic carbonyl
functionality and its interplay on generation of an anionic state
prior to electrocyclic ring opening at low to room temperature.
With the optimized reaction conditions in place, we set out
to investigate the scope and limitations of this transformation
(Table 2). Firstly, iodoform was substituted for bromoform and
gave access to attractive meta-iodo phenols 6c, e in average to
good yields (47 and 73%). Unfortunately, using chloroform and
dibromofluoromethane to introduce meta-chloro and meta-
fluoro substituents was not successful. The former led to sole
formation of the 1,2-adduct, whereas the latter resulted in
formation of a complex reaction mixture. Next, the option of
quenching the phenoxide product in situ was intriguing to us.
Addition of 1.5 equiv. of TsCl to the reaction mixture at room
temperature, gave the corresponding tosylate 6f in excellent
yield (78%), opening up for efficient onward functionalization
of the 1-position. Finally, we turned to investigate the
compatibility with substituents in the 2, 3, 4 and 5 positions of
the cyclopentenone core.
At this stage, we had already demonstrated that methyl
groups in all four positions of cyclopentenone was well-
tolerated (6d, 89%) and a methyl group in the 4-position (6b,
75%). Alkyl substituents in the 2-position were extended to the
2-n-pentyl analog 6g in high yield (83%) and also the cis-2-
(pent-2’-enyl), 4-methyl analog 6h derived from natural product
cis-jasmone was obtained in excellent yield (92%) with full
retention of regio- and stereochemistry of the alkene. A 2-
hydroxy group was also compatible with the reaction con-
ditions, allowing the synthesis of 1,2-catechols 6i in 40% yield,
while the catechol-2-ethers 6j, k were obtained in 55 and 68%,
respectively, showing the strength of this transformation for
selective synthesis of mono-O-alkylated catechols.
The two heterobicyclic systems 6l and 6m were obtained in
modest to average yield, and serve to demonstrates the
expedite synthesis of complex scaffolds using starting materials
readily accessible by Pauson-Khand reaction. The 2,3-dibromo-
and 2-iodo-3-bromo phenols 6n and 6o were obtained in 83
and 45%, respectively. Free benzylic alcohol 6p was obtained
in 57% and finally we showed that biaryls 2-phenyl 6q and 4-
phenyl 6r could be obtained in 29 and 65% yields, respectively.
The strength of the methodology was further underlined by
conducting a gram-scale synthesis of fully substituted meta-
bromophenol 6d. We were pleased to see that we could isolate
6d in 5.80 g corresponding to 88% yield (Scheme 5).
The mechanism for this base-triggered transformation was
investigated in a detailed ab initio study. A rationale for the
distinctively different reactivity in basic and neutral medium,
can be rationalized based on calculated geometries and relative
energies of reactants, products and the transition states that are
involved. At the computational level, the problem was reduced
to first calculating the geometries of the parental system
dibromocyclopropane 5a and its 5,5-dimethyl analog 14 (Fig-
ure 1).
For the reaction to proceed under neutral conditions the
initial step is a heterolytic cleavage of either of the two carbon-
bromine bonds to form a cyclopropane cation which then
undergoes 2π-disrotatory electrocyclic ring opening to give 15.
However, all attempts to locate and calculate the geometry of
the resulting carbocation after heterolytic cleavage of the either
of the carbon-bromine, were not successful as the structure
Scheme 4. Investigation of the mechanism. 1) CHBr3 (1.0 equiv), LiHMDS
°
(3.1 equiv.), THF, 0 C to RT, 30 min; 2) CHBr3 (1.0 equiv), LiHMDS (2.1 equiv.),
1
°
THF, À 78 C to RT, 18 h. [a] Ratio determined by H NMR of the crude
product.
Scheme 5. Gram-scale synthesis of tetramethylated meta-bromophenol 6d.
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Table 2. Scope and limitations of employed haloform, in situ quenching
Table 2. continued
with TsCl and substituents on the cyclopentenone.
13
14
1
2
15
16
3
4
°
°
[a] 4.1 equiv. LiHMDS were used. [b] 1.0 equiv. LiHMDS, À 78 C to 0 C, 1 h,
°
2.1 equiv. LiHMDS, 0 C to RT.
5
7
6
8
Figure 1. Calculated geometries (the G4MP2 composite method) of parental
system 5a and 5,5-dimethylated analog 14 with selected bond lengths in
ångström.
9
10
11
12
Figure 2. The calculated geometry (the G4MP2 composite method) from
heterolytic cleavage of either of the two carbon-bromine bonds in 5a to
give directly ring-opened carbocation 18. Selected bond lengths are given in
ångström.
immediately collapsed to the ring-opened product 15 (Fig-
ure 2).
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Figure 3. Calculated geometries (the G4MP2 composite method) with selected bond lengths in ångström.
This result shows that as soon at the energy barrier for
carbocation formation has been overcome the thermally
allowed 2π-electrocyclic ring opening proceeds without addi-
tional energy demand. There is no reason to believe that
heterolytic cleavage of the carbon-bromine bond is particularly
fast. It takes place from a secondary carbon with an electro-
negative substituent and the sp3 to sp2 rehybridization will
induce additional strain in the three membered ring. Thus, the
requirement for high temperatures to proceed.
We next turned to investigate the reaction under basic
conditions with the aim to explain the differences in reactivity
between the parental system 5a and its 5,5-dimethylated
analog 14. For this part, we selected the hydroxide anion as the
prototypical base. The calculated geometries of the reactants,
transition states and products are shown in Figure 3.
The study shows that for 5a, the hydroxide base attacks the
hydrogen anti to the cyclopropane unit (ring carbon number
four) and in a concerted fashion expels the endo-bromine atom
Figure 4. Schematic energy profile showing the competition between the
(5a-A to 5a-C, Figure 3). This is in agreement with the Wood-
ward-Hoffmann rules for thermally allowed 2π-disrotatory
electrocyclic ring openings, as expulsion of the exo-bromine
would lead to a highly strained intermediate (Figure S1 in the
Supporting Information).[10] A syn attack by the base leads to a
slightly more complex reaction pathway with an energy barrier
about five times higher (not shown). The study did not identify
enolate 9b (Scheme 3, pathway C) as a potential energy
minimum in the sense that any attempt at optimization led to
ring opening. This finding further strengthens a concerted
base-triggered 2π-electrocyclic ring opening as the reaction
mechanism (Scheme 3, pathway B).
The explanation for the stereoselective proton abstraction is
found in the combination of stereo-electronic- and steric
effects. Finally, it is noteworthy that the study does not suggest
enolate formation (abstraction of a proton from the 5-carbon)
to be the initial step and driver for subsequent cleavage of the
carbon-bromine bond. For dimethylated analogs 14 the reac-
base-assisted concerted ring opening of the parental system 5a and
dimethylated analog 14. The free energies at 298.18 K are calculated at the
G4MP2 level of theory.
Scheme 6. Chemical structure of the natural product and neurotoxin
caramboxin and its corresponding inactive lactam.
tion pathway follows the same anti pathway as identified for 5a
(14-A to 14-C, Figure 3). The energy barriers and reaction
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Scheme 7. Retrosynthetic analysis of natural product caramboxin.
energies for both 5a and 14 are summarized in a schematic
energy profile (Figure 4). It shows that the reaction barrier is in
the order of 3 kcal/mol higher for the dimethylated analog 14
compared to 5a. This, however, cannot alone explain the fact
that no product formation is observed for 14, and we speculate
if steric hindrance may play a key role.
In summary, the ab initio study shows that base-mediated
abstraction of the proton anti to the cyclopropane ring is the
initiation stage. This promotes a concerted reaction pathway in
which the concave carbon-bromine bond is cleaved in a
heterolytic fashion, and the electrocyclic ring-opening of dihalo-
cyclopropanes 5 proceeds to their corresponding meta-halo-
phenols 6. The possibility of enolate formation seems to be of
little importance to the mechanism.
The natural product caramboxin (Scheme 6) is a constituent
of starfruit and shown to be a neurotoxin acting on the
glutamatergic neurotransmitter system. Upon its isolation it has
been reported to readily cyclize in water even under neutral
conditions to form its inactive corresponding tetrahydroisoqui-
nolinic derivative (Scheme 6).[11] The absolute stereochemistry
of caramboxin remains unknown, however, due to its structural
similarity with phenylalanine, it is assumed to be S, based on
the fact that caramboxin has identical optical rotation phase
with (S)-phenylalanine (negative).[11]
Considering the fact that caramboxin comprises a tri-
substituted phenol, we decided to conduct a retrosynthetic
analysis to explore the application of the methodology reported
here (Scheme 7). Our strategy builds on the 4-methoxy group
to originate from methylation of a phenol formed at a late
stage in our methodology, with the starting material being a
structural motif readily recognized as the product of a Pauson-
Khand reaction.
Scheme 8. Total synthesis of the lactam analog of caramboxin. 1) SOCl2,
MeOH, RT, quant.; 2) LiOH·H2O, propargyl bromide, 3 Å molecular sieve, DMF,
°
RT, 61%; 3) Boc2O, NEt3, CH2Cl2, RT, 86%; 4) Co2(CO)8, DMSO, THF, 50 C, 80%;
°
5) 3.1 equiv. LiHMDS (1.0 M in THF), 1.0 equiv. CHBr3, THF, À 78 C to RT, 30%;
°
6) MeI, K2CO3, acetone, 60 C, 64%; 7) RuCl3, NaIO4, EtOAc, H2O, RT, 55%; 8)
°
Cu2O, nBu4NBr, pyridine-2-aldoxime, CsOH·H2O, H2O, 100 C.
chemoselectivity.[12] The last step comprising the hydroxylation
of the arylbromide was expected to deliver globally depro-
tected caramboxin due to the elevated temperatures being
employed, leading to hydrolysis of the ester, amide and
carbamate. Unfortunately, even careful neutralization was found
to promote ring closure to the inactive lactam analogue 27.
Although further attempts to isolate uncyclized caramboxin
failed, this synthesis highlights the applicability of the herein
reported methodology towards diversely substituted phenol
derivatives.
The synthesis of caramboxin (Scheme 8) commenced with
esterification of (S)-2-allyl glycine to give the corresponding
ester in quantitative yield. N-Alkylation with propargyl bromide Conclusion
in 61% yield, followed by Boc-protection gave corresponding
alkyne 23 in 57% yield. The following Pauson-Khand reaction to
give 24 proceeded in excellent yield of 80%. Applying the
standard procedure, the corresponding phenol 25 was obtained
in 30% yield, being acceptable considering the high functional
group density of the product. After methylation of the
phenoxide under basic conditions with methyl iodide, the
resulting product 26 was oxidized to the lactam using a variant
of ruthenium catalysis previously reported for transformation of
In conclusion, we have reported a methodology for the
expedited synthesis of substituted meta-halophenols 6 from
their corresponding cyclopentenones 3 in good to high yields
(18 examples, 29–92% yield, average 65%, and on an up to
5.8 g scale). Several of the phenols reported herein are new
chemical entities and difficult to synthesize by means of
conventional strategies. Furthermore, the methodology was
applied to the synthesis of the lactam form of the natural
a
structurally
related
compound
with
excellent
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product caramboxin, which contains a densely functionalized
phenol.
The base-triggered ring-opening reaction of 6,6-dibromobi-
cyclo[3.1.0]hexan-2-ones 5 was investigated in an ab initio
study that suggested that proton abstraction anti to the
cyclopropane ring proceeds in a concerted fashion with
heterolytic cleavage of the endo carbon-bromine bond. To the
best of our knowledge, the methodology reported herein
represents the first example of an anion-accelerated 2π-electro-
cyclic ring opening of a dihalocyclopropane.
Acknowledgements
We would like to thank the Danish Research Council (DFF/FSS)
and the University of Copenhagen for financial support.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: 2pi-electrocyclic ring opening · ab initio study ·
anion-assisted · meta-halophenols · natural product synthesis
Manuscript received: March 15, 2021
Accepted manuscript online: May 27, 2021
Version of record online: ■■■, ■■■■
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FULL PAPER
Dr. M. Staudt, Prof. T. Sølling, Prof. L.
Bunch*
1 – 8
Synthesis of Polysubstituted Meta-
Halophenols by Anion-Accelerated
2π-Electrocyclic Ring Opening
Opening the way to densely func-
tionalized natural products: We
report the first anion-accelerated,
thermally allowed, 2π-electrocyclic
ring opening as a novel route to sub-
stituted phenols 6a–r and prove its
efficacy in the total synthesis of the
densely functionalized phenolic
natural product caramboxin (isolated
as the lactam dehydrate).