Ring Opening of Bicyclo[3.1.0]hexan-2-ones: A Versatile Synthetic Platform for the Construction of Substituted Benzoates

Article abstract of DOI:10.1002/anie.201506232

Described is the development of a highly efficient 2πdisrotatory ring-opening aromatization sequence using bicyclo[3.1.0]hexan-2-ones. This unprecedented transformation efficiently proceeds under thermal conditions and allows facile construction of uniquely substituted and polyfunctionalized benzoates. In the presence of either amines or alcohols formation of substituted anilines or ethers, respectively, is achieved. Additionally, the utility of this method was demonstrated in a short synthesis of sekikaic acid methyl ester. Cracked open: A highly efficient thermal 2πdisrotatory ring-opening aromatization sequence of bicyclo[3.1.0]hexan-2-ones is described. The transformation proceeds in sulfolane to give uniquely substituted benzoates. In the presence of either amines or alcohols, formation of substituted anilines or ethers, respectively, is achieved.

Full text of DOI:10.1002/anie.201506232

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201506232
German Edition: DOI: 10.1002/ange.201506232
Arenes
Ring Opening of Bicyclo[3.1.0]hexan-2-ones: AVersatile Synthetic
Platform for the Construction of Substituted Benzoates
Johannes Feierfeil, Adriana Grossmann, and Thomas Magauer*
Abstract: Described is the development of a highly efficient
2p disrotatory ring-opening aromatization sequence using
bicyclo[3.1.0]hexan-2-ones. This unprecedented transforma-
tion efficiently proceeds under thermal conditions and allows
facile construction of uniquely substituted and polyfunc-
tionalized benzoates. In the presence of either amines or
alcohols formation of substituted anilines or ethers, respec-
tively, is achieved. Additionally, the utility of this method was
demonstrated in a short synthesis of sekikaic acid methyl ester.
S
ubstituted benzoic acid derivatives are ubiquitous in nature
and they are highly valuable building blocks for organic
synthesis.[1] Within this substance class, the 3-hydroxyben-
zoate structural motif constitutes a prominent subunit that
can be found in several biologically active molecules
(Figure 1).[2]
Figure 2. a) Traditional methods for the synthesis of polyfunctionalized
benzoates. b) Thermal ring-opening aromatization of bicyclo-
[3.1.0]hexan-2-ones.
(method C) usually require symmetrical substrates to allow
formation of the desired 1,3-orientation.[4]
As part of our recent efforts to develop new chemical
methods for the synthesis of uniquely substituted phenols and
naphthols,[5] we discovered that bicyclo[3.1.0]hexan-2-ones
undergo an efficient thermal 2p disrotatory ring-opening
aromatization sequence to afford a broad array of highly
substituted benzoates (Figure 2b). By virtue of its substrate
structure, this transformation enables simple control of
selectivity and reactivity, and expands the repertoire of
retrosynthetic bond disconnections for natural product syn-
thesis. Herein, we report our preliminary results of this
unprecedented transformation.[6–8]
Figure 1. The 3-hydroxybenzoate structural motif as a component of
biologically active natural products. LHMDS=lithium hexamethyldisi-
lazane.
Conventional syntheses of polysubstituted 3-hydroxyben-
zoates from either aromatic (linear assembly) or acyclic
(convergent assembly) precursors are complicated by diffi-
culties arising from low reactivity and poor selectivity (Fig-
ure 2a, methods A–C). The electrophilic aromatic substitu-
tion of electron-poor benzoates (method A) requires harsh
reaction conditions and shows limited functional-group
tolerance.[3] For method B, the directing electronic effects of
the ester and electron-donating substituents (Y= OR, NRR’)
are mismatched and result in poor regioselectivity. Strategies
based on the [4+2] cycloaddition of dienes with alkynoates
We began our investigations with bicyclo[3.1.0]hexan-2-
ones 1a/b (d.r. = 4:1), which are readily available from the
reaction of 3-methyl-2-cyclopenten-1-one with the lithium
enolate of inexpensive methyl dichloroacetate (Scheme 1).[9]
[*] J. Feierfeil, A. Grossmann, Dr. T. Magauer
Department of Chemistry and Pharmacy
Ludwig-Maximilians-University Munich
Butenandtstrasse 5–13, 81377 Munich
E-mail: thomas.magauer@lmu.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506232.
Scheme 1. 2p Disrotatory ring-opening aromatization of a 4:1 diaste-
reomeric mixture of 1a and 1b (sulfolane, 1908C) to afford 4.
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Conceptually, we envisioned the mixture of the cis-trans and
cis-cis diastereomers 1a and 1b, respectively, to undergo
a thermally allowed cyclopropyl allyl cation type ring opening
(2p disrotatory) to afford 2.[10] For the initial ring-opening
the final aromatization, attempts to promote the ring-opening
reaction at 1408C by addition of either DBU (entry 9) or
DIPEA (entry 10) led to partial decomposition of 5 and
diminished yields of 6a.
À
step, the C C bond cleavage with concomitant loss of
chloride, we expected the reaction rate of 1a and 1b to be
The methodology outlined above was then applied to
a wide range of bicyclo[3.1.0]hexan-2-ones which were
synthesized from readily available 2-cyclopenten-1-ones.
Table 2 depicts a number of examples of polysubstituted
governed by the relative orientation of the substituents to the
leaving group.[11] Monitoring the reaction by H NMR spec-
1
troscopy proved that, after heating a solution of 1a and 1b in
dimethyl [D6]sulfoxide at 1108C for 40 minutes, the diaste-
reomeric ratio was changed from 4:1 to 1:3. While complete
consumption of the major diastereomer 1a was observed after
80 minutes, 1b was reluctant to undergo ring opening at this
temperature. However, exchanging dimethyl sulfoxide for
sulfolane and increasing the temperature to 1908C led to
a drastic increase of the overall reaction rate and 4 was
formed in 73% yield.
Table 2: Synthesis of substituted methyl 3-hydroxybenzoates from
bicyclo[3.1.0]hexan-2-ones.[a]
Based on these preliminary results, we investigated the
conversion of diastereomerically pure 5[9] into 6 under varying
reaction conditions (Table 1). An examination of various
Table 1: Thermal 2p disrotatory ring opening of 5 under varying reaction
conditions.[a]
Entry
Solvent
Additive
T [8C]
t [h]
Yield [%]
6a
6b
1
2
3
4
5
6
7
8
9
10
sulfolane
sulfolane
NMP
none
none
none
none
190
140
190
180
140
190
80
70
140
140
0.25
8
1
16
3
17
16
3
99
41
99
81
60
0
0
0
17
56
0
0
0
0
0
86
0
0
0
0
ODCB
[b]
sulfolane
sulfolane
MeCN
TFE
sulfolane
sulfolane
AgNO3
LiCl[c]
p-TsOH[d]
none
DBU[e]
DIPEA[f]
8
8
[a] Yield of the isolated product. [b] 1.0 equiv AgNO3. [c] 2.1 equiv LiCl.
[d] 20 mol% p-TsOH. [e] 1.0 equiv DBU. [f] 1.0 equiv DIPEA. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, DIPEA=N,N-diisopropylethylamine,
NMP=N-methyl-2-pyrrolidone, ODCB=1,2-dichlorobenzene,
TFE=2,2,2-trifluoroethanol, Ts =4-toluenesulfonyl.
[a] Yield is that of the isolated product.
methyl 3-hydroxybenzoates. Reaction times were generally
short (< 1 h) and an inert atmosphere was not required. When
aliphatic groups were present, the products were formed in
excellent yields of up to 99%. Heteroaromatic substituents
such as 2-thienyl or 2-furyl, and substrates containing fluoro
or chloro substituents were also well tolerated under the
reaction conditions.
With these results in hand, we tried to extend this
methodology to other substrates. First, the tricycle 25,
obtained from the cyclopropanation of cyclopentadienone
dimer,[12] was investigated (Scheme 2a). This substrate under-
went the ring opening with concomitant CO extrusion to give
methyl 4-hydroxy-2-naphthoate (26). Application of the
standard reaction conditions to the C2-elongated a,b-unsatu-
rated ester 27 was also successful and provided the diester 28
in 78% yield (Scheme 2b).
solvents established that the reaction is efficiently promoted
by polar, high-boiling solvents and proceeds fastest in
sulfolane at 1908C (entries 1–4). The effect of Lewis acids
on the reaction yield at different temperatures was inves-
tigated next (entries 5–7). Thermolysis of 5 in the presence of
AgNO3 (1408C) was less efficient and afforded 6a in 60%
yield (entry 5). The use of excess lithium chloride at elevated
temperatures (entry 6) enabled the direct formation of the
acid 6b (86% yield). Low-boiling polar solvents (entries 7–8)
were ineffective regardless of the additives and the starting
material was recovered unchanged from these reactions.
While enol formation was considered to play a crucial role for
the stabilization of the initial carbocation intermediate and
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Scheme 4. Thermal ring opening with simultaneous [1,2] shift to give
highly substituted methyl 3-hydroxybenzoates.
Scheme 2. Extension of the ring-opening reaction. AIBN=2, 2’-azoiso-
butyronitrile.
carbon center to undergo a consecutive ring opening/[1,2]
shift (Scheme 4). To determine if this [1,2] shift can be
triggered under the standard reaction conditions, we prepared
the model substrates 32, 34, and 36. To our delight,
thermolysis of 32 and 34 led to the formation of the
regioisomeric products 33a/b and 35a/b, respectively, in
good yield, and they were readily separated by column
chromatography on silica gel. For 32, exclusive migration of
the benzyl group in preference to the methyl group was
observed. Installation of an additional substituent as shown
for 36 enabled access to the hexasubstituted benzoate 37 in
53% yield.
Finally, we set out to apply this methodology to the
synthesis of the highly potent GACKIX inhibitor sekikaic
acid methyl ester (43; Scheme 5).[2d] We began our synthesis
with 3-ethoxy-2-cyclopentenone (38) which was converted
into 39 in two steps. Upon exposure of the lithium enolate of
39 to dimethyldioxirane and treatment of the resulting
Scheme 3. Synthesis of a) aryl ethers, b) amines, and c) polycyclic ring
structures in the presence of O or N nucleophiles.
To further explore the synthetic utility of our method-
ology, we investigated the in situ condensation of the carbonyl
group with simple
O and N nucleophiles (Scheme 3).
Remarkably, in the presence of an amine (2 equiv) the ring-
opening reaction of 5 to the aniline derivatives 29a–d
proceeded efficiently at temperatures as low as 1008C. This
observation supports our mechanistic hypothesis that enoli-
zation (enamine formation) plays a key role for the stabiliza-
tion of the intermediate carbocation formed during the ring
opening.
Substitution of sulfolane with high-boiling alcohols such
as benzyl alcohol, phenol, cyclopentanol, or 1-pentanol
allowed the straightforward synthesis of the protected phe-
nols 29e–h in good yield (Scheme 3b). Lower-boiling alcohols
such as hexafluoro-2-propanol, 2,2,2-trifluoroethanol, or 2-
methyl-1-butanol resulted in no product formation.[13] To
demonstrate that this reaction also enables access to polycyc-
lic ring structures, the nucleophile was tethered to the
bicyclo[3.1.0]hexan-2-one framework as shown in Scheme 3c.
According to the previously presented mechanistic
hypothesis, we envisioned substrates containing a quaternary
Scheme 5. Synthesis and X-ray structure[16] of sekikaic acid methyl
ester (43). Reagents and conditions: a) nPrMgCl, THF, then 6n HCl,
74%; b) LHMDS, Cl2CHCO2Me, THF, À788C to 238C, 23%;
c) LHMDS, DMDO, THF, À788C, 60%; d) MeI, Ag2O, MgSO4, 94%;
e) sulfolane, 1908C, 20 min, 71%; f) MeI, K2CO3, DMF, 558C, 94%;
g) phthaloyl peroxide, TFE, then MeOH, aq. NaHCO3, 94%; h) BCl3,
CH2Cl2, 08C, 59%; i) EDCI, DMAP, THF, 42, 80%. DMAP=4-(di-
methylamino)pyridine, DMDO=dimethyldioxirane, DMF=N,N-dime-
thylformamide, EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
THF=tetrahydrofuran.
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Modern Nucleophilic Aromatic Substitution, Wiley-VCH, Wein-
heim, 2013.
a-hydroxy ketone with methyl iodide, clean formation of the
a-methoxy product was observed. Ring opening of 40
proceeded smoothly and afforded 24 in 71% yield. After
methylation of the free phenol, the phthaloylperoxide-
mediated oxidation recently developed by Siegel and co-
workers[14] proceeded in high yield with excellent regioselec-
tivity. Selective demethylation gave 41, which was then
coupled with acid 42[15] to afford 43 in 80% yield. The
structure of 43 was confirmed by single-crystal X-ray dif-
fraction and the spectroscopic data were in full agreement
with those reported previously.[2d]
In summary, we have developed a highly versatile
methodology which converts bicyclo[3.1.0]hexan-2-ones into
a broad array of valuable benzoates. In the presence of amines
or alcohols, the ring-opening reaction proceeds by the
intermediacy of an enamine or enol ether and provides
straightforward access to aniline or ether derivatives. A broad
application of this method for the synthesis of biologically
active molecules is currently underway in our laboratories.
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Acknowledgements
We gratefully acknowledge financial support from the FCI
(Sachkostenzuschuss to T.M.) and the DFG (SFB 749 and
Emmy-Noether Program to T.M.). We thank Dr. David
Barber (LMU Munich) and Dr. Kevin Mellem (Revolution
Medicines) for helpful discussions during the preparation of
this manuscript, and Dr. Peter Mayer (LMU Munich) for X-
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Keywords: arenes · aromaticity · fused-ring systems ·
synthetic methods · X-ray diffraction
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11835–11838
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Received: July 7, 2015
Published online: August 7, 2015
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