Synthesis of gem-difluoromethylenated bicyclo[ m.n. 0]alkan-1-ols and their ring-expansion to gem-difluoromethylenated macrocyclic lactones

Article abstract of DOI:10.1021/ol3004194

Fluoride-catalyzed stereoselective nucleophilic addition of PhSCF ₂SiMe₃ (1) to α-carboethoxycycloalkanones 2 followed by intramolecular radical cyclization of the resulting cis-3 adduct afforded the corresponding gem-difluoromethyle

Full text of DOI:10.1021/ol3004194

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1820–1823
Synthesis of gem-Difluoromethylenated
Bicyclo[m.n.0]alkan-1-ols and Their Ring-
Expansion to gem-Difluoromethylenated
Macrocyclic Lactones
Teerachai Punirun, Krisana Peewasan, Chutima Kuhakarn, Darunee Soorukram,
Patoomratana Tuchinda, Vichai Reutrakul, Palangpon Kongsaeree, Samran Prabpai,
and Manat 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
scmpk@mahidol.ac.th
Received February 21, 2012
ABSTRACT
Fluoride-catalyzed stereoselective nucleophilic addition of PhSCF2SiMe3 (1) to R-carboethoxycycloalkanones 2 followed by intramolecular
radical cyclization of the resulting cis-3 adduct afforded the corresponding gem-difluoromethylenated bicyclic compounds 4, which underwent
ring-expansion followed by the BaeyerÀVilliger-type oxidation of the resulting macrocyclic ketone intermediates to give gem-difluoro-
methylenated macrocyclic lactones 5.
Remarkable efforts have been devoted to the develop-
ment of generaland efficient synthetic strategies toorgano-
fluorine compounds,1 including analogues of natural
products.2 Compounds containing a monofluoroalkyl- or
difluoromethylene moiety often enhance the chemical,
physical, and biological activities in a large number of
biologically active pharmaceuticals and agrochemicals.3
Recently, PhSCF2SiMe3 (1) has been demonstrated as
a difluoromethylating4 and gem-difluoromethylenating
agent.5
As a part of our continuing efforts in developing an
efficient gem-difluoromethylenation6 employing 1 as a
difluoromethylene radical anion equivalent (•CF2À),7,8
we report herein a general synthetic route leading to gem-
difluoromethylenated bicyclic compounds 4, which under-
go ring-expansion followed by the BaeyerÀVilliger oxida-
tion to gem-difluoromethylenated macrocyclic lactones 5
upon treatment with Pb(OAc)4/I2 in toluene under
(1) See for examples: (a) Soloshonok, V. Fluorine-Containing Syn-
thons; Oxford University Press: New York, 2005. (b) Welch, J. T., Ed.
Selective Fluorination in Organic and Bioorganic Chemistry; American
Chemical Society: Washington, DC, 1991. (c) Shen, X.; Zhang, L.; Zhao, Y.;
Zhu, L.; Li, G.; Hu, J. Angew. Chem., Int. Ed. 2011, 50, 2588. (d)
Lundgren, R. L.; Stradiotto, M. Angew. Chem., Int. Ed. 2010, 49, 2.
(e) Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132, 12150.
(f) Wang, W.; Jasinski, J.; Hammond, G. B.; Xu, B. Angew. Chem., Int.
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(h) Qing, F.-L.; Chu, L. Org. Lett. 2010, 12, 5060. (i) Lui, J.; Hu, J.
Chem.;Eur. J. 2010, 16, 11443. (j) Ni, C.; Hu, J. Synlett 2011, 770 and
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2250. (l) Zhang, W.; Huang, W.; Hu, J. Angew. Chem., Int. Ed. 2009, 48,
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Percy, J. M.; Yang, H. Org. Lett. 2004, 6, 4269. (f) Chang, C. -S.;
Negishi, M.; Nakano, T.; Morizawa, Y.; Matsumura, Y.; Ichikawa, A.
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Prostaglandins 1997, 53, 83. (g) Fourriere, G.; Van Hijfte, N.; Lalot, J.;
Dutech, G.; Fragnet, B.; Coadou, G.; Quirion, J.-C.; Leclerc, E. Tetra-
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r
10.1021/ol3004194
Published on Web 03/14/2012
2012 American Chemical Society

Table 1, entry 1). Similar stereoselectivity and yield of 3a
(cis: 63%, trans: 15%) were obtained when tetrabutylam-
moniumtriphenyl difluorosilicate (TBAT) was employed
in place of TBAF. Under standard reaction conditions
employing either TBAF or TBAT as a catalyst, compound
1 reacted with R-carboethoxycyclopentanones 2bÀe pro-
viding the corresponding adducts 3bÀe in moderate to
good yields with moderate stereoselectivities (entries 2À5).
Interestingly, highly stereoselective nucleophilic addition
of 1 toward R-carboethoxycyclohexanones was observed
when 1 was reacted with R-carboethoxycyclohexanone 2f
by using TBAT as a catalyst, giving cis- and trans-3f in 76%
and 3% yields, respectively (entry 6). The stereochemistry of
the cis-3f was confirmed by X-ray crystallography (see the
Supporting Information). Similarly, the reaction of 1 with
R-carboethoxycyclohexanones 2gÀi using either TBAF or
TBAT as a catalyst proceeded with high stereoselectivityand
exclusively provided the cis-isomers of the adducts 3gÀi in
moderate to good yields (entries 7À9).
Scheme 1. Synthesis of Compounds 4 and Their Ring Expan-
sions
photolysis (Scheme 1). It should be noted that the observed
tandem oxidative fragmentation followed by the BaeyerÀ
Villiger type oxidation has not been previously reported in
the literature.
Our investigation began with fluoride-catalyzed stereo-
selective nucleophilic addition of 1 to R-carboethoxycy-
clopentanone 2a9 using 10 mol % of anhydrous tetra-
butylammonium fluoride (TBAF) in dry THF at À78 °C
to room temperature overnight (15 h) to afford an adduct
3a, after acidic workup, as a mixture of trans- and cis-
isomers. After separation by means of preparative thin-
layer chromatography (PLC), cis- and trans-3a were ob-
tained in 62% and 15% yields, respectively (Scheme 1,
On the basis of our previous work,7 a two-step strat-
egy, involving fluoride-catalyzed (phenylsulfanyl)difluoro-
methylation and reductive cleavage of the phenylsulfanyl
group followed by radical-mediated intramolecular cycli-
zation, took the route to the gem-difluoromethylenated
bicyclic compounds 4. Overall, reductive cyclization of
the cis-adducts 3 smoothly took place affording cis- and
trans-4,10 separable by chromatography, in good yields but
only modest selectivities. Thus, the reaction of cis-3b with
Bu3SnH and a catalytic amount of AIBN in refluxing
toluene for 8 h afforded, after column chromatography,
cis- and trans-4b in 63% and 28% yields, respectively
(Scheme 1, Table 1, entry 2). As expected, reductive
cleavage of the phenylsulfanyl group of trans-3b led com-
pletely to the corresponding gem-difluoromethyl deriva-
tive, and no cyclized product was observed. Under similar
radical cyclization conditions, cis-3a and cis-3cÀi yielded
bicyclic compounds 4a and 4cÀi, respectively (Table 1,
entries 1 and 3À9). The trans- and cis-isomers of 4aÀd, 4f,
g, and 4i, of which yields are shown in Table 1 (entries 1À4,
6, 7, and 9), could be chromatographically separated. We
proposed that the major isomers of compounds 4aÀc and
4f,g are the cis-isomers, whereas the trans-isomers are the
major isomers of 4d,e and 4h,i. These stereochemical out-
comes can be rationalized by considering the intramole-
cular radical cyclization that should proceed via 5-exo or
6-exo cyclization mode through the more favorable transi-
tion state 6A or 6B, resulting in the formation of the cis-
isomers of bicyclic compounds 4aÀc and 4f,g, and the
trans-isomers of 4d,e and 4h,i, respectively (Scheme 2).
Having established a general strategy to gem-difluoro-
methylenated bicyclic compounds 4aÀi, we turned our
attention to the synthetic utilities of these compounds for
the preparation of gem-difluoromethylenated macrocyclic
lactones 5. Initially, attempted ring-expansion of 4f as
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ment of the corresponding cyclic β-ketoesters with alkenyl bromide in
the presence of potassium tert-butylate in DMSO or NaH in THF.
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Org. Lett., Vol. 14, No. 7, 2012
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Table 1. Preparation of Compounds 3À5
a Isolated yields. b Obtained as a mixture of diastereomers. c Using TBAF. d Using TBAT. e Prepared from a mixture of isomers of 4. f Determined by
1H NMR. g Prepared from the major isomer of 4. h The reactions were not performed. i The reaction led to the recovery of 4i.
a mixture of isomers (trans/cis = 1:3) by employing either
KHMDS/18-crown-6/THF11 or NaH/THF, t-BuOK/
THF at 0 °C to room temperature led completely to the
recovery of the starting material. Similar results were
obtained when 4f (trans/cis = 1:3) was treated with DIB/
Et4NBr/CH2Cl2/H2O/rt, IBX/I2/DMSO/rt, or HgO/I2/
CCl4/reflux.12 Gratifyingly, when a mixture of 4f (trans/
cis = 1:3) was treated with DIB (3 equiv), I2 (3 equiv) in
CH2Cl2 under photolysis (tungsten filament lamp (100W))
for 3 h, compound 5f, resulting from ring-expansion
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Org. Lett., Vol. 14, No. 7, 2012

However, the conformation 7Da suffered with dipole/
dipole interaction between the iodine and the fluorine
atoms. Therefore, the most favorable conformation for
the Criegee intermediate would be conformation 7Db in
which the ÀCF2 group is stereoelectronically favorable for
rearrangement.
Scheme 2. Proposed Transition States for the Intramolecular
Radical Cyclization of cis-3
Scheme 3. Proposed Mechanism for the Formation of 5
followed by the BaeyerÀVilliger-type oxidation, was iso-
lated in 35% yield. High-resolution mass data, 1H and 13
C
NMR, aswellas CÀH correlation in 2DNMR confirmthe
structure of5f(see the Supporting Information). Improved
results were obtained when cis-4f was treated with Pb-
(OAc)4 (2 equiv) and I2 (2 equiv) in dry toluene under
photolysis13 for 3 h, providing 5f in 67% yield (Table 1,
entry 6). Under similar reaction conditions, cis-4aÀc,
trans-4d, and cis-4g provided the corresponding ring-
expanded products 5aÀd and 5g in 50À78% yields as
summarized in Table 1. Compounds 5c and 5g were
obtained as the 4-iodinated methoxybenzene derivatives
which resulted from the electrophilic iodination of the
corresponding initially formed gem-difluoromethylenated
macrocyclic lactones. Attempts to perform ring-expansion
of a mixture of cis- and trans-4i, under the standard
conditions, were not successful, and 4i was recovered
(80À90%). The explanation for the failure of the oxidative
ring expansion of 4i is still unclear. The mechanism for the
formation of gem-difluoromethylenated macrocyclic lac-
tones 5 was proposed as shown in Scheme 3. Under
photolytic conditions, an intermediate 7A, initially formed
from the reaction of 4 with Pb(OAc)4, underwent homo-
lytic cleavage of the PbÀO followed by CÀC bond break-
ing leading to a radical intermediate 7B, which was then
trapped by an iodine atom to give 7C, which further
reacted with acetoxy radical (AcO•) and an iodine atom
to give an intermediate 7D. The BaeyerÀVilliger-type
oxidation of 7D afforded 7E, which was finally converted
to gem-difluoromethylenated macrocyclic lactones 5 after
hydrolysis. The observed regiospecific migration of the
gem-difluoro-bearing carbon can be explained by primary
and secondary stereoelectronic effects as well as a dipole/
dipole interaction.14 Conformations 7Da and 7Db fulfill
both primary and secondary stereoelectronic effects.
In conclusion, we have demonstrated a general strategy
for the preparation of gem-difluoromethylenated bicyclic
compounds 4 by employing a fluoride-catalyzed nucleo-
philic addition of PhSCF2SiMe3 to R-carboethoxycyclo-
alkanones followed by radical cyclization of the resulting
adducts cis-3. Compounds 4 underwent ring-expansion to
provide gem-difluoromethylenated macrocyclic lactones
5 by reacting with Pb(OAc)4/I2/toluene/hν.
Acknowledgment. We acknowledge financial supports
from the Thailand Research Fund (to M.P., BRG5380019,
and to P.K., DBG5480015), the Office of the Higher
Education Commission and Mahidol University under
the National Research Universities Initiative, and the
Center of Excellence for Innovation in Chemistry
(PERCH-CIC). We are grateful to Chulabhorn Research
Institute for the HRMS data of some compounds.
Supporting Information Available. Experimental pro-
1
cedures, spectroscopic data, and copies of H and 13C
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NMR spectra for all compounds and single crystal X-ray
analysis of cis-3f (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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