Electrophilic fluorocyclization of ally silanes

Full text of DOI:10.1002/anie.200901795

Angewandte
Chemie
DOI: 10.1002/anie.200901795
Fluorination
Electrophilic Fluorocyclization of Allyl Silanes**
Susan C. Wilkinson, Oscar Lozano, Marie Schuler, Maria C. Pacheco, Roger Salmon, and
Vꢀronique Gouverneur*
Halocyclization reactions have countless applications
throughout organic chemistry.[1] This area of research con-
tinues to attract attention, especially in terms of the validation
of asymmetric variants for the construction of halogenated
natural products.[2] Despite the great utility of fluorinated
hetero- and carbocycles as pharmaceuticals and agrochem-
icals,[3] the development of fluorocyclization reactions has
been slow. Such reactions have only been applied to a limited
range of alkenes.[4] For the continued advancement of this
field, the design and implementation of novel strategies that
enable fluorocyclization reactions to become a more general
and powerful transformation used by all practi-
nucleophile may be rerouted to deliver fluorinated hetero-
cycles. We reasoned that alkenes temporarily activated by a
silyl group other than the trimethylsilyl group would display
the reactivity profile necessary for the fluorocyclization to
occur and bypass the competing fluorodesilylation process.[6]
In this approach, the allyl silane functions as a 1,2-dipole, and
the silyl group is amenable to oxidative cleavage after the
cyclization event (Scheme 1). We describe herein the first use
of allyl silanes in endo fluorocyclization reactions, the
stereochemical outcome of which is dictated by the alkene
geometry.
tioners of synthetic chemistry is highly desirable.
To reach this objective, fundamental problems of
reactivity and selectivity must be addressed. The
À
low reactivity of commonly used N F electrophilic
fluorinating reagents towards feedstock olefins
(e.g. cyclohexene or acyclic alkenes) is particularly
restrictive in the context of fluorocyclization,
especially when combined with complications
arising from the poor regioselectivity observed
with some unsymmetrical substrates. The lack of
stereocontrol more often encountered in the
nucleophilic and electrophilic fluorocyclization
reactions reported to date must also be overcome,
Scheme 1. Electrophilic fluorocyclization versus fluorodesilylation.
ideally with a solution amenable to the development of an
asymmetric variant.
To test the proposed strategy, we carried out initial
investigations to identify the optimum F+ reagent as well as
silicon substituents that would promote cyclization versus
desilylation. A fluoroetherification was chosen as the model
reaction (Table 1).[7]
Our research group developed the concept of the electro-
philic fluorodesilylation of organosilanes. This approach
enables the synthesis and manipulation of various fluorinated
building blocks and more complex targets.[5] Provoked by the
potential of developing a conceptually novel stereoselective
fluorocyclization process, we questioned whether the electro-
philic fluorination of allyl silanes that contain a pendent
The silyl groups of the homoallylic alcohols 2a–d were
selected on the basis of the ability of structurally related allyl
silanes to participate in various annulations when treated with
an aldehyde in the presence of a Lewis acid.[8] Apart from 2a,
all substrates contained silyl groups amenable to oxidative
cleavage.[9] Attempts at the fluorocyclization of allyl silanes
2a–c were successful; the allyl dimethylphenylsilane 2d was
the only substrate to undergo exclusive fluorodesilylation.
The benzhydryldimethylsilyl group was not retained for
further studies, as side products were formed in significant
amounts in reactions of the homoallylic alcohol 2c (Table 1,
entries 5–7). When used in combination with NaHCO3,
Selectfluor (A) was found to be the reagent of choice for
the fluoroetherification of the allyl triisopropylsilane 2a; with
this reagent, the fluorinated tetrahydrofurans 3a were formed
in up to 90% yield (Table 1, entries 1 and 2). The fluorocy-
clization of the allyl p-tolyldiisopropylsilane 2b was most
efficient with N-fluorobenzenesulfonimide (NFSI, B) in
MeCN at reflux (Table 1, entries 3 and 4). This set of
preliminary data also indicated that the geometry of the
[*] S. C. Wilkinson, Dr. O. Lozano, Dr. M. Schuler, Dr. M. C. Pacheco,
Prof. V. Gouverneur
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX13TA (UK)
Fax: (+44)1865-275-644
E-mail: veronique.gouverneur@chem.ox.ac.uk
R. Salmon
Syngenta Limited, Jealotts Hill International Research Centre
Bracknell, Berkshire, RG426YA (UK)
[**] This research was supported by the EPSRC, Syngenta, and the EU
(PIEF-GA-2008-220034, MEIF-CT-2006-03970, and MEIF-CT-2004-
515589). We thank Dr. Barbara Odell for NMR spectroscopic studies
and Dr. Amber L. Thompson of the Oxford Chemical Crystallog-
raphy Service.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901795.
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À
Table 1: Influence of the silyl group and the N F reagent on the
fluorocyclization.
of the Z-allyl silanes 9b, 11a, and 11b than for substrates 8a,b
and 10a,b (Table 2, entries 6–8).
The fluorocyclization was also validated with the more
functionalized allyl silane 12a (Table 2, entry 9). The pres-
ence of additional functionality is an important consideration
for the synthesis of pharmaceuticals (Table 2, entry 9). The
silylated carboxylic acid 13a was also a suitable substrate for
this cyclization procedure (Table 2, entry 10). This interesting
result indicates that the reaction conditions are sufficiently
mild to prevent b-fluoride elimination after the fluorocycli-
zation event. In this transformation, the E/Z ratio of 13a was
translated accurately into the cis/trans ratio of the fluorinated
lactone 23a, which was formed in 80% yield.
Entry
2
E/Z
Reagent
Yield of 3 [%][d]
cis/trans
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
2c
2c
2c
2d
2d
2:1
1:10
1:18
2:1
2:1
2:1
2:1
4:1
4:1
A[a]
A[a]
A[a]
B[b]
A[a]
B[b]
C[c]
A[a]
B[b]
90
58
49
60
41
41
37
0[e]
0[e]
2.5:1
1:8
1:6
3:1
3:1
2.5:1
2.7:1
–
The stereochemical outcome of these kinetically con-
trolled reactions[7,11] is consistent with a predominant overall
syn addition to the double bond. According to our studies on
the fluorodesilylation of allyl silanes and allenyl silanes,[5] the
À
electrophilic addition of the N F reagent is expected to take
place anti to the silyl group. In the reactive conformation of
–
À
the allyl silanes, the C Si bond is probably aligned parallel to
[a] Reaction conditions: A, NaHCO3, MeCN, room temperature. [b] Reac-
tion conditions: B, NaHCO3, MeCN, reflux. [c] Reaction conditions: C,
NaHCO3, MeCN, room temperature. [d] Yield of the isolated product.
[e] Only fluorodesilylation was observed. Tf=trifluoromethanesulfonyl.
the empty p orbital of the carbocation intermediate to enable
s–p hyperconjugative stabilization. Subsequent cyclization
through the addition of the alcohol to the b-silyl cation occurs
preferentially anti to the bulky silyl group (Scheme 2).
alkene influenced the stereochemical outcome of the fluo-
rocyclization. The cyclization of samples enriched in (E)-2a
and (Z)-2a led preferentially to the cis and trans tetrahy-
drofuran, respectively.
As highlighted in Table 2, a wide range of silyl-activated
di- and trisubstituted alkenes are suitable substrates for this
reaction. Both E and Z-allyl silanes underwent fluorocycliza-
tion. The desired fluorinated tetrahydrofurans 14–22 were
isolated in yields ranging from 47 to 83%.[7,10] In accord with
the fluorocyclization of (E)- and (Z)-2a, various E- and Z-
allyl silanes underwent cyclization to give cis- and trans-
substituted fluorinated tetrahydrofurans, respectively. The
transfer of stereochemical information was excellent in the
fluoroetherification of E-allyl silanes (Table 2, entries 1, 2, 5,
7, and 9). In the case of starting materials used as a single
E isomer (Table 2, entries 2 and 7), only the cis product was
observed by 1H or 19F NMR spectroscopy of the crude
reaction mixture. No trace of the trans isomer was detected.
The trans products were accessible by the fluorocyclization of
Z-allyl silanes, albeit with some stereochemical erosion
(Table 2, entries 3, 4, 6, and 8). The fluorocyclization of 7b
stands out, as this phenyl-substituted Z-allyl silane was
converted exclusively into diastereomer 17b with the fluorine
substituent and the silylmethyl group oriented trans to one
another (Table 2, entry 4).
Scheme 2. Predominant syn addition in the fluorocyclization.
These fluorocyclization reactions follow a stereochemical
pathway that contrasts with the well-documented overall anti
addition observed for the endo iodocyclization of nonsilylated
alkenes.[12] The stereochemical erosion observed for Z-allyl
silanes indicates that a competing reaction pathway leads to
overall anti addition to the double bond.
To demonstrate the applicability of the methodology to
the synthesis of fluorinated tetrahydrofurans, the silyl group
of 14b was subjected to oxidative cleavage. Protodesilylation
of the tolyl group, followed by oxidation, gave the hydroxy-
lated tetrahydrofuran 24 in 62% overall yield (Scheme 3).[9]
Fluoroetherification of the homoallylic alcohols 8–11 was
also successful (Table 2, entries 5–8). The relative configura-
tion at C3 and C2 was still dictated by the alkene geometry,
with the best selectivity observed for the E-allyl silanes 8a,b
and 10a,b (Table 2, entries 5 and 7). Better diastereoselectiv-
ity (up to 4:1) was observed for the newly formed fluorinated
carbon center (C3) with respect to C4 in cyclization reactions
Scheme 3. Oxidative cleavage of 14b. TBAF=tetrabutylammonium
fluoride.
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Table 2: Scope of the electrophilic fluorocyclization.[a]
Heartened by these results, we
next probed the value of our strat-
egy for the development of
reagent-controlled asymmetric flu-
orocyclization. This preliminary
study was carried out with allyl
silane 7b. An asymmetric fluoro-
cyclization of this prochiral alkene
Entry
Allyl silane
Product[b]
Yield [%][c]
cis/trans[d]
a
a SiR3 =SiiPr3
b SiR3 =SiiPr2p-Tol
a SiR3 =SiiPr3
b SiR3 =SiiPr2p-Tol
1
4a E/Z 6:1
4b E/Z 5:1
14a
14b
73
52
7:1
5:1
À
was attempted with a chiral N F
reagent prepared in situ from
Selectfluor and a cinchona alkaloid.
This type of reagent was previously
found to enable access to enantio-
merically enriched allylic fluo-
rides.[13] Pleasingly, the allyl silane
7b reacted with Selectfluor/-
(DHQ)2PHAL in the presence of
NaHCO3 in MeCN at À208C to
2
5a E/Z>20:1
5b E/Z>20:1
15a
15b
72
47
>20:1
>20:1
3
6b Z/E>20:1
7b Z/E>20:1
16b
17b
67
65
1:16
1:20
4[e]
afford
the
enantiomerically
enriched product (+)-17b in 70%
yield with 45% ee (Scheme 4).[14] In
accord with the results observed for
the racemic substrate 7b, only one
diastereomer was formed, with the
fluorine substituent and the silyl-
methyl group in a trans arrange-
ment. This reaction is the first
example of an asymmetric fluoro-
cyclization that proceeds through a
cascade fluorination–ring-closure
process.
5
8a E/Z 10:1
8b E/Z 13:1
18a
18b
83
62
16:1[f,g]
16:1[f,g]
6
7
9b Z/E>20:1
19b
58
1:12[f,h]
In conclusion, we have devel-
oped the first fluorocyclization of
allyl silanes to give either cis or
10a E/Z>20:1
10b E/Z>20:1
20a
20b
83
55
>20:1[f,i]
>20:1[f,j]
trans fluorocyclized products.
A
preliminary experiment demon-
strated that this transformation is
amenable to the development of an
asymmetric variant. The temporary
activation of alkenes with a silyl
group is critical to address the
reactivity problem encountered
with nonsilylated alkenes and
serves as a device for the regiocon-
trol of the fluorocyclization event.
8
11a Z/E 12:1
11b Z/E>20:1
21a
21b
59
62
1:6[f,k]
1:11[f,l]
9
12a E/Z 6:1
22a
23a
54
80
6:1
3:1
À
The use of easy-to-handle N F
10
reagents is a particularly attractive
feature of the reaction. This study
forms a foundation for the develop-
ment of stereocontrolled syntheses
of enantiomerically enriched mono-
and polycyclic fluorinated hetero-
cycles. Full details will be disclosed
in due course.
13a E/Z=3:1
[a] Reaction conditions: A, NaHCO3, MeCN, room temperature when SiR3 is SiiPr3; B, NaHCO3, MeCN,
reflux when SiR3 is SiiPr2p-Tol. [b] The major isomer is shown. [c] Yield of the isolated product. [d] The cis/
trans ratio with respect to the silylmethyl and fluoro substituents at C2 and C3 was determined by
19F NMR spectroscopy of the crude product. [e] Reaction conditions: A, NaHCO3, MeCN, room
temperature. [f] The cis/trans ratio with respect to the fluoro substituent at C3 and the hydrogen atom at
C4 was determined by 19F NMR spectroscopy of the crude product. [g] cis/trans (C3,C4): 1.3:1. [h] trans/
cis (C3,C4): 4:1. [i] trans/cis (C3,C4): 1.7:1. [j] trans/cis (C3,C4): 1.6:1. [k] trans/cis (C3,C4): 3:1. [l] trans/cis
(C3,C4): 4:1.
Received: April 2, 2009
Revised: July 12, 2009
Published online: August 20, 2009
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McCullough, T. Rees, T. D. W. Claridge, V. Gouverneur, Org.
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[7] Competitive desilylation probably occurs in the case of low-
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Scheme 4. Asymmetric fluorocyclization of allyl silane 7b.
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Keywords: allyl silanes · asymmetric synthesis · cyclization ·
fluorination · oxidative cleavage
.
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[14] A control experiment was performed on a structurally related
nonsilylated diol. The reaction of this substrate with Selectfluor/
(DHQ)2PHAL at room temperature was extremely slow. After
12 days, 48% of the starting material was recovered along with
an aldehyde resulting from oxidation of the allylic alcohol in
16% yield and the fluorocyclized product (27% ee) in 36%
yield. See the Supporting Information for details.
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