Novel tartrate-based guanidines for enantioselective fluorination of 1,3-Dicarbonyl and α-cyano carbonyl compounds

Article abstract of DOI:10.1071/CH14179

A novel library of chiral guanidines featuring the tartaric acid skeleton is easily accessed with tunable steric and electronic properties. A guanidine molecule of this library with an incorporated 2,6-diisoaniline fragment was identified as a suitable promoter for the enantioselective fluorination of 1,3-dicarbonyl and α-cyano carbonyl compounds to furnish the fluorinated product with up to 84% ee and 99% yield using N-fluorobenzenesulfonimide (NFSI) as the fluorinating agent. CSIRO 2014.

Full text of DOI:10.1071/CH14179

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 1115–1118
Communication
http://dx.doi.org/10.1071/CH14179
Novel Tartrate-Based Guanidines for Enantioselective
Fluorination of 1,3-Dicarbonyl and a-Cyano
Carbonyl Compounds
A
A
A
A
Liwei Zou, Xiaoze Bao, Huanrui Zhang, Yuming Song,
A
A B
,
Jingping Qu, and Baomin Wang
A
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science
and Technology, Dalian University of Technology, Dalian 116024, China.
Corresponding author. Email: bmwang@dlut.edu.cn
B
A novel library of chiral guanidines featuring the tartaric acid skeleton is easily accessed with tunable steric and electronic
properties. A guanidine molecule of this library with an incorporated 2,6-diisoaniline fragment was identified as a suitable
promoter for the enantioselective fluorination of 1,3-dicarbonyl and a-cyano carbonyl compounds to furnish the
fluorinated product with up to 84 % ee and 99 % yield using N-fluorobenzenesulfonimide (NFSI) as the fluorinating agent.
Manuscript received: 31 March 2014.
Manuscript accepted: 28 April 2014.
Published online: 21 May 2014.
Within the domain of asymmetric organocatalysis, chiral
guanidines constitute a prominent catalyst class.[1] Generally,
their catalytic property arises from the combination of the
strong basicity of the guanidine moiety and the notable
hydrogen-bond donor capacity of its conjugate acid. To date, a
broad spectrum of asymmetric organic reactions have been
effected by chiral guanidine catalysis. Meanwhile, a diverse
range of guanidine catalysts have been designed with varying
chiral sources. Of particular note are the chiral scaffolds of
amino acids[2] and binaphthols,[3] which produced some lead-
ing guanidine molecules that exhibit prominent catalytic
activities and stereoselectivities. Despite these advances,
however, privileged[4] guanidine catalysts are very rare and the
full evolvement of this area is still hampered by the lack of a
skeleton that is both easily accessible and readily tunable in
terms of steric and electronic properties. Hence, the develop-
ment of chiral guanidines from simple precursors with readily
tunable steric and electronic factors for more asymmetric
applications is highly desirable.
Given the abundant availability and ready diversification of
tartaric acid and derivatives thereof, we have very recently
developed a novel library of chiral guanidines with ethyl tartrate
as the chiral source (Scheme 1).[5] The advantageous features of
this library of guanidines include the following points. First,
these guanidines are easily accessible, as can be seen from the
synthetic route; even though seven steps are needed, all are
routine, high-yielding operations. Second, the steric and elec-
tronic property of the guanidines can be readily tuned by varying
the changeable substituents Ar and R. Third, since any primary
or secondary amine can theoretically be incorporated in a
modular manner at the final stage of the guanidine synthesis,
the volume of this guanidine library can be exceptionally huge,
thereby ensuring the possibility of a high-throughput screening
for the best guanidine for a given reaction.
In a preliminary catalytic performance survey, we disclosed
that this library of guanidines showed remarkable catalytic
activity and enantioselectivity towards the asymmetric
a-hydroxylation of b-dicarbonyl compounds.[5a] In a further
Ar
NH
Ar
Ar
Ar
N
O
O
O
O
RNH2, CuCl, K2CO3
H
N
S
R
THF, 40ЊC
NH
Ar
NH
Ar
Ar
Ar
1: Yield: 60–93 %
1a: Ar ϭ Ph, R ϭ Bn
1b: Ar ϭ Ph, R ϭ 4-tert-butylbenzyl
1c: Ar ϭ Ph, R ϭ 9-anthracenylmethyl
1d: Ar ϭ Ph, R ϭ diphenylmethyl
1e: Ar ϭ Ph, R ϭ (S)-hydroxymethyl-tert-butylmethyl
1f: Ar ϭ Ph, R ϭ Cy
1g: Ar ϭ Ph, R ϭ 4-methylphenyl
1h: Ar ϭ Ph, R ϭ 2,6-dimethylphenyl
1i: Ar ϭ Ph, R ϭ 2,6-di-iso-propylphenyl
1j: Ar ϭ Ph, R ϭ 3,5-di-tert-butylphenyl
1k: Ar ϭ p-bisphenyl, R ϭ 2,6-di-iso-propylphenyl
O
n
N
HN
N
H
N
NH
N
O
O
H
N
3a: n ϭ 1
3b: n ϭ 2
N
N
H
N
2
4
Scheme 1. Catalysts used in this work.
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

1116
L. Zou et al.
Table 1. Survey of the base additives and solvent effect
Table 2. Further optimization of reaction conditions
O
O
O
O
NFSI, 1a, additives
NFSI, guanidine
Na2CO3, PhMe
O
O
O
O
O
O
solvent, rt
F
OR
F
OR
5a
6a
5a
6a
EntryA
R
Cat.
Na2CO3
[equiv.]
Time
[h]
Yield
[%]B
ee
[%]C
EntryA
Additive
Solvent
[mL]
Time
[h]
Yield
[%]B
ee
[%]C
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
1a
1b
1c
1d
1e
1f
1g
1h
1i
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.1
1.5
1.1
1.1
1.1
1.1
1.1
1.1
6
5.5
2
99
99
99
99
98
99
99
99
99
99
99
99
99
99
76
99
99
99
99
99
95
96
99
99
47
47
4
1
Na2CO3
K2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
6
99
99
45
99
99
50
99
99
99
99
99
99
99
99
99
99
47
42
32
34
29
40
33
32
47
36
26
28
34
14
16
35
2
2
3D
3 d
4 d
5
3
Li2CO3
4
8.5
4
1
4
Cs2CO3
5
ꢁ10
10
31
37
60
12
55
50
ꢁ17
ꢁ9
20
65
64
61
40
34
43
44
73
81
5
6D
K3PO4ꢀ3H2O
11
5 d
55
20
6
6
19
4.5
3
K2HPO4ꢀ3H2O
KF
Toluene
Toluene
Toluene
Toluene
PhCF3
7
7
8
8
KOAc
9E
10
11
12
13
14
15
16
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
9
8.5
4
10
11
12
13
14
15
16D
17D
18D
19D
20D
21D
22D
23E
24F
1j
1k
2
4
2
CH2Cl2
CHCl3
24
12
3
7
3a
3b
4
3
Et2O
8
THF
0.5
0.5
5
4
Dioxane
Methyl tert-
butyl ether
Ethyl acetate
Acetone
CH3CN
Toluene
1i
24
11.5
10
14
15
18
15
25
116
1i
1i
17
Na2CO3
Na2CO3
Na2CO3
Na2CO3
1.5
0.5
1
99
99
99
95
32
11
11
4
1i
18
iso-Pr
tert-Bu
Bn
1i
19
20F
1i
3.5
1i
AUnless otherwise noted, reactions were conducted with 5a (0.1 mmol), 1a
(10 mol-%), NFSI (0.12 mmol), and additive (0.1 mmol) in 1 mL of solvent
at room temperature.
Me
1i
Me
1i
AUnless otherwise noted, all reactions were carried out with 5a (0.1 mmol),
BIsolated yields.
CThe ee values were determined by HPLC (Chiralcel OD-H).
DNot completely reacted.
EFinely ground Na2CO3 powder was used.
FSelectfluor was used in place of NFSI.
catalyst (10 mol-%), NFSI (0.12 mmol), and additive (0.1–0.15 mmol) in
1 mL of toluene at room temperature.
BIsolated yields.
CThe ee values were determined by HPLC (Chiralcel OD-H).
D08C.
E–208C.
F–408C.
study, we found that this guanidine library can catalyze the
Michael addition of oxindoles to nitroolefins in high yields with
excellent diastereo- and enantioselectivities over an extraordi-
narily broad substrate scope.[5b] To further expand the catalytic
application of this chiral guanidine library, herein we report the
asymmetric fluorination of 1,3-dicarbonyl and a-cyano carbonyl
compounds under the catalysis of the tartrate-based guanidines.
Since the initial report by Hintermann and Togni on the catalytic
asymmetric fluorination of b-ketoesters with chiral titanium
(Table 1, entries 2–4). Further investigation on the use of other
inorganic bases afforded inferior ee values (Table 1, entries
5–8). The use of Na2CO3, which was ground into fine powders,
gave the same enantioselectivity (entry 9, 47 % ee). With
Na2CO3 as the additive and 1a as the catalyst, other solvents
were then surveyed and the results indicated that toluene
remained the solvent of choice (Table 1, entries 10–19). We
also attempted the use of Selectfluor in place of NFSI in
the presence of 10 mol-% of 1a in toluene using Na2CO3
(1.0 equiv.) as the additive at room temperature. However, the
reaction gave very poor enantioselectivity with 95 % yield
(Table 1, entry 20).
With the optimal base additive and solvent identified, other
reaction parameters were then examined. The amine moiety,
which was introduced at the final stage as an integral component
of the guanidine catalyst, has a marked influence on the
enantioselectivity of the hydroxylation reaction.[5a] The same
phenomenon was also seen in the fluorination reaction (Table 2,
entries 1–10). While benzyl amine derived guanidine 1a exhi-
bited promising enantioselectivity at room temperature, other
TADDOLate
(TADDOL ¼ a,a,a0,a0-tetraaryl-1,3-dioxolan-
4,5-dimethanol) complexes and Selectfluor,[6] both chiral metal
complexes[7] and organocatalysts[8] have been investigated for
this transformation. But, to our knowledge, no guanidine cata-
lyst has been documented for this reaction.
The enantioselective fluorination of indanone derived
b-ketoester was selected as a model reaction to identify optimal
reaction conditions. Base additives were first screened using the
model fluorination reaction of 5a in toluene with 10 mol-% of
1a and N-fluorobenzenesulfonimide (NFSI) as the fluorinating
reagent (Table 1, entries 1–8). When Na2CO3 was used as an
additive, the reaction was completed in 6 h with full conversion
and a promising enantioselectivity of 47 % ee (Table 1, entry 1).
While the reactions with K2CO3 and Li2CO3 were very sluggish,
Cs2CO3 reacted faster but afforded lower enantioselectivity

Tartrate-Based Guanidines for Organocatalysis
1117
sterically bulky amine-derived guanidine catalysts generally
showed poor enantiocontrol except for the 4-tert-butylbenzyl
amine derived guanidine which afforded 6a with the same
enantioselectivity as 1a (Table 2, entries 1–4). When bifunc-
tional catalyst 1e was used in the reaction, the enantioselectivity
of the product was reversed but with a very poor ee value
(Table 2, entry 5). Guanidine 1f derived from cyclohexylamine
also afforded poor enantiocontrol (Table 2, entry 6). To further
improve the enantioselectivity, aryl amine derived guanidines
were examined (Table 2, entries 7–10). While 4-methylaniline
and 2,6-dimethylaniline derived guanidines gave lower enan-
tioselectivities than 1a (Table 2, entries 7 and 8), to our delight,
2,6-diisopropylaniline-based guanidine 1i gave 60 % ee
(Table 2, entry 9). In sharp contrast, the guanidine derived from
3,5-di-tert-butylaniline gave a poor ee of 12 % (Table 2, entry
10). Further variation of the aryl groups at the 1,4-positions of
the tartaric acid backbone with p-bisphenyl functionality
decreased the enantioselectivity to 55 % ee (Table 2, entry
11). Cyclohexanone ketal catalyst 2 gave the product in good
yield but the ee value was lower (Table 2, entry 12). For
comparison, some amino acid based guanidine catalysts were
tested.[2c,d] The results indicated that these guanidines showed
inferior asymmetric induction compared with 1i (Table 2,
entries 13–15). Based on the above results, we then focussed
on the use of guanidine 1i for further screening efforts. Dropping
the temperature to 08C appreciably improved the enantioselec-
tivity (Table 2, entry 16), while changing the Na2CO3 loading
(Table 3, entries 17 and 18) had little effect on ee values. A brief
survey on the ester moiety of the substrate revealed that the
introduction of the sterically bulky group instead of methyl ester
group led to reduction of the reactivity and enantioselectivity in
the catalytic enantioselective fluorination reaction (Table 2,
entries 18–21). Finally, we found that the enantioselectivity of
this reaction was sensitive to temperature and lowering the
temperature to ꢁ408C gave the product in a reasonable 81% ee
and 99 % yieldwith a prolonged reaction time (Table 2, entry 24).
With the optimized conditions for the guanidine-catalyzed
asymmetric fluorination reaction in hand, the scope of the
substrate was investigated. The effect of the substituent identi-
ty and substitution pattern on the phenyl ring was first studied.
Both electron-withdrawing and electron-donating substituents
at the 5-position all gave the desired products in quantitative
yield with a reasonable level of enantioselectivity (Table 3,
6b–e). It was found that substitution at the 4- or 6-position
on the aromatic ring of the substrate did not obviously influ-
ence the efffciency of the asymmetric induction. For example,
the 4- and 6-methyl substituted substrates afforded slightly
decreased enantioselectivities of 75 and 78 % ee values (6f and
6g), respectively. Notably, the substrate with a six-membered
ring also underwent the fluorination reaction smoothly and a
good ee value and excellent yield was obtained (6h, 80 % ee,
90 % yield).
Table 3. Catalytic asymmetric fluorination of 1,3-dicarbonyl and
a-cyano carbonyl compounds
O
O
NFSI, 1i
R1
R1
R2
R2
Na2CO3, PhMe, Ϫ40ЊC
n F
n
5a–n
6a–n
O
O
O
O
O
O
O
O
O
F
F
F
F
Cl
6a
6b
6c
99 % yieldA,B
99 % yield
99 % yield
81 % eeC
84 % ee
84 % ee
O
O
O
O
O
O
O
F
O
O
F
F
MeO
Br
6d
99 % yield
78 % ee
6e
6f
98 % yield
93 % yield
75 % ee
79 % ee
O
O
O
F
O
CN
O
O
F
O
F
6g
6h
6i
84 % yield
82 % ee
98 % yield
90 % yield
78 % ee
80 % ee
O
O
O
O
O
CN
F
F
F
F
6j
6k
6l
89 % yield
91 % yield
99 % yield
40 % ee
39 % ee
33 % ee
O
O
O
O
O
O
O
MeO
F
Bn
6o
F
F
Cl
6m
6n
82 % yield
25 % ee
--% yieldD
--% ee
90 % yield
43 % ee
AUnless otherwise noted, all reactions were carried out with 5 (0.2 mmol),
1i (10 mol-%), NFSI (0.24 mmol), and Na2CO3 (0.22 mmol) in 2 mL of
toluene at ꢁ408C.
BIsolated yields.
CThe ee values were determined by HPLC.
DReacted for three days under the same reaction conditions.
In summary, we have developed a tartrate-based guanidine
catalyzed asymmetric fluorination reaction for 1,3-dicarbonyl
and a-cyano carbonyl compounds with NFSI as the fluori-
nating agent. A guanidine molecule with an incorporated 2,6-
diisoaniline fragment was identified as a suitable catalyst for this
reaction to furnish the fluorinated product with up to 84 %
enantioselectivity and 99 % yield. Studies towards extending
the catalytic applications of this chiral guanidine library for
other asymmetric transformations are currently underway in our
laboratory.
To further expand the utility of our guanidine catalysts, the
fluorination procedure was extended to a-cyano carbonyl and
b-diketone compounds. Six-membered cyclic a-cyano carbonyl
compound 5i under the same reaction conditions gave a good ee
value, but the corresponding five-membered product 6j was
obtained with a low ee value (Table 3). Cyclic b-diketones 5k–n
could be fluorinated smoothly but the enantioselectivity
was generally poor in comparison with b-ketoester substrates.
When an acyclic b-ketoester 5o was used, no obvious fluorina-
tion reaction occurred after three days under the same reaction
conditions.
General Procedure for the Fluorination of 1,3-Dicarbonyl
and a-Cyano Carbonyl Compounds
A Schlenk tube equipped with a magnetic stirrer bar was
charged with compound 5 (0.2 mmol) and toluene (2 mL),

1118
L. Zou et al.
followed by the guanidine catalyst 1i (0.02 mmol). The resulting
mixture was stirred at room temperature for 5 min before
cooling to ꢁ408C. To this mixture was then added NFSI
(0.24 mmol). After stirring at ꢁ408C for another 10 min, solid
Na2CO3 (0.22 mmol) was added to the resulting solution. The
resulting solution was stirred at ꢁ408C until complete con-
sumption of 5. The reaction mixture was allowed to warm to
room temperature and the solution of the crude product was
concentrated under vacuum. The residue was purified by
column chromatography on silica gel (light petroleum/ethyl
acetate) to give the product 6.
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Supplementary Material
Characterization data for guanidines 1 and 2, and compounds 6,
and copies of NMR spectra and HPLC traces are available on the
Journal’s website.
Acknowledgements
We thank the National Natural Science Foundation of China (Nos.
21076035, 20972022), the Program for New Century Excellent Talents in
University (NCET-11–0053), the Fundamental Research Funds for the
Central Universities (DUT13ZD202), and the Science and Technology
Department of Liaoning Province (No. 20102032) for support of this work.
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