Radical cyclization/ipso-1,4-aryl migration cascade: Asymmetric synthesis of 3,3-difluoro-2-propanoylbicyclo[3.3.0]octanes

Article abstract of DOI:10.1002/anie.201310747

A novel method for the asymmetric synthesis of 3,3-difluoro-2- propanoylbicyclo-[3.3.0]octanes involves an unprecedented intramolecular radical cyclization/ipso-1,4-aryl migration cascade. Copyright

Full text of DOI:10.1002/anie.201310747

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Angewandte
Communications
DOI: 10.1002/anie.201310747
Synthetic Methods
Radical Cyclization/ipso-1,4-Aryl Migration Cascade: Asymmetric
Synthesis of 3,3-Difluoro-2-propanoylbicyclo[3.3.0]octanes**
Watcharaporn Thaharn, Darunee Soorukram, Chutima Kuhakarn, Patoomratana Tuchinda,
Vichai Reutrakul, and Manat Pohmakotr*
Abstract: A novel method for the asymmetric synthesis of 3,3-
difluoro-2-propanoylbicyclo-[3.3.0]octanes involves an unpre-
cedented intramolecular radical cyclization/ipso-1,4-aryl
migration cascade.
I
n recent years radical chemistry has played a great role in
the development of modern organic synthesis. The synthetic
methodologies based on radical species have been extensively
ꢀ
exploited, including intermolecular C C bond formations,
cyclizations, annulations, and cascade reactions, thus leading
to construction of various types of compounds.[1] Among
these synthetic transformations, radical 1,2-, 1,4-, and 1,5-aryl
migrations by radical ipso substitution at the aromatic ring
have been reported in the literature.[2] We and others have
recently reported the syntheses of gem-difluoromethylenated
carbocyclic and dihydroxy-1-azabicyclic compounds by
employing a fluoride-catalyzed nucleophilic addition of
PhSCF2TMS and subsequent radical cyclization.[3] Organo-
fluorine compounds have found wide applications in phar-
maceuticals, agrochemicals, and materials science.[4] There-
fore, numerous works aimed at developing general methods
for the introduction of the gem-difluoromethylene group into
organic compounds have rapidly increased.[5] In an effort to
develop methodologies for asymmetric preparation of fluo-
rine-containing molecules (5; for structure see Scheme 1), we
report herein an unprecedented asymmetric synthesis of the
3-difluoro-2-propanonylbicyclo[3.3.0]octanes 6 by a radical
cyclization/ipso-substitution at the aromatic ring of the cyclo-
pentene derivatives 4.
Scheme 1. Preparation of the compounds 4 by fluoride-catalyzed
nucleophilic addition of PhSCF2TMS (1) to the chiral ketones 3 and
their radical cyclization/ipso-1,4-aryl migration cascade to give the
compounds 6.
Table 1: Synthesis of 4 by fluoride-catalyzed nucleophilic addition of
PhSCF2TMS (1) to the chiral ketones 3.[a]
Entry
Ar
Yield [%][b]
d.r.[c]
1
2
3
4
5
6
7
8
9
3a (Ph)
4a, 96
4b, 81
4c, 82
4d, 85
4e, 82
4 f, 99
4g, 86
4h, 85
4i, 92
4j, 97
50:50
51:49
47:53
48:52
49:51
50:50
50:50
51:49
49:51
49:51
3b (4-MeC6H4)
3c (4-MeOC6H4)
3d (2-MeOC6H4)
3e (4-Me2NC6H4)
3 f (4-ClC6H4)
3g (2-Naphthyl)
3h (3-FC6H4)
3i (2,4-(MeO)2C6H3)
3j (2-Me,4-FC6H3)
As shown in Scheme 1, the required precursors 4 were
readily prepared by treatment of the chiral ketones 3,[6]
derived from the chiral bicyclic lactone (3aR,6aS)-2[7] (see
the Supporting Information), with PhSCF2TMS (1) and
tetrabutylammonium fluoride (TBAF) as a catalyst in tetra-
hydrofuran (THF; 08C!RT) for 24 hours. In all cases, the
10
[a] For the preparation of 3, see the Supporting Information. [b] Yield of
the isolated product. [c] Determined by 19F NMR spectroscopy.
[*] W. Thaharn, Dr. D. Soorukram, Dr. C. Kuhakarn, Dr. P. Tuchinda,
Prof. Dr. V. Reutrakul, Prof. Dr. M. Pohmakotr
Center of Excellence for Innovation in Chemistry (PERCH-CIC) and
Department of Chemistry, Faculty of Science
Mahidol University, Rama VI Road, Bangkok 10400 (Thailand)
E-mail: manat.poh@mahidol.ac.th
compounds 4 were obtained as an inseparable mixture of
diastereomers. The results are summarized in Table 1.
Having the compounds 4 in hand, we initially focused our
study on a radical cyclization of 4a. Thus, 4a (1:1 mixture of
two diastereomers) was treated with Bu3SnH (1.75 equiv) in
the presence of a catalytic amount of AIBN in toluene
(0.02m) at reflux for 9 hours (Table 2, entry 1). Interestingly,
instead of obtaining the expected tricyclic compound 5a, the
reaction provided a mixture of the radical cyclization product
7a (23%) together with radical cyclization/ipso-1,4-aryl
[**] We are grateful to the Center of Excellence for Innovation in
Chemistry (PERCH-CIC), the Office of Higher Education Commis-
sion and Mahidol University under the National Research Univer-
sities Initiative, and the Thailand Research Fund (to M.P.,
BRG5380019) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310747.
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Table 2: Radical cyclization of 4a under various reaction conditions.
Entry Bu3SnH [eqiuv] Concentration [m] t [h]
Yield [%][a]
6a 7a 8a 9a
1
2
3
1.75
1.2
1.0
0.02
0.02
0.005
9
2
5
–
–
78
23 10 40
16 42
3
–
3
–
[a] Yield of isolated product.
migration products 8a and 9a, in 10 and 40% yield,
respectively (Table 2, entry 1). These results prompted us to
carefully study this reaction in detail. Reduction of the
amount of Bu3SnH employed and a shorter reaction time
resulted in the formation of 7a, 8a, and 9a in 16, 42, and 3%
yield, respectively (Table 2, entry 2). After some experimen-
tation, it was found that the reaction carried out employing
Bu3SnH (1 equiv) at low concentration (0.005m) in refluxing
toluene for 5 hours provided the difluoroketone 6a almost
exclusively in 78% yield together with a small amount of 7a
(3%, Table 2, entry 3). It is worth noting that this radical
cyclization/ipso-1,4-aryl migration cascade proceeded with
excellent stereoselectivity, thus providing 6a, 8a, and 9a, each
Scheme 2. A plausible mechanism for the formation of the compounds
6a, 7a, 8a, and 9a.
Bu3SnH (1.20 or 1.75 equiv), the intermediate 4aE can
further react with the tributylstannyl radical, thus leading to
defluorinated products 8a and 9a, after treatment with silica
gel in CH2Cl2. As shown in the proposed mechanism, it is
therefore crucial to perform the reaction at a low concen-
tration of 4a, and to use an equivalent of Bu3SnH to prevent
ꢀ
a successive a-reductive cleavage of the C F bond from the
firstly formed intermediate 4aE. To the best of our knowl-
edge, our finding reports the first asymmetric radical cycliza-
tion/ipso-1,4-aryl migration/elimination sequence, thus lead-
ing to an asymmetric synthesis of 3,3-difluoro-2-
propanoylbicyclo[3.3.0]octanes.
1
as a single isomer as revealed by H and 13C NMR spectra.
Their relative stereochemistries were also confirmed by the
NOE experiments (see the Supporting Information).
Based on the obtained experimental results, the formation
of phenyl-migrated products 6a, 8a, and 9a resulted from
a radical cyclization/ipso-1,4-phenyl migration cascade of 4a
(by 1,4-ipso-substitution at the phenyl ring). The mechanism
supporting this process is proposed as illustrated in Scheme 2.
First, a tributylstannyl radical chemoselectively adds to the
terminal carbon atom of the alkyne moiety of 4a,[8] thus
resulting in the vinylic radical 4aA, which undergoes exo-
mode cyclization[9] to produce the bicyclic radical 4aB.
Stereospecific ipso substitution of the radical 4aB, via the
spirohexadienyl radical 4aC, and subsequent fragmentation/
elimination of the phenylsulfanyl group leads to 4aD and
subsequently to 4aE. The gem-difluoromethylketobicyclic
compound 6a was obtained after passing the crude reaction
mixture through silica gel, eluting with CH2Cl2.[10] Alterna-
tively, 7a resulted from 4aB upon hydrogen atom abstraction
from Bu3SnH and subsequent reductive cleavage of the
phenylsulfanyl group initiated by a tributylstannyl radical. At
a high concentration of 4a in toluene (0.02m) and excess
Having the optimized reaction conditions (Table 2,
entry 3), we then applied the optimal conditions to a variety
of substrates to verify the generality of the method and the
results are summarized in Table 3. The compounds 4b–j, each
as a 1:1 mixture of two diastereomers, containing either
electron-deficient or electron-rich-substituted aryl groups
smoothly underwent the reaction, thus affording the corre-
sponding products 6b–j, each as a single isomer, in good
yields. It is worth noting that electronically different aryl
groups on the substrates 4b–j had negligible impact on the
rate of the reactions as monitored by thin-layer chromatog-
raphy and 1H NMR spectroscopy, thus leading to the products
6b–j in comparable yields. Finally, the stereochemistry of 6a–
j was established by the NOE and NOESY experiments (see
the Supporting Information).
Intrigued by this finding, we further investigated the
necessity of the difluoro(phenylsulfanyl)methyl motif
(“PhSCF2”) in facilitating the ipso substitution at the aro-
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Table 3: Preparation of chiral compounds 6b–j from 4b–j.[a]
10a[11] afforded the bicyclic alcohol 11a in 73% yield without
the detection of any ipso-1,4-aryl migration products
(Scheme 3). Similarly, 10b,[12] containing an electron-with-
drawing trifluoromethyl group, gave only 11b (63%) and
recovery of 10b (17%, Scheme 3). It should be noted here
that the tributylstannyl-radical-mediated intramolecular rad-
ical cyclization of 10a and 10b proceeded with high stereo-
selectivity, thus affording the corresponding all-cis-bicyclic
alcohols 11a and 11b, respectively. At this point, we assumed
that the phenylsulfanyl moiety (“PhS”) was important for
driving the ipso-1,4-substitution at the phenyl ring to give
4aC, which underwent rearomatization/aryl migration
through an elimination of the phenylsulfanyl group. As
a consequence, 10a and 10b, which do not contain the
phenylsulfanyl moiety, are unable to undergo ipso-1,4-phenyl
migration and subsequent elimination. On the basis of these
experiments, and to further probe the importance of the gem-
difluoro moiety, we next carried out the reactions of the
phenylsulfanylmethyl carbinol 10c[13] and phenylsulfonyl-
methyl carbinol 10d (Scheme 3).[14]
Under similar reaction conditions as those used for 10a
and 10b, radical cyclization of 10c yielded 9a in 42% yield as
a single stereoisomer along with 11c in 22% yield as a 72:28
diastereomeric mixture. Not to our surprise, the sulfonyl-
methyl ketone 10d readily underwent the reaction to provide
9a in good yield (76%) along with 11d (9%) as a minor
product. This outcome further emphasizes a greater leaving
group ability of the phenylsulfonyl group versus the phenyl-
sulfanyl group, and thus aids the elimination step. The
mechanism for the formation of 9a from both 10c and 10d
is straightforward and is similar to that of the formation of 6a
from 4a in that the tributylstannyl radical mediated an
intramolecular radical cyclization/ipso-1,4-aryl migration cas-
cade and subsequent elimination (Scheme 2). Comparatively,
the rate of the reaction for the conversion of 10c and 10d into
9a is much lower than that of 4a into 6a, as monitored by
thin-layer chromatography and 1H NMR analysis. This differ-
ence may be attributed to the electronegative gem-difluoro
moiety, thus enhancing the rate of the radical cyclization/ipso-
1,4-aryl migration cascade of 4a to give 6a.
[a] Values in parentheses are yields of the isolated products.
matic ring with subsequent fragmentation and elimination of
the phenylsulfanyl group. Therefore, radical cyclization of the
compounds 10a–d (each as approximately 1:1 mixture of two
diastereomers) was examined to gain insight into the impor-
tance of the R group in the radical cyclization/ipso-1,4-aryl
migration cascade (Scheme 3).
Under the standard reaction conditions (Table 2, entry 3),
but at a prolonged reaction time (24 h), radical cyclization of
In summary, we have developed a novel method for the
asymmetric synthesis of the 3,3-difluoro-2-propanoylbicyclo-
[3.3.0]octanes 6a–j on the basis of the unprecedented intra-
molecular radical cyclization/ipso-1,4-aryl migration cascade
of 4a–j, which were readily obtained by fluoride-catalyzed
nucleophilic addition of PhSCF2TMS (1) to the chiral
ketocyclopentenes 3. The chiral compounds of type 6 may
be useful in further synthetic applications. Furthermore, this
approach was also successfully applied to the phenylsulfanyl-
methyl carbinol 10c and phenylsulfonylmethyl carbinol 10d
to provide the chiral bicyclic ketone 9a. Further applications
of our reaction to the synthesis of fluorinated analogues of
naturally occurring bioactive compounds are currently under
investigation.
Experimental Section
Synthesis of the compounds 4 from the corresponding chiral ketones
3: A mixture of PhSCF2TMS (1) (464 mg, 2 mmol), and 3 (1 mmol) in
Scheme 3. Intramolecular radical cyclization of compounds 10a–d.
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anhydrous THF (2 mL) was treated with a solution of 10 mol%
TBAF (1m in anhydrous THF, 0.1 mL, 0.1 mmol) at 08C to RT for
24 h. The reaction mixture was quenched with an excess amount of
saturated aqueous TBAF and the resulting mixture was stirred at RT
for 2 h. The reaction mixture was then quenched with saturated
aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3 ꢀ 10 mL).
The combined organic phases were washed successively with brine
(10 mL) and dried over anhydrous Na2SO4. Filtration and evapora-
tion gave a crude reaction mixture, which was purified by gradient
column chromatography (SiO2, 5–10% EtOAc in hexanes) to yield
the corresponding adducts 4 as mixtures of diastereomers.
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Synthesis of the difluoroketones 6 from compounds 4: An argon
gas was bubbled through a solution of the compound 4 (0.3 mmol) in
anhydrous toluene (60 mL) for 30 min, and a mixture of Bu3SnH
(0.08 mL, 0.3 mmol) and AIBN (5 mg, 0.03 mmol) in anhydrous
toluene (60 mL) was then added dropwise at reflux over a 1 h period.
After the completion of the reaction, the tin by-products were
removed by column chromatography [SiO2, hexanes (200 mL) and
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Received: December 11, 2013
Published online: January 29, 2014
Keywords: cyclization · fluorine · radical reactions ·
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reaction mechanism · synthetic methods
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