Asymmetric electrophilic fluorocyclization with carbon nucleophiles

Article abstract of DOI:10.1002/anie.201304845

Twist of 'F'ate: Various helical-shaped fluorinated tetracyclic molecules were prepared by fluorocarbocyclization of prochiral alkenes. The development of a new class of chiral Selectfluor (1) proved instrumental in developing an asymmetric variant of this transformation. These novel chiral N-F reagents are readily accessible by fluorine transfer from shelf-stable N-fluoropyridinium salts. Copyright

Full text of DOI:10.1002/anie.201304845

Angewandte
Chemie
Communications
Synthetic Methods
J. R. Wolstenhulme, J. Rosenqvist,
O. Lozano, J. Ilupeju, N. Wurz,
K. M. Engle, G. W. Pidgeon, P. R. Moore,
G. Sandford,
V. Gouverneur*
&&&& — &&&&
Asymmetric Electrophilic
Fluorocyclization with Carbon
Nucleophiles
Twist of ‘F’ate: Various helical-shaped
fluorinated tetracyclic molecules were
prepared by fluorocarbocyclization of
prochiral alkenes. The development of
a new class of chiral Selectfluor (1)
proved instrumental in developing an
asymmetric variant of this transforma-
tion. These novel chiral N-F reagents are
readily accessible by fluorine transfer
from shelf-stable N-fluoropyridinium
salts.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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DOI: 10.1002/anie.201304845
Synthetic Methods
Asymmetric Electrophilic Fluorocyclization with Carbon
Nucleophiles**
Jamie R. Wolstenhulme, Jessica Rosenqvist, Oscar Lozano, John Ilupeju, Nathalie Wurz,
Keary M. Engle, George W. Pidgeon, Peter R. Moore, Graham Sandford, and
Vꢀronique Gouverneur*
The electrophilic halogenation reaction of olefins coupled
with cascade carbocyclization is an iconic biomimetic process
for the construction of complex molecules.[1] In 2007, Ishihara
and co-workers reported the first example of enantioselective
iodocarbocyclization of polyenes with N-iodosuccinimide,
a reaction promoted by stoichiometric quantities of a chiral
phosphoramidite nucleophile.[2] This system was less effective
for bromo- and chlorocarbocyclizations. Indeed, the enantio-
purity of the products was significantly lower with N-
bromosuccinimide, and the reaction did not proceed in the
presence of N-chlorosuccinimide. As a matter of fact, the
identification of competent electrophilic halogen sources
which allow high-yielding product formation is not trivial, and
conceptual advances to control enantioselectivity of these
complex processes are in high demand. Since 2007, progress
has been slow and in line with the well-recognized challenges
associated with halocyclizations involving carbon nucleo-
philes.[3]
nation/carbocyclization process for the synthesis of fluori-
nated carbocyclic products from prochiral precursors. A new
class of chiral N-F reagents based on the dicationic structural
core of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]-
octane bis(tetrafluoroborate) (Selectfluor) allowed access to
enantioenriched fluorocyclized products (Scheme 1).
To the best of our knowledge, the synthesis of enantioen-
riched fluorinated carbocycles from prochiral polyenes is
limited to the recent contribution of Gagnꢀ and co-workers
who reported a unique transformation using a chiral dicat-
ionic platinum catalyst.[4] However, this transition-metal-
catalyzed process is characterized by a stereoretentive elec-
trophilic fluorination of a cyclized cationic platinum/alkyl
intermediate and is therefore distinct from a mechanistic
scenario in which a fluorinated cation is formed prior to
p cyclization. Herein, we disclose the first metal-free fluori-
Scheme 1. Metal-free asymmetric halocyclization with a C nucleophile.
Tf =trifluoromethanesulfonyl.
In the first instance, we focused our efforts towards
developing a non-enantioselective version of the envisioned
transformation, since cation–p cyclizations induced by an
electrophilic fluorine source are not known (Table 1).[5] The
prototypical structure selected for validation and optimiza-
tion studies was the indene 1a bearing a 2-phenylethyl
substituent at the C2 position. The pendant phenyl group was
chosen as a C nucleophile to encourage chemo- and regiose-
lective electrophilic fluorination at the carbon–carbon double
bond. The resulting intermediate would undergo aryl cycliza-
tion leading to the tetracyclic fluorinated product 2a.
[*] J. R. Wolstenhulme, J. Rosenqvist, Dr. O. Lozano, J. Ilupeju,
N. Wurz, K. M. Engle, G. W. Pidgeon, Prof. V. Gouverneur
Chemistry Research Laboratory, University of Oxford
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: veronique.gouverneur@chem.ox.ac.uk
When 1a was reacted with 1.1 equivalents of Selectfluor in
acetonitrile in the presence of an excess NaHCO3 (3 equiv),
2a was formed together with the product 3a, which arises
from competitive capture of the fluorinated carbocationic
intermediate by the reaction solvent, acetonitrile (Table 1).[6]
Under these reaction conditions, 2a was isolated in 26% yield
(entry 1). Varying the reaction temperature or the nature of
the base did not prove beneficial (entries 2–4). N-Fluoroben-
zenesulfonimide (NFSI) was less satisfactory than Selectfluor
as this fluorinating agent led predominantly to 4a, thus
resulting from regioselective net NFSI addition across the
double bond. The formation of 4a with NFSI encouraged us
to reconsider Selectfluor. The replacement of acetonitrile
Dr. P. R. Moore
AstraZeneca Pharmaceutical Development
Macclesfield, Cheshire, SK10 4TG (UK)
Prof. G. Sandford
Department of Chemistry, Durham University
South Road, Durham, DH1 3LE (UK)
[**] We thank AstraZeneca (J.W.), the European Union (PIEF-GA-2008-
220034 to O.L), the EPSRC (J.W. and J.I.), the Skaggs-Oxford
Scholarship Program, and NSF GRFP (predoctoral fellowships to
K.M.E) for generous funding and Dr. Lorraine Combettes for
preliminary experimentation. V.G. holds a Royal Society Wolfson
Research Merit Award.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304845.
2
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Table 1: Fluorocarbocyclization of indene 1a.
Entry[a] N-F
Source[b]
Solvent T [8C] 1a/2a/3a/4a/5a[c]
2a
Yield [%][d]
1
2
3
A
MeCN
MeCN
MeCN
MeCN
MeCN
MeNO2
MeNO2
MeNO2
MeNO2
RT
0
0:29:63:0:8
0:26:69:0:5
81:3:14:0:2
19:22:49:0:10
56:10:0:33:1
0:93:0:0:7
0:96:0:0:4
0:86:0:0:14
0:98:0:0:2
26
–
–
–
–
59
89
72
92
A
A
A
B
A
C
C
C
À40
RT
RT
RT
RT
0
4[e]
5
6[f]
7[f]
8[f]
9[f]
40
[a] General conditions: 1a (50 mg), solvent (5 mL), NaHCO3 (3.0 equiv),
N-F reagent (1.1 equiv), 1 h. [b] A=Selectfluor, B=N-fluorobenzene-
sulfonimide (NFSI), C=N-fluoro-2,6-dichloropyridinium triflate.
[c] Determined by integration of the 1H NMR signals using 1-fluoro-3-
nitrobenzene as an internal reference. [d] Yield of isolated product.
[e] Reaction performed with 3 equivalents of K2CO3. [f] Reaction per-
formed in the presence of molecular sieves (3 ꢀ).
with nitromethane was found to be effective, thus delivering
2a in 59% yield. The reaction was further optimized using N-
fluoro-2,6-dichloropyridinium triflate in nitromethane at
408C. Under these optimal reaction conditions, 2a was
obtained in 92% yield. The use of freshly activated 3 ꢁ
molecular sieves (M.S.) was found to be critical to suppress
the formation of undesired fluorohydrin 5a.[7]
Scheme 2. Fluorocarbocyclization of indenes and 1,2-dihydronaphta-
lenes. Cs=4-chlorobenzenesulfonyl, Ms=methanesulfonyl, Ns=4-
nitrobenzenesulfonyl.
A series of variously C2-substituted indenes and 1,2-
dihydronaphthalenes effectively participated in the fluoro-
carbon-cyclization (Scheme 2).[8] The reaction tolerates sub-
stitution of the aryl C nucleophile at the para-position with
fluoro, chloro, and alkyl groups. Substrates with N-sulfonyla-
nilines acting as C nucleophiles also underwent successful
fluorocyclization to afford a range of novel fluorinated
tetrahydro-5H-indeno[2,1-c]quinolines and hexahydroben-
zo[k]phenanthridines which were isolated in yields ranging
from 52% to 99%. All products were formed exclusively as
the corresponding syn diastereomers. The stereochemical
assignment was based on the vicinal scalar coupling constant
between the fluorine and the hydrogen located at the ring
junction. These coupling constants were of the order of 15 Hz
for 2d–o and 21 Hz for 2a–c.[8] Single-crystal X-ray crystallo-
graphic analysis of 2i [3J(F6a,H12b) = 14.7 Hz] revealed its
nonplanar helical structure and confirmed that the fluorine
substituent is disposed syn to the hydrogen atom at C12b
(Figure 1).[8]
Figure 1. Structure of 6a-fluoro-5,6,6a,7,8,12b-hexahydrobenzo-
[c]phenanthrene (2i) from single-crystal X-ray diffraction data.
developed in the context of fluorocyclization with heteroatom
nucleophiles. The reaction of 1a with chiral N-F reagents
derived from cinchona alkaloids (type A[9]; Figure 2) failed to
proceed.[8] This result contrasts with the ability of these
reagents to promote asymmetric fluoroheterocyclization of
more nucleophilic substrates, including allylsilanes[10] and
indoles.[11] The recovery of 1a upon treatment with type A N-
F reagents highlights the difference of reactivity between N-F
reagents derived from quinuclidine and 1,4-diazabicyclo-
[2.2.2]octane (DABCO). We next considered chiral anion
phase-transfer catalysis.[12] This catalytic manifold was applied
by Toste and co-workers to Selectfluor, a cationic reagent
insoluble in nonpolar media.[13] In the presence of bulky chiral
phosphate (10 mol%), anion exchange with tetrafluoroborate
Our next goal was the development of an asymmetric
variant of this reaction. Preliminary experiments revealed the
limitations of currently available strategies for (catalytic)
asymmetric electrophilic fluorination, many of which were
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Figure 2. Chiral N-F reagents of types A, B, and C.
brings the N-F reagent into solution, thus allowing catalytic
asymmetric fluoroheterocyclization of various substrates
inclusive of 1,2-dihydronaphthalenes. Conceptually, this cata-
lytic system relies on in situ formation of chiral Selectfluor of
type B (Figure 2), in which the stereogenic elements are
located on the anionic component. In the present reaction, we
found that no reaction occurred when 1a was reacted with
1.5 equivalents of Selectfluor, 1.25 equivalents of NaHCO3,
and 10 mol% of the chiral phosphonic acid (R)-TRIP (3,3’-
bis(2,4,6-triisopropylphenyl)-1,1’-binaphthyl-2,2’-diylhydro-
genphosphate) in hexanes. The use of nitromethane instead of
hexanes induced fluorocarbocyclization, but as expected, this
polar solvent afforded 2a as a racemate. Similarly, the indene
1d did not react upon treatment at room temperature for
24 hours with Selectfluor (1.5 equiv), NaHCO3 (1.5 equiv),
and 10 mol% of (R)-TRIP using hexanes, hexanes/fluoro-
benzene (1:1), or fluorobenzene as solvent.[8]
At this point, we considered a new approach to access
enantioenriched fluorocarbocycles resulting from cation–p
cyclization induced by an electrophilic fluorine source. Our
studies in the racemic series informed us that the critical
components necessary to convert 1a into 2a are the combined
used of nitromethane as the solvent and either Selectfluor or
N-fluoro-2,6-dichloropyridinium triflate as the fluorine
source. These considerations led us to design a new class of
chiral N-F reagents (type C; Figure 2) which are based on the
structural core of Selectfluor with the stereogenic elements on
the dicationic DABCO core. These chiral Selectfluor deriv-
atives are predicted to be more reactive than the type A N-F
reagents and offer a platform to investigate how solubility,
reactivity, and enantiocontrol can be tuned by varying the
R substituents of the DABCO core.
To this end, the chiral N-F reagents (2R,3R)-6a, (2S,3S)-
6b, and (2S,3S)-6c, substituted with phenyl, p-(trifluorome-
thyl)phenyl, and o-toluoyl groups, respectively, were prepared
(Scheme 3). The chiral DABCO (2R,3R)-7a was a necessary
precursor to access (2R,3R)-6a. This compound was assem-
bled from the corresponding enantiopure vicinal diamine
using a protocol disclosed by Oi and Sharpless.[14] N-Quater-
nization of (2R,3R)-7a performed with methyl triflate
afforded (2R,3R)-8a in 97% yield. The subsequent fluorina-
tion was achieved using fluorine gas (10% v/v in N2) in
acetonitrile (Method 1). Extensive optimization varying the
amount of F2, the reaction temperature, and the concentra-
tion was essential to identify reaction conditions which
suppressed indiscriminate fluorination of the aryl groups.
The best reaction conditions offered (2R,3R)-6a in 97%
Scheme 3. Chiral reagents (2R,3R)-6a, (2S,3S)-6b, and (2S,3S)-6c.
DMAP=4-(dimethylamino)pyridine, DMF=N,N-dimethylformamide,
THF=tetrahydrofuran.
yield. Pleasingly, (2R,3R)-6a could also be prepared at room
temperature in acetonitrile using commercially available N-
fluoropentachloropyridinium triflate[15] in the presence of
sodium bicarbonate (Method 2). This latter protocol is
advantageous as it allows in situ formation of chiral Select-
fluor reagents of type C[8] as an alternative to the use of
isolated reagents. The chiral N-F reagents (2S,3S)-6b and
(2S,3S)-6c were prepared in comparable yields by applying
the same reaction sequence.[8]
Asymmetric fluorocyclization of 1d was carried out in the
presence of the chiral N-F reagents (2R,3R)-6a, (2S,3S)-6b,
and (2S,3S)-6c (Table 2).[8] For this study, the reaction solvent
was reconsidered since we suspected that the solubility profile
of the chiral reagents 6a–c might differ from that of
Selectfluor. All reagents mediated the conversion of 1d into
the enantioenriched 2d when the reaction was performed in
nitromethane, with each giving drastically different reactivity
and enantioselectivity (entries 1–3). The reagent (2S,3S)-6b
with the para-electron-withdrawing CF3 substituents on the
aryl rings was the most reactive, as 1d was entirely converted
into 2d (entry 2). Collectively, these experiments demon-
strate that one can tailor the reactivity of this new class of
chiral reagents by varying the steric and electronic properties
of the substituents located at C2 and C3. Pleasingly, (2S,3S)-
6b was also the most effective for enantiocontrol as 2d was
formed in 60% ee. The reagents (2R,3R)-6a and (2S,3S)-6c
gave ee values of 32% and 55%, respectively. Based on this
lead result, all subsequent reactions were performed with
(2S,3S)-6b. The reaction solvent had an influence on yield and
ee value (entry 4–10). The compound 2d was obtained with
81% ee in THF but with a significant decrease in yield
(entry 6). 1,4-Dioxane afforded 2d in 88% yield and 74% ee
(entry 7). The nature of the inorganic base had no effect on
the ee value but substituting NaHCO3 with K2CO3 or Cs2CO3
was detrimental to the yield (entries 12 and 13). Notably, the
ee value was found to be 74% when the reaction was
performed at either 508C or 108C (entries 14 and 15). Thus,
under the optimized reaction conditions, treating 1d with
4
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Table 2: Asymmetric fluorocarbocyclization of 1d.
Entry Solvent
N-F Source 1d
Recovery [%][a]
Yield [%][a] ee [%][b]
1
2
MeNO2
MeNO2
MeNO2
CH2Cl2
DCE
(2R,2R)-6a
(2S,2S)-6b <5
(2S,2S)-6c
(2S,2S)-6b
(2S,2S)-6b
(2S,2S)-6b
18
63
>95
44
14
59
22
88
0
14
37
62
39
23
46
47
13
48
À32
60
55
77
74
81
74
–
72
52
76
76
79
74
74
80
80
3[c]
4
38
65
30
6
5
6
7
8
9
10
THF
1,4-dioxane (2S,2S)-6b <5
DMF
acetone
MeCN
Scheme 4. Synthesis of enantioenriched fluorotetrahydro-5H-indeno-
(2S,2S)-6b
(2S,2S)-6b
(2S,2S)-6b
92
50
26
38
47
67
39
34
84
32
[2,1-c]quinolones. Structure of (6aR,11bR)-2d from single-crystal X-ray
diffraction data.[17]
11[d] 1,4-dioxane (2S,2S)-6b
12[e]
13[f]
14[g]
1,4-dioxane (2S,2S)-6b
1,4-dioxane (2S,2S)-6b
1,4-dioxane (2S,2S)-6b
operationally simple using shelf-stable N-fluoropyridinium
salts, which require no special handling procedures. These
novel N-F reagents, with their dicationic chiral DABCO core,
may find applications for the asymmetric fluorination of other
substrates which are problematic using currently available
strategies. Since the solubility profile of this new class of chiral
N-F reagents can be tuned through variation of the substitu-
ents located on the DABCO core, it should be possible to
adapt these chiral dicationic salts for use in phase-transfer
catalysis.[18] Probing these principles with an eye towards the
development of catalytic asymmetric fluorocarbocyclization
and other challenging transformations is the subject of
a current study in our laboratory.
15[h] 1,4-dioxane (2S,2S)-6b
16[i]
17[j]
1,4-dioxane (2S,2S)-6b
1,4-dioxane (2S,2S)-6b
[a] Determined by 1H NMR spectroscopy using 1-fluoro-3-nitrobenzene
as internal reference. [b] Determined by HPLC on a chiral stationary
phase. [c] N-F Reagent prepared in situ. [d] NaHCO3 replaced with
Na2CO3 (3 equiv). [e] NaHCO3 replaced with K2CO3 (3 equiv).
[f] NaHCO3 replaced with Cs2CO3 (3 equiv). [g] Reaction at 508C.
[h] Reaction at 108C. [i] Concentration: 0.0025m. [j] Concentration:
0.025m. DCE=1,2-dichloroethane.
3 equivalents of NaHCO3 and 1.5 equivalents of (2S,3S)-6b in
1,4-dioxane at room temperature for 1 hour afforded (+)-2d Experimental Section
General procedure for asymmetric fluorocarbocyclization with
in 62% yield and 76% ee.
(2S,3S)-6b prepared in situ: N-fluoro-pentachloropyridinium triflate
(1.5 equiv) was added to a solution of pro-reagent (2S,3S)-8b
(1.5 equiv) and NaHCO3 (3.0 equiv) in 1,4-dioxane (2.5 mL) over
3 ꢁ molecular sieves at room temperature and the reaction was
stirred overnight. The prochiral indene was added and the reaction
was stirred for 1–3 h before being concentrated in vacuo. Purification
by silica gel column chromatography (EtOAc/petroleum ether)
afforded the enantioenriched fluorocarbocyclized products.
A series of enantioenriched fluorotetrahydro-5H-indeno-
[2,1-c]quinolines was obtained by applying this protocol, with
yields reaching 99% and ee values averaging 71%. Hexahy-
drobenzo[k]phenanthridine (2j) was formed in 83% yield
with a diminished ee value of 19%, thus indicating that
structural variation of the substrate can have a dramatic
influence on the ee value (Scheme 4). The absolute config-
uration of 2d was assigned as (6aR,11bR) by single-crystal X-
ray crystallographic analysis,[8,16] which also confirmed the syn
stereochemistry at the ring junction [3J(F6a,H11b) = 15.7 Hz].
This fluorocarbocyclization process is a unique example of
asymmetric synthesis leading to enantioenriched fluorine-
containing helical molecular motifs.
The fluorocarbocyclization presented herein generates
various tetracyclic molecules possessing a carbon–fluorine
quaternary stereocenter. These compounds would be difficult
to access using alternative approaches. The design and
preparation of a new class of chiral Selectfluor N-F reagents
led to the successful development of an asymmetric variant of
this fluorocarbocyclization reaction. These reagents, which
are soluble in 1,4-dioxane or THF, are readily synthesized
from chiral DABCO derivatives and commercially available
N-fluoro-pentachloropyridinium triflate. Their preparation is
Received: June 5, 2013
Published online: && &&, &&&&
Keywords: asymmetric synthesis · cyclization · fluorine ·
.
helical structures · synthetic methods
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[18] For an example of dicationic phase-transfer catalyst, see:
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[7] W. Wang, B. Xu, G. B. Hammond, Synthesis 2011, 2383 – 2386.
[8] For details, see the Supporting Information.
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