2-Fluoro-l,3-benzodithiole-1,1,3,3-tetraoxide: A reagent for nucleophilic monofluoromethylation of aldehydes

Article abstract of DOI:10.1002/anie.200906866

Chemical Equation Presented Matter of choice: The title compound (FBDT), a cyclic analogue of 1-fluorobis(phenylsulfonyl)methane (FBSM), was developed as a reagent for the nucleophilic monofluoromethylation of aldehydes. By choice of an appropriate base it is possible to achieve selective 1,2- or 1,4addition of FBDT to conjugated aldehydes. The method was applied to the synthesis of a fluorinated isostere of osmundalactone.

Full text of DOI:10.1002/anie.200906866

Communications
DOI: 10.1002/anie.200906866
Fluoromethylation
2-Fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide: A Reagent for
Nucleophilic Monofluoromethylation of Aldehydes**
Tatsuya Furukawa, Yosuke Goto, Jumpei Kawazoe, Etsuko Tokunaga, Shuichi Nakamura,
Yudong Yang, Hongguang Du, Akikazu Kakehi, Motoo Shiro, and Norio Shibata*
In recent years, fluorine-containing organic molecules have
been identified as strong candidates for pharmaceuticals and
advanced materials because of their unique properties,[1]
despite their extremely rare natural occurrence.[2] Particu-
larly, monofluorinated analogues of biologically active com-
pounds are a peerless class of drug nominees, which are
considered to be promising bioisosteres of the parent
molecules.[3] In this respect, compounds with monofluoro-
methyl groups are particularly valuable because they can
mimic the methyl or hydroxymethyl group, which are often
encountered in biologically active materials.[4] The fluoro-
methyl group is best known as an effective functional group
for the “Trojan horse” inhibition of vitamin B6 dependent
enzymes.[4a] Monofluoromethylated amino acids such as d-
fluoroalanine are well known to act as “suicide substrates”
causing inactivation of the enzyme by alkylative capture of
the aminoacrylate-pyridoxal-P species.[4j] Monofluoroacetic
acid is responsible for “lethal synthesis” and it blocks the
tricarboxylic acid cycle (Krebs cycle).[4f–h]
fluoromethane[9] and is becoming popular in the nucleophilic
monofluoromethylation reaction. However, FBSM failed to
undergo nucleophilic addition to aldehydes regardless of the
reaction conditions, leading instead to starting materials by a
retro-type reaction (Scheme 1, top). This behavior presum-
ably results from the instability of the resulting b-hydroxy-a-
fluorobis(phenylsulfonyl)methanes caused by the steric hin-
drance of the two phenylsulfonyl groups. The use of sterically
less demanding reagents should avoid this problem.
As a part of our efforts to develop efficient reaction
systems for the synthesis of organofluorine compounds,[5] we
developed 1-fluorobis(phenylsulfonyl)methane (FBSM) as a
synthetic equivalent of a fluoromethide species.[6–8] FBSM
reacts with a greater variety of electrophiles and has been
widely applied in nucleophilic monofluoromethylation reac-
tions based on Tsuji–Trost allylation, Mannich, Mitsunobu,
Michael, and ring-opening reactions, as well as other reac-
tions.[7,8] FBSM is much superior to (phenylsulfonyl)mono-
Scheme 1. Nucleophilic monofluoromethylation of aldehydes with
FBSM or FBDT.
In an attempt to develop an alternative and efficient
method, we now disclose a novel reagent, 2-fluoro-1,3-
benzodithiole-1,1,3,3-tetraoxide (FBDT), for the first nucle-
ophilic monofluoromethylation of aldehydes (Scheme 1,
bottom). The FBDT adducts of aldehydes are readily trans-
formed in high yields into monofluoromethylated alcohols in
a single step. Notable advantages of the present reagent
include 1) the ability to perform 1,2-addition reactions of
aldehydes, and 2) control of the 1,2- versus 1,4-regioselectivity
of the reaction with a,b-unsaturated aldehydes by base. We
also report the application of this strategy to the enantiose-
lective syntheses of a fluorinated isostere of osmundalactone.
Previously unknown FBDT was prepared from readily
available nonfluorinated precursor[10] by electrophilic fluori-
nation.[11] The addition reaction was tested with benzaldehyde
(1a) in the presence of base. No reaction of 1a with FBSM
proceeded at all, regardless of the base, presumably because
of a facile retro-type reaction by two bulky bis(phenylsulfo-
nyl)methane moieties (Table 1, entries 1–4). In contrast, the
reaction with FBDT in the presence of tBuOK proceeded
readily at room temperature to give monofluoromethylated
product 2a in 31% yield (Table 1, entry 5). Encouraged by
this initial result, we pursued the reaction of 1a with FBDT
under various conditions. The reaction was next attempted
using Et3N or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as
the base, but the results did not improve (Table 1, entries 6
[*] T. Furukawa, Y. Goto, J. Kawazoe, E. Tokunaga, Dr. S. Nakamura,
Prof. N. Shibata
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya, 466-8555 (Japan)
Fax: (+81)52-735-5442
E-mail: nozshiba@nitech.ac.jp
Y. Yang, Prof. H. Du
Department of Applied Chemistry, Beijing University of Chemical
Technology, Beijing 100029 (China)
Prof. A. Kakehi
Department of Applied Chemistry, Shinshu University
4-17-1, Wakasato, Nagano, 380-8553 (Japan)
Dr. M. Shiro
Rikagaku Corporation
3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666 (Japan)
[**] This study was financially supported in part by Grants-in-Aid for
Scientific Research (B) (JSPS) No. 21390030. We also thank TOSOH
F-TECH Inc.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906866.
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Chemie
Table 1: Optimization of the reaction conditions.[a]
afforded products 2 in good to excellent yields. A series of
aldehydes with a variety of substituents, such as methyl,
bromo, chloro, and nitro, on their aromatic rings 1b–g were
nicely converted into the corresponding monofluoromethy-
lated products 2b–g in good yields (Table 2, entries 1–6).
Conjugated aldehyde 1h was also compatible with the same
reaction conditions and afforded 1,2-addition product 2h
selectively in 60% yield (Table 2, entry 7). The reaction of
sterically demanding naphthyl aldehyde 1i and heteroaryl
aldehyde 1j also proceeded in 73 and 77% yields, respectively
(Table 2, entries 8 and 9). Good results were also observed
with aliphatic aldehydes 1k and 1l, which have enolizable
protons (Table 2, entries 10 and 11). The resulting 1,2-adducts
2 were readily transformed into the corresponding mono-
fluoromethylated alcohols 3 by reductive desulfonylation
using SmI2 (Scheme 2). A slight excess of SmI2 (4.0 equiv-
alents is the stoichiometric amount) was used because of the
instability of the reagent.
Entry
Base
Solvent
Yield [%][b]
1[c]
2[c]
3[c]
4[c]
5
6
7
8
9
10
11
12
13
tBuOK
Et3N
DBU
DABCO
tBuOK
Et3N
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3CN
DMF
MeOH
toluene
0
0
0
0
31
34
29
62
64
78
47
64
81
DBU
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
[a] Reactions were carried out using FBDT (1.0 equiv), 1a (1.2 equiv),
and base (2.0 equiv) in solvent at room temperature for 1 day unless
otherwise noted. Yields were calculated based on FBDT. [b] Yield of
isolated product. [c] FBSM was used as a nucleophile instead of FBDT.
and 7). The yield improved to 62% when 1,4-diazabicyclo-
[2.2.2]octane (DABCO) was used (Table 1, entry 8). An
attempt to improve the yield of 2a by varying the solvent
was successful (Table 1, entries 9–12), and a high yield of 2a
was observed in toluene (Table 1, entry 13).
With the optimized conditions established, the scope of
substrates in the FBDT-based 1,2-addition reaction was
investigated (Table 2). By using DABCO, all substrates 1
Scheme 2. Conversion of 1,2-adducts into monofluoromethylated com-
pounds. Reactions were carried out using 2 (1.0 equiv) and SmI2
(5.0 equiv) in THF and MeOH at À60 to À408C for 3 h.
Attention was next turned to control of the selectivity of
1,2- versus 1,4-addition of FBDT to conjugated aldehyde 1h.
While 1,2-addition was predominantly observed in the
presence of DABCO to afford 2h as mentioned in the
previous section (Table 1, entry 7), 1,4-adduct 4 was selec-
tively obtained in the presence of pyrrolidine because of the
formation of enamine as an intermediate (Scheme 3). It
should be noted that excellent diastereoselectivity (> 99%)
was observed for the 1,2-addition of FBDT with FBDT-
attached aldehyde 4 to give 5, which has 1,3-stereocenters
(Scheme 3).
Table 2: Monofluoromethylation of aldehydes.[a]
Entry
1
R
2
Yield [%][b]
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1 f
1g
1h
1i
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
3-MeC6H4
3-ClC6H4
trans-PhCH CH
2-naphthyl
2-thienyl
2b
2c
2d
2e
2 f
2g
2h
2i
80
88
90
94
73
95
60
73
77
74
86
=
1j
2j
2k
2l
10
11
1k
1l
n-octyl
cyclohexyl
[a] Reactions were carried out using FBDT (1.0 equiv), aldehyde
(1.2 equiv), and DABCO (2.0 equiv) in toluene at room temperature
for 1 day unless otherwise noted. Yields were calculated based on FBDT.
[b] Yield of isolated product.
Scheme 3. a) 1h (1.5 equiv), pyrrolidine (20 mol%), FBDT (1.0 equiv),
CH2Cl2, RT, 2 d, 51%; b) FBDT (1.0 equiv), DABCO (2.0 equiv), CH2Cl2,
reflux, 5 h, 76%.
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The structural investigation of a-fluorinated carbanions is
a challenge.[12] It seems likely that the a-fluorine atom
effectively stabilizes the carbanions through its strong elec-
tron-withdrawing effect; however, in practice, fluorine often
destabilizes a-carbanions through Coulombic repulsion
between the vicinal lone pairs of electrons of the carbanion
and the neighboring fluorine atom.[12] Very recently, Prakash
et al. reported studies on the a-fluorocarbanion of FBSM
based on X-ray crystallographic analysis, NMR spectroscopy,
and computations.[13] The X-ray crystallographic analysis of
carbanion of FBSM revealed a syn-pyramidal conforma-
tion.[13] Both syn-pyramidal and trans-planar structures of
FBSM were also found to be minima at the both B3LYP/6-
31G(d) and B3LYP/6-311 + G(2d,p) level of calculations,
although the trans-planar structure was not observed exper-
imentally (Scheme 4, X = F). In contrast, the carbanions of
Figure 1. A) X-ray crystal structure of FBDT. B) Optimized structure of
FBDT anion I (eqA-axF conformation; 0 kcalmolÀ1) calculated at the
B3LYP/6-31+G(d,p) level. C) Optimized structure of FBDT anion II
(eqF-axA conformation; 3.49 kcalmolÀ1) calculated at the B3LYP/6-
31+G(d,p) level. D) Optimized structure of CBDT anion III (eqA-axCl
conformation; 0 kcalmolÀ1) calculated at the B3LYP/6-31+G(d,p)
level. E) Optimized structure of CBDT anion IV (eqCl-axA conforma-
tion; 3.48 kcalmolÀ1) calculated at the B3LYP/6-31+G(d,p) level.
F) Optimized structure of BDT anion I (eqA-axH conformation). The
corresponding eqH-axA conformation does not have a local minimum.
(d,p) level. Two optimized conformations I (equatorial anion
and axial fluorine conformation; eqA-axF) and II (eqF-axA)
were generated, both of which show the pyramidal nature of
a-fluorocarbanion (Figure 1B,C, Scheme 5). The fluorine
Scheme 4. Conformations of carbanions derived from FBSM, BSM,
and CBSM proposed by Prakash et al.[13] syn-Pyramidal conformation
occurs only with highly electronegative a-fluorine substituents.
bis(phenylsulfonyl)methane (BSM, CH2(SO2Ph)2), and
chlorobis(phenylsulfonyl)methane (CBSM, CHCl(SO2Ph)2)
were both revealed to be trans-planar conformations
(Scheme 4, X = H, Cl). On the basis of their work, we decided
to investigate the conformations of FBDT and its carbanion.
FBDT was characterized by single-crystal X-ray crystallog-
raphy, which showed that the a-fluorinated carbon atom
(C14) has an sp3 structure, as evidenced by the angles S1-C14-
F3 (110.98), S2-C14-F3 (107.58), H19-C14-F3 (110.78), and S1-
Scheme 5. Calculated conformations of carbanions derived from FDT,
BDT, and CBDT. Equatorial anion conformations are always more
stable than their counterparts independent of the substituents (X=F,
H, Cl) because of nC–s*SAr negative hyperconjugation.
À
C14-S2 (105.98). The C14 F3 bond length of 1.366 ꢀ, which is
À
typical for Csp3 F bonds in fluorocarbons and slightly shorter
than that reported for FBSM (1.404 ꢀ).[13,14] The most
interesting point is that FBDT has a structure possessing an
equatorial hydrogen atom and an axial fluorine atom, which is
contrary to their steric factors (Figure 1A). The preferred
conformation has the hydrogen atom bisecting the two
atom occupies the axial position in conformation I, whereas
conformation II has an equatorial fluorine atom. Calculations
led to the prediction that the axial fluorine conformation I
should be slightly more stable by 3.49 kcalmolÀ1. We next
examined the conformations of carbanions of 2-chloro-1,3-
benzodithiole-1,1,3,3-tetraoxide (CBDT) and 1,3-benzodi-
thiole-1,1,3,3-tetraoxide (BDT) under the same computation
method. The results are quite surprising. Similar to the case of
FBDT, the equatorial carbanion conformations are more
stable than axial ones, independent of the substituents
(Figure 1D–F and Scheme 5). Thus, the axial chlorine con-
formation III is more stable by 3.48 kcalmolÀ1 than the
equatorial chlorine conformation IV (Figure 1D,E), and the
axial hydrogen conformation was found to be a minimum in
the BDT carbanion (Figure 1F). These results are distinct
À
flanking SO2 groups. Regarding the C H bond as the more
À
C lone-pair-like s bond than the strongly polarized C F bond,
À
one would expect the C H bond to bisect the two flanking
SO2 groups; furthermore, this arrangement exhibits poten-
tially stabilizing electrostatic interactions between the pos-
itively polarized hydrogen atom and the four negatively
polarized sulfonyl oxygen atoms, in contrast to the alternative
arrangement, in which the hydrogen atom is axial and the
negatively polarized fluorine ligand is juxtaposed to the four
negatively polarized sulfonyl oxygen atoms.
Next, the conformation of carbanion of FBDT was
investigated by computations based on the B3LYP/6-31 + G- from those of FBSM and its analogues shown in Scheme 4.
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The constraints of the five-membered ring have a profound
effect upon the stereochemistry of the anion. While Prakash
et al. have shown that the a-fluoroanion adopts a conforma-
tion that is distinct from all other derivatives, the five-
membered ring yields isostructural anions for all a-substitu-
ents. The conformational stability of FBDT as well as its
carbanion and analogues is governed essentially by the
stabilization effects originating from nC–s*SAr negative hyper-
conjugation,[15] which was estimated to be 10.42 kcalmolÀ1
(5.21 kcalmolÀ1 ꢁ 2) each by natural bond order (NBO)
analysis (B3LYP/6-31 + G**),[16] but not by the effects of the
substituents such as fluorine, chlorine, or hydrogen. Since in
the more stable equatorial carbanion configurations the anion
lone pair orbital lies in the plane that contains the two
Scheme 6. a) Lipase-PS, vinyl acetate, iPr2O, 378C, 6 h; b) 1n aq.
NaOH, MeOH, RT, 30 min, 33%, over two steps; c) 3-butenoic acid
(1.2 equiv), DCC (1.1 equiv), 4-dimethylaminopyridine (10 mol%),
CH2Cl2, RT, 1 h; d) 2nd generation Grubbs catalyst (1.3 mol%),
CH2Cl2, reflux, 4 h, 84%; e) CF3COCH3 (14.0 equiv), KHSO5
(4.0 equiv), NaHCO3 (6.2 equiv), EDTA buffer, CH3CN, RT, 4 h;
f) (MeO)2CH2, CHCl3, RT, 30 min, 72% (anti: 46%, syn: 26%) over
two steps.
À
s* orbitals of S Ar, whereas there is hardly any interaction
À
between anion lone pair orbital and two s* orbitals of S Ar in
the less stable axial isomers, the stabilization occurs depends
À
on the degree to which the empty s* orbital of the S Ar bond
participates (Scheme 5).
With facile access to this range of a-monofluoromethy-
lated alcohols 3, we finally considered synthetic applications.
Osmundalactone 6 (R = H) is an aglycon of osmundalin
isolated from Osmunda japonica by Hollenbeak and Kuehne
in 1974.[17] Fluorinated isostere 7 was selected as our synthetic
target from a pharmaceutical point of view.[1] The interest in
fluoro-substituted osmundalactone 7 stems from the fact that
osumundalactone is not only a biologically active natural
product but also a useful reactive intermediate in organic
synthesis, since it readily undergoes Michael addition, Baylis–
Hillman reaction, 1,3-dipolar cycloaddition, and other olefin-
related reactions.[18] In addition, hydroxylated analogues 8
(R’ = H) are widely useful synthetic intermediates for the
preparation of various types of biologically attractive com-
pounds (Figure 2).[18] Consequently, compound 7 should
ted,[18h] the method was found not to be applicable for the
synthesis of the fluorinated analogue, and several modifica-
tions were eventually required for conversion of 3h into
fluorinated isosteres of osmundalactone. Hence, the enzyme-
catalyzed reaction for dynamic kinetic resolution of 3h using
lipase-PS in the presence of vinyl acetate proceeded smoothly
to give enantiomerically pure 9 with greater than 99% ee.[19]
Removal of acetyl group followed by esterification with 3-
butenoic acid under 1,3-dicyclohexylcarbodiimide (DCC)
coupling conditions furnished 10 via (R)-3h in high yield.
Vinyl ester 10 was subjected to ring-closing metathesis by the
use of 2nd generation Grubbs catalyst[20] to form b,g-
unsaturated lactone 11 in 84% yield. Finally, in situ catalytic
epoxidation of 11 using methyl(trifluoromethyl)dioxirane[21]
with subsequent ring-opening reaction gave the target
fluorinated osmundalactone 12 as a mixture of diastereoiso-
mers. Treatment of crude 12 with dimethoxymethane in the
presence of P2O5 in CHCl3 afforded anti-13 (46%) and syn-13
(26%), both of which should be attractive as building blocks
for the synthesis of nonnatural fluorinated sugars and
biologically active compounds.[18]
In summary, we have developed a novel nucleophilic
monofluoromethylating reagent, FBDT, which was shown to
be suitable for the first nucleophilic monofluoromethylation
of aldehydes based on the generation of an a-fluorocarban-
ion. Control of the selectivity of 1,2- versus 1,4-addition of
FBDT to conjugated aldehydes was achieved by the choice of
organic base. Monofluoromethylated alcohols can be
accessed from aldehydes by this method in only two steps in
good to high yields. The a-fluorocarbanion of FBDT was
structurally characterized by X-ray crystallographic analysis
and theoretical calculations. Both FBDT and its carbanion
have structures possessing an axial fluorine atom, which is
contrary to its steric factors, as a result of nC–s*SAr negative
hyperconjugation. We close with a brief discussion of the
Figure 2. Osmundalactone (6), its fluorinated isostere 7, and various
biologically active target compounds.
become a sought-after building block in the synthesis of
fluorinated isosteres of biologically relevant compounds
derived form 6 or 8 because of the isosteric relationships
between fluorine and hydrogen or the hydroxy group. The
approach to fluorinated isosteres of osmundalactone is shown
in Scheme 6. Although the synthesis of osmundalactone from
nonfluorinated (E)-4-phenylbut-3-en-2-ol has been repor-
=
functionally equivalent McCarthy reagent, (EtO)2P(
O)CHFSO2Ph,[22] of which FBDT is essentially a sulfonyl
analogue. The McCarthy reagent has been effectively used for
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Communications
[8] FBSM was developed independently by us and the Hu group:
a) C. Ni, Y. Li, J. Hu, J. Org. Chem. 2006, 71, 6829 – 6833;
b) G. K. S. Prakash, S. Chacko, S. Alconcel, T. Stewart, T.
Mathew, G. A. Olah, Angew. Chem. 2007, 119, 5021 – 5024;
Angew. Chem. Int. Ed. 2007, 46, 4933 – 4936; c) C. Ni, L. Zhang,
J. Hu, J. Org. Chem. 2008, 73, 5699 – 5713; d) G. K. S. Prakash, X.
Zhao, S. Chacko, F. Wang, H. Vaghoo, G. A. Olah, Beilstein J.
Org. Chem. 2008, 4, 17; e) A.-N. Alba, X. Companyꢄ, A.
Moyano, R. Rios, Chem. Eur. J. 2009, 15, 7035 – 7038; f) H. W.
Moon, M. J. Cho, D. Y. Kim, Tetrahedron Lett. 2009, 50, 4896 –
4898; g) S, Zhang, Y. Zhang, Y. Ji, H. Li, W. Wang, Chem.
Commun. 2009, 4886 – 4888; h) F. Ullah, G.-L. Zhao, L. Deiana,
M. Zhu, P. Dziedzic, I. Ibrahem, P. Hammar, J. Sun, A. Cꢄrdova,
Chem. Eur. J. 2009, 15, 10013 – 10017; i) W.-B. Liu, S.-C. Zheng,
H. He, X.-M. Zhao, L.-X. Dai, S.-L. You, Chem. Commun. 2009,
6604 – 6606.
fluoromethylenation of aldehydes to give fluoromethylene
compounds. Hydrogenation of the resulting fluoromethylene
group might give the fluoromethyl group being installed
herein. Although McCarthy chemistry has been shown to be
quite robust, strong inorganic bases such as lithium diisopro-
pylamide and lithium hexamethyldisilazanide are required for
deprotonation. The advantage of FBDT will be much clearer,
provided the organocatalyzed enantioselective monofluoro-
methylation of aldehydes is achieved, and we are now
working in this direction.
Received: December 5, 2009
Published online: January 29, 2010
Keywords: aldehydes · fluorine · monofluoromethylation ·
[9] Y. Li, C. Ni, J. Liu, L. Zhang, J. Zheng, L. Zhu, J. Hu, Org. Lett.
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[11] See the Supporting Information for details.
[12] H. G. Adolph, M. J. Kamlet, J. Am. Chem. Soc. 1966, 88, 4761 –
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