Synthesis of fluorinated allenes via palladium-catalyzed monofluoromethylation using FBSM

Article abstract of DOI:10.1039/b912531k

Palladium-catalyzed monofluoromethylation of substituted 2-bromo-1,3-dienes using fluorobis(phenylsulfonyl)methane (FBSM) as a pronucleophile gave previously unknown monofluoromethylated allenes in high yields, which are the isosteres of biologically attr

Full text of DOI:10.1039/b912531k

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Synthesis of fluorinated allenes via palladium-catalyzed
monofluoromethylation using FBSMw
Masamichi Ogasawara,*a Hidetoshi Murakami,a Tatsuya Furukawa,b Tamotsu Takahashi*a
and Norio Shibata*b
Received (in Cambridge, UK) 25th June 2009, Accepted 16th October 2009
First published as an Advance Article on the web 2nd November 2009
DOI: 10.1039/b912531k
Palladium-catalyzed monofluoromethylation of substituted
2-bromo-1,3-dienes using fluorobis(phenylsulfonyl)methane
(FBSM) as a pronucleophile gave previously unknown mono-
fluoromethylated allenes in high yields, which are the isosteres of
biologically attractive allenic alcohols.
Allenes have received considerable attention as unique building
blocks in medicinal chemistry.1 Due to perpendicular orientation
of the two cumulated carbon–carbon double bonds in an
allenic framework, allenes can be axially chiral with proper
substitution, which enables the generation of stereochemical
Scheme 1 Strategy for preparing monofluoromethylated allenes.
diversity in drug candidates. Although about 150 natural
products comprising an allenic or a related cumulenic structure
have been known, the design and synthesis of biologically
active allenic compounds is a relatively undeveloped area.2 We
considered that the incorporation of a fluorine atom into
allenic compounds could provide new building blocks where
the unique properties of allenes and fluorine might contribute
to new biological activities.3 It is evident that fluorinated
molecules play a crucial role in the pharmaceutical as well as
agrochemical fields,4 and nowadays fluorinated allenes are an
emerging class of synthetic targets.3 Among such fluorinated
allenes, we became interested in monofluoromethylated allenes
1 as our synthetic targets based on the isostere design of the
corresponding allenic alcohols. Allenic alcohol moiety is
frequently found in allenic natural products and pharma-
ceuticals, such as grasshopper ketone and adenallene.2 Recent
evidence indicates that replacement of a hydroxy group by a
fluorine atom is often regarded as an isosteric substitution.5
Thus, the monofluoromethylated allenes 1 are potential
mimics of the corresponding allenic alcohols and can have a
significant impact on pharmacological properties. In 2006, a
nucleophilic monofluoromethylation reagent, fluorobis(phenyl-
sulfonyl)methane (FBSM), was developed as a synthetic
equivalent of a fluoromethide species by Shibata’s group in
Nagoya.6 This work sparked the imagination of chemists to
design new nucleophilic monofluoromethylation reactions
using FBSM which affords a variety of monofluoromethylated
compounds.7,8 As a part of our research program in Sapporo
involving the development of a novel synthetic method for
preparing a variety of functionalized allenes,9 we report herein
the efficient, simple synthesis of monofluoromethylated allenes
1 from substituted 2-bromo-1,3-dienes (or a related triflate) 2.
Our protocol comprises of two steps: after preparation of
fluorobis(phenylsulfonyl)methylated allenes
3
using the
palladium-catalyzed nucleophilic substitution reaction based
on the FBSM chemistry, following reductive desulfonylation
gives the previously unknown monofluoromethylated allenes 1
in high yields with excellent selectivity (Scheme 1).
Our initial studies were focused on the development of
suitable reaction conditions including base, solvent, and
palladium precursor for the Pd-catalyzed reaction of
(Z)-tBuCHQCBrCHQCH2 (2a) and FBSM producing the
allene 3a (Table 1). Under the conditions optimized for a
methylmalonate pronucleophile CHMe(CO2Me)2,9a which
were with [PdCl(p-allyl)]2 and NaH in THF, the reaction
was very sluggish and 3a was obtained in 24% in 12 h (entry 1).
The use of KOtBu as a base in place of NaH increased the
yield of 3a to 86% (entry 2) and the yield was further improved
to 90% by running the reaction in dichloromethane (entry 4).
A catalyst generated from Pd(dba)2 and dpbp showed the
lower catalytic activity and gave only 78% of 3a under
otherwise identical reaction conditions (entry 5). Thus, a
mixture of 2a (37.8 mg, 0.20 mmol), FBSM (70 mg,
0.22 mmol), KOtBu (27 mg, 0.24 mmol), [PdCl(p-allyl)]2
(1.8 mg, 5.0 mmol), and dpbp10 (5.7 mg, 11 mmol) in CH2Cl2
(2 mL) was heated at 40 1C. The reaction was complete within
12 h, and 76.1 mg (90% yield based on 2a) of 3a was isolated
as a colorless viscous liquid by silica gel chromatography.
Under these optimized conditions, the Pd-catalyzed
reactions took place very cleanly for a wide range of dienyl
substrates 2 to give the allenic compounds 3 in high yields.
a Catalysis Research Center and Graduate School of Life Science,
Hokkaido University, Kita-ku, Sapporo 001-0021, Japan.
E-mail: ogasawar@cat.hokudai.ac.jp, tamotsu@cat.hokudai.ac.jp;
Fax: +81-11-706-9150
b Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555,
Japan. E-mail: nozshiba@nitech.ac.jp; Fax: +81-52-735-5442
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. See DOI:
10.1039/b912531k
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Table 1 Optimization of palladium-catalyzed reaction of 2a with
FBSM
Indeed, poorly characterized gummy material was observed
in the reaction mixture. Similarly, the reactions of silylmethyl-
substituted dienes 2h and 2i yielded the corresponding
homoallenylsilanes 3h and 3i, respectively, in good yields
(entries 8 and 9). The present Pd-catalyzed reaction was
applicable to preparation of multisubstituted FBSM-allenes
(entries 10–13). The reaction of 2j provided a persubstituted
allene 3j in 82% (entry 10). A dienyl triflate was equally
reactive as the bromodienes: the triflate 2k furnished the
trisubstituted allene 3k in 86% yield under identical conditions
(entry 11). Cyclic dienylbromides 2l and 2m also underwent
the Pd-catalyzed reaction to give the corresponding endocyclic
allenes 3l and 3m in 82% and 87% yields, respectively
(entries 12 and 13).
Entry
Base
Solvent
Pd-precursor
Yield (%)a
1
2
3
4
5
NaH
THF
THF
THF
CH2Cl2
CH2Cl2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
[PdCl(p-allyl)]2
Pd(dba)2
24
86
72
90
78
KOtBu
Cs2CO3
KOtBu
KOtBu
With various fluorobis(phenylsulfonyl)methylallenes 3 in
our hands, reductive desulfonylation of 3, which should lead
to the envisaged monofluoromethylallenes 1, was examined.
Whereas a significant decrease of molecular weight (i.e.,
increase of volatility) was expected upon the transformation,
the desulfonylation was performed on the selected FBSM-
allenes of relatively larger molecular weight. The short list of
the FBSM-allenes for the desulfonylation, however, was
carefully chosen to demonstrate sufficient diversity of the
present chemistry, which included disubstituted allenes with
an alkyl (3b), an aryl (3f), or a silylmethyl (3i) group and a
trisubstituted endocyclic allene (3m). Desulfonylation of 3 was
carried out according to the Carpino’s procedure11 with slight
modifications. Due to low solubility of the FBSM-allenes in
methanol, a MeOH–THF mixture was used as a solvent.
a
Isolated yield by silica gel chromatography.
The results of the Pd-catalyzed reaction are summarized in
Table 2. Bromodienes with a sterically diverse alkyl substituent
afforded the corresponding allenes in excellent yields (89–93%;
entries 1–3). Arylallenes 3d–f were obtained as well in 81–83%
yields by the present reaction (entries 4–6), however, the
aryldiene bearing an electron withdrawing trifluoromethyl
substituent 2g gave 3g in as low as 42% (entry 7). Whereas
all the substrate 2g was consumed during the reaction, the low
yield of 3g could be ascribed to oligomerization/polymerization
of the dienyl substrate 2g and/or the allenic product 3g.
Table 2 Palladium-catalyzed reaction of 2 with FBSM giving allene 3a
Entry
1
Substrate 2
FBSM-allene 3
Yield (%)b
90
2
3
4
5
6
7
8
9
2b (R = PhCMe2CH2)
)
3b
3c
3d
3e
3f
3g
3h
3i
89
93
83
81
82
42
85
85
n
2c (R = C8H17
2d (R = Ph)
2e (R = p-MeOC6H4)
2f (R = 2,4,6-Me3C6H2)
2g (R = p-CF3C6H4)
2h (R = Me3SiCH2)
i
2i (R = Pr3SiCH2)
10
11
82
86
12
82
87
13
2m (n = 12)
3m
a
Reaction was carried out with 2 (0.20 mmol), FBSM (0.22 mmol), and KOtBu (0.22 mmol) in CH2Cl2 at 40 1C for 12 h in the presence of the
b
catalyst (5 mol%) generated from [PdCl(p-allyl)]2 and dpbp. Isolated yield by silica gel chromatography.
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Table 3 Desulfonylation of 3 giving CH2F-allene 1a
This work was supported by
a
Grant-in-Aid for
Scientific Research on Priority Areas ‘‘Advanced Molecular
Transformations of Carbon Resources’’ from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Entry FBSM-allene 3 CH2F-allene 1
Yield (%)b
Notes and references
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H. F. Schuster, Allenes in Organic Synthesis, Wiley, New York,
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2 (a) S. R. Landor, in The Chemistry of the Allenes, ed. S. R. Landor,
Academic Press, London, 1982, pp. 679–707; (b) A. Claesson, in
The Chemistry of the Allenes, ed. S. R. Landor, Academic Press,
London, 1982, pp. 709–733; (c) C. H. Robinson and D. F.
Covey, in The Chemistry of Ketenes Allenes, and Related
Compounds, ed. S. Patai, Wiley, Chichester, 1980, pp. 451–485;
1
2
3
3b
3f
59 (495)
52 (495)
3i
70 (495)
65 (495)
(d) A. Hoffmann-Roder and N. Krause, Angew. Chem., Int. Ed.,
2004, 43, 1196.
¨
4
3m
3 (a) G. B. Hammond, ACS Symp. Ser., 2005, 911, 204;
(b) M. C. Pacheco, S. Purser and V. Gouverneur, Chem. Rev.,
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4 (a) P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH,
Weinheim, 2004; (b) A. M. Thayer, Chem. Eng. News, 2006,
84, 15.
a
Reaction was carried out with 3 (0.30 mmol) and activated Mg turnings
b
(ca. 30 equiv. to 3) in MeOH–THF (1/3) at 0 1C for 3 h. Isolated yield
by silica gel chromatography. GC yield in parentheses.
5 B. E. Smart, in Organofluorine Chemistry: Principles and Commercial
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T. Toru, Angew. Chem., Int. Ed., 2006, 45, 4973.
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in THF, were extremely effective in the reductive desulfonylation
and the reaction completed within 3 h even at 0 1C. The results
of the desulfonylation are listed in Table 3. In all cases, the
reactions were very clean under these conditions. GC and
NMR analyses of the crude reaction mixtures showed
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exclusive formation of
1 in nearly quantitative yields
(495%). The isolated yields of the desulfonylated products
1, however, were relatively poor, which could be ascribed to
handling loss of the products due to their high volatility.
It should be noted that the allenic frameworks in 3 were
completely retained in 1 during the reductive desulfonylation
and isomerization into conjugated dienes and/or alkynes
(propargyls) were not detected at all.
In summary, we have developed a novel protocol for
preparing a series of monofluorinated allenic compounds.
The palladium-catalyzed nucleophilic substitution of
2-bromo-1,3-dienes 2 with FBSM affords the desired fluorobis-
(phenylsulfonyl)methylated allenes 3 in high yields. The two
phenylsulfonyl moieties in 3 can be easily and cleanly removed
by a treatment with Mg in MeOH–THF to provide the
previously unknown monofluoromethylated allenes exclusively,
which are non-polar isosteres of allenic alcohols. The use of a
chiral Pd-catalyst in this protocol is presently under investigation
to develop an enantioselective synthesis of axially chiral
monofluoromethylated allenes. The design and synthesis of
biologically attractive fluoromethylated compounds is also in
progress and will be reported in due course.
11 A. C. Brown and L. A. Carpino, J. Org. Chem., 1985, 50, 1749.
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7368 | Chem. Commun., 2009, 7366–7368