Enantioselective fluoroamination: 1,4-addition to conjugated dienes using anionic phase-transfer catalysis

Article abstract of DOI:10.1002/anie.201302002

Chiral-anion phase-transfer catalysis (PTC) has been applied towards the enantioselective fluorocyclization reactions of 1,3-dienes. The method affords unprecedented fluorinated benz[f]isoquinoline and octahydroisoquinoline products in high yields and up

Full text of DOI:10.1002/anie.201302002

Angewandte
Chemie
Communications
Asymmetric Fluorination
H. P. Shunatona, N. Frꢀh, Y.-M. Wang,
V. Rauniyar, F. D. Toste*
&&&& — &&&&
Enantioselective Fluoroamination: 1,4-
Addition to Conjugated Dienes Using
Anionic Phase-Transfer Catalysis
Chiral-anion phase-transfer catalysis
(PTC) has been applied towards the
enantioselective fluorocyclization reac-
tions of 1,3-dienes. The method affords
unprecedented fluorinated benz[f]isoqui-
noline and octahydroisoquinoline prod-
ucts in high yields and up to 96% ee. New
fluorinated amine reagents outperformed
Selectfluor in the desired transformation.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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1
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DOI: 10.1002/anie.201302002
Asymmetric Fluorination
Enantioselective Fluoroamination: 1,4-Addition to Conjugated Dienes
Using Anionic Phase-Transfer Catalysis**
Hunter P. Shunatona, Natalja Frꢀh, Yi-Ming Wang, Vivek Rauniyar, and F. Dean Toste*
[
8,9]
The halogen-promoted cyclization reactions of alkenes is an
invaluable method for synthetic chemistry, generating
carbon–heteroatom bonds and providing access to a wide
precedented,
been rare.
reports using nitrogen nucleophiles have
Previous examples of enantioselective amino-
[
10–12]
fluorination reactions of isolated olefins have been disclosed,
but to the best of our knowledge the analogous transforma-
tion utilizing 1,3-dienes is unknown. Herein we report the first
catalytic asymmetric 1,4-aminofluorination of conjugated
[1]
range of products from relatively simple starting materials.
Recently, the development of enantioselective versions of
these reactions has become a topic of considerable interest for
[
2]
[13]
the synthetic community, as these reactions allow for the
dienes using chiral-anion phase-transfer catalysis.
[
3]
generation of vicinal stereocenters. Extension of this
reactivity to enantioselective 1,4-halofunctionalization of
Substrates of type 1 (Table 1) were chosen for this
investigation in the hope of achieving the desired fluoroami-
nation reaction. If successful, the 6-endo-trig fluoroamination
of diene substrate 1a would produce an allylic fluoride, an
important scaffold in many areas of chemistry. Addition-
ally, these products are fluorinated analogues of pharmaco-
logically relevant benz[f]isoquinolines, and because of the
unique pharmacological effect of substituting a fluorine for
a hydrogen atom, products of this reaction could be quite
interesting for biological studies.
1
,3-dienes requires controlling regio- (1,2- vs. 1,4-functional-
ization) and diastereoselectivity (syn vs. anti; Figure 1). While
[
14]
[
15]
With substrate 1a in hand, phase-transfer fluorination was
attempted using Selectfluor (3a), Na CO , and (R)-TRIP
2
3
(10 mol%) in fluorobenzene (Table 1, entry 3) without spe-
cial precautions to exclude air or water. To our delight, the
desired 1,4-fluoroamination product was formed, albeit with
poor selectivity (37% ee). After this encouraging result,
additional BINOL-derivatives were examined as phase-trans-
fer catalysts in hopes of enhancing the solubility and
selectivity of the fluorinating reagent without compromising
reactivity. The (R)-TCYP (entry 2) emerged as the optimal
catalyst, producing 2a in the highest enantiomeric excess.
Drastic effects on reactivity and selectivity were observed
depending on the identity and stoichiometry of the base
employed. Initial studies performed using sodium carbonate
(Na CO ) as an insoluble base suffered from poor conversion
Figure 1. Possible diastereomers resulting from 1,2- or 1,4-addition to
an acyclic olefin (a) or diene (b).
enantioselective oxidative 1,4-difunctionlization reactions of
[4]
conjugated dienes have been reported, enantioselective 1,4-
halofunctionalization reactions of 1,3-dienes have yet to be
[5]
developed.
Previous examples of 1,4-halofunctionalization reactions
have mainly utilized chlorine, bromine, or iodine electro-
2
3
(Table 1, entries 1–6). Other insoluble bases were then
evaluated to alleviate this problem. Various sodium salts
were chosen with basicities similar to Na CO . Sodium sulfite
[6]
philes in the presence of oxygen or nitrogen nucleophiles.
Due to their unique biological activity, the synthesis of
fluorine containing small molecules has recently received
2
3
(entry 7) did not perform as well as sodium carbonate, while
the use of dibasic sodium phosphate did not afford any of the
desired product (entry 8). However, tribasic sodium phos-
phate (Na PO ) resulted in 100% conversion of the starting
[
7]
a significant amount of interest. Aminofluorination, owing
to the ubiquity of amines as bioactive motifs, has been an
especially desirable transformation. While electrophilic fluo-
rination of olefins with oxygen nucleophiles has been well-
3
4
material (entry 9), forming the product in 82% ee. By
lowering the stoichiometry of the base in the reaction, the
enantioselectivity could be further improved to 89% ee with
full conversion of the starting material in fluorobenzene
[*] H. P. Shunatona, N. Frꢀh, Y.-M. Wang, Dr. V. Rauniyar,
Prof. Dr. F. D. Toste
Department of Chemistry, University of California—Berkeley
Latimer Hall, Berkeley, CA (USA)
(entry 10). Subsequent solvent and concentration screening
revealed that a,a,a-trifluorotoluene (PhCF ) was the ideal
3
solvent for the transformation (entries 11–14), affording 2a in
E-mail: fdtoste@berkeley.edu
9
6% ee with complete conversion of the starting material
(entry 13).
The configuration and absolute stereochemistry of the
major diastereomer was determined unambiguously by X-ray
[**] We would like to thank the University of California at Berkeley for
funding and David S. Tatum for X-ray crystallography analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302002.
2
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Table 1: Optimization of reaction conditions.
Having achieved an optimized
set of conditions, the scope of the
fluoroamination was examined for
various 1,3-dienes. Substitution at
various positions on the aryl ring of
the styrenyl fragment was well-tol-
erated (Table 2). A methyl group at
the ortho position displays the high-
est selectivity of 96% ee with > 20:1
d.r. (Table 2, entry 1). However,
a methyl group at the meta position
(entry 2) or an unsubstituted phenyl
ring (entry 3) gives slightly lower
selectivity but with no loss in yield.
Furthermore, without the ortho
substitution, the diastereoselectiv-
ity for the products 2b and 2c drops
to 5.9:1 and 6.9:1, respectively.
Dienes containing both electron-
rich and electron-poor aryl groups
are viable substrates in the fluoroa-
mination reaction (entries 6 and 7)
exhibiting excellent enantiomeric
excesses and increases in diastereo-
selectivity relative to an electroni-
cally neutral phenyl ring.
An electron-rich tetralone
derivative (entry 4) exhibited excel-
1
2
Entry
R
R
Base (Equiv)
Na CO (1.5)
Solvent, [m]
Conversion
ee
[%]
[
a]
[b]
[%]
1
2
3
4
5
6
7
8
9
3,5-(CF ) C H
H
H
H
H
C8H17
C8H17
PhF, [0.05]
PhF, [0.05]
PhF, [0.05]
PhF, [0.05]
PhF, [0.05]
PhF, [0.05]
PhF, [0.05]
PhF, [0.05]
PhF, [0.05]
PhF, [0.05]
30
50
50
80
70
100
33
0
100
100
50
46
92
37
50
88
16
80
–
82
89
93
91
96
97
3
2
6
3
2
3
2,4,6-(Cy) C H
2,4,6-(iPr) C H
2,4,6-(iPr) C H
2,4,6-(Cy) C H
Na CO (1.5)
3
6
2
2
3
Na CO (1.5)
3
6
2
2
2
2
3
Na CO (1.5)
3
6
2
3
Na CO (1.5)
3
6
2
3
Ph Si
Na CO (1.5)
3
2
3
2,4,6-(Cy) C H
2,4,6-(Cy) C H
2,4,6-(Cy) C H
2,4,6-(Cy) C H
2,4,6-(Cy) C H
2,4,6-(Cy) C H
2,4,6-(Cy) C H
2,4,6-(Cy) C H
C H
Na SO (1.5)
2 4
3
6
2
2
2
2
2
2
2
2
12 25
H
H
H
H
H
H
H
Na HPO (1.5)
3
6
2
4
Na PO (1.5)
3
6
3
4
10
11
12
13
14
Na PO (1.25)
3
6
3
4
Na PO (1.25)
PhCF , [0.05]
3
6
3
4
3
Na PO (1.1)
PhCF , [0.05]
73
100
56
3
6
3
4
3
Na PO (1.1)
PhCF , [0.10]
3
6
3
4
3
Na PO (1.0)
PhCF , [0.10]
3
6
3
4
3
1
[
a] Conversion determined by integration of H NMR spectra with internal standard. [b] % ee determined
by chiral-phase HPLC. Cy=cyclohexyl, iPr=2-propyl, Ph=phenyl.
lent selectivity and reactivity (93%
ee, 90% yield); however a slight
reduction in selectivity and yield is
crystallography of derivative 2c and shows that the aryl group
and the fluorine atom are anti on the newly formed hetero-
cycle (Scheme 1). The transition-state model in Scheme 1
accounts for the observed stereochemistry of the fluorine
stereocenter and is consistent with our previously established
observed for a chromanone-based substrate (entry 5). The
reaction also proved to be amenable towards a trisubstituted
styrene derivative (entry 8), forming compound 2h in excel-
lent selectivity (94% ee, > 20:1 d.r.).
Substrates 1d and 1e highlight the mildness of the
reaction conditions. These electron-rich substrates decom-
[13d,e]
model for enantioselective fluorination.
We hypothesized
that the diastereoselectivity could either arise from selective
anti-1,4-addition to the diene or through a stepwise process
that generates an equilibrating allyl cation in which one
isomer reacts preferentially. To distinguish these possibilities
Table 2: Substrate scope with Selectfluor.
(Z)-1c was subjected to the optimized reaction conditions and
showed no reactivity. This observation is most consistent with
1
,3
a concerted process that is prevented by the increased A
strain in the transition state for cyclization of (Z)-1c.
1
2
2
[c]
Entry Product
Ar
R
R
R
Yield ee
d.r.
[
a]
[b]
[%] [%]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
2-MeC H
H
H
H
H
H
H
H
nBu
H
H
H
-CH2- 91
-CH2- 92
-CH2- 90
96 >20:1
6
4
4
3-MeC H
92
92
93
91
95
93
5.9:1
6.9:1
6.9:1
5.5:1
10:1
6
C6H5
C6H5
C6H5
OMe -CH2- 90
H
H
H
H
O
85
4-CF C H
4
-CH2- 94
-CH2- 89
-CH2- 85
3
6
2g
2h
4-MeOC H
7.5:1
6
4
[
d]
C6H5
94 >20:1
[
[
a] Yield given after purification as a combination of both diastereomers.
b] % ee determined by chiral-phase HPLC. [c] d.r. calculated by
1
Scheme 1. Suggested origin of diastereo- and regioselectivity.
integration of H NMR spectra. [d] Reaction run in benzene.
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Communications
pose in a homogeneous acetonitrile solution of Selectfluor.
However, the phase-transfer conditions allow for clean
fluoroaminations in high yields with no observable decom-
position products.
Table 4: Utility of new electrophilic fluorination reagent.
Although far from the reactive center, substitution on the
benzamide arene exerts a surprisingly strong influence on
selectivity. The results in Table 3 highlight the advantage of
+
F
[c]
Table 3: Scope of benzamide moiety.
Entry
Source
Product
Ar
Yield
ee
[%]
d.r.
[
a]
[b]
[%]
[
d]
1
2
3
4
5
3a
6a
6a
6a
6b
6c
C6H5
C6H5
C6H5
<10
70
15
65
75
0
76
5
73
89
–
14:1
–
8.3:1
>20:1
3b
3c
3b
3b
2-MeC H
6
4
[
c]
Entry
Product
Ar
Yield
ee
[%]
d.r.
4-CF
3
C
6
H
4
[
a]
[b]
[%]
[a] Yield of isolated product given as combination of two diastereomers.
1
2
3
4
5
2i
2j
2k
2l
C6H5
95
96
97
82
0
86
92
90
88
–
6.3:1
8.7:1
7.5:1
8.8:1
–
[b] ee determined by chiral-phase HPLC; given as average of two runs.
[c] d.r. calculated by integration of F NMR spectra. [d] 1.5 equiv of 3a
used.
1
9
4-BrC H4
6
3,5-(MeO) C H
2
6
3
3,5-(CF ) C H
3
2
6
3
2m
2,4,6-(Me)
3
C
6
H
2
[
[
a] Yield given after purification as a combination of both diastereomers.
b] % ee determined by chiral-phase HPLC. [c] d.r. calculated by
1
integration of H NMR spectra.
Scheme 2. Preparation of new electrophilic fluorinating reagents.
using the 4-tert-butylbenzamide as the nucleophile. For
example, removal of all substitution on the benzamide aryl
ring afforded the product in 86% ee (Table 3, entry 1).
Selectivity is increased to 88–90% ee as substituents are
added to the meta positions of the benzamide (entries 3 and
transformation with 3b, albeit with modest yield and enan-
tioselectivity (entry 4). However, the electron-deficient spe-
cies 5c produced the cyclized product with the highest levels
of enantioselectivity (89% ee) for this substrate class
(entry 5).
4
), with a further enhancement to 92% ee when it is para-
substituted (Table 3, entry 2). Conversely, the benzamide 2m
Table 3, entry 5) containing methyl groups at both ortho
(
In conclusion, enantioselective 1,4-aminofluorocycliza-
tion of 1,3-dienes was developed using lipophilic chiral
phosphates as anionic phase-transfer catalysts. The mild
reaction conditions allow for the fluorination of substrates
that are typically incompatible with homogeneous Selectfluor
conditions. Despite the synthetic challenges of 1,4-function-
alization of these conjugated dienes, exclusive formation of
the 6-endo-trig cyclization was observed with varying levels of
diastereoselectivity. The resulting benz[f]isoquinoline deriv-
atives were formed with high levels of enantiomeric excess,
providing the first reported example of a metal-free catalytic
asymmetric 1,4-fluoroamination of conjugated dienes. This
reaction also expands the scope of competent nucleophiles in
our previously published PTC halocylization reactions to
nitrogen nucleophiles. Furthermore, a novel method for the
fluorination of dabconium salts was utilized to prepare a new
Selectfluor type derivative that was shown to have increased
reactivity relative to Selectfluor in preparing octahydroiso-
quinoline derivatives.
positions of the phenyl ring is unreactive under the reaction
conditions, as this substitution pattern twists the aryl ring out
of the amide plane.
[
16]
Our attention then focused on the fluorocyclization of
a less-reactive diene of type 5 (Table 4). When subjected to
the optimized reaction conditions using Selectfluor as the
electrophilic fluorine source, diene 5a reacted sluggishly,
affording racemic product with very low conversion (Table 4,
entry 1). We hypothesized that the electrophilicity of the
fluorine source could be increased by attaching an electron-
poor aryl group, which is more electron-deficient than the
chlorine atom on Selectfluor. Previous syntheses of Select-
fluor and its derivatives required the use of elemental fluorine
[17]
to install the fluorine atom onto dabconium intermediates.
To avoid the use of elemental fluorine, we developed a facile
method for preparation of novel Selectfluor-type derivatives.
By treating the known tetrafluoroborate salts 4 with XeF2,
different Selectfluor derivatives were synthesized in decent
yields (Scheme 2). Whereas Selectfluor was not synthetically
useful in the fluoroamination reaction with diene 5a, we were
pleased to find that reagent 3b outperformed Selectfluor and
derivative 3c, affording the octahydroisoquinoline product 6a
in good yield with 76% enantiomeric excess (Table 4,
entry 2). Substrate 6b, containing an ortho-methyl substituent
on the tethered phenyl ring, also underwent the desired
Experimental Section
General procedure for PTC reactions: Amide 1a (0.03 mmol,
1
1.0 mg), Selectfluor (0.045 mmol, 16.0 mg, 1.5 equiv), Na PO4
3
(0.033 mmol, 5.4 mg, 1.1 equiv), (R)-TCYP catalyst (0.003 mmol,
3.0 mg, 0.1 equiv), and a magnetic stir bar were added to a 3 mL
4
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3
6 h. During this time, the vial was periodically shaken to agitate
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2
3
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2 4
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2
2
2
(
9
R ꢀ 0.45 in 50:40:10). Product 2a was isolated as a white solid in
f
1% yield as a mixture of two diastereomers (0.025 mmol, 12.0 mg,
>
20:1 d.r.).
Received: March 9, 2013
Revised: May 3, 2013
Published online: && &&, &&&&
[
9] For enantioselective fluorocyclization using O-nucleophiles, see:
H.-F. Wang, H.-F. Cui, Z. Chai, P. Li, C.-W. Zheng, Y.-Q. Yang,
G. Zhao, Chem. Eur. J. 2009, 15, 13299.
Keywords: amination · asymmetric catalysis · cyclization ·
fluorine · phase-transfer catalysis
.
[
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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