2,2-Difluoro-1,3-diketones as gem-Difluoroenolate Precusors for Asymmetric Aldol Addition with N-Benzylisatins

Article abstract of DOI:10.1002/adsc.201600392

2,2-Difluoro-1,3-diketones are introduced as gem-difluoroenolate precursors for the first example of an organocatalytic asymmetric aldol addition with N-benzylisatins to form 3-difluoroalkyl-3-hydroxyoxindoles. (Figure presented.).

Full text of DOI:10.1002/adsc.201600392

UPDATES
DOI: 10.1002/adsc.201600392
2,2-Difluoro-1,3-diketones as gem-Difluoroenolate Precusors for
Asymmetric Aldol Addition with N-Benzylisatins
Jinlong Qian,a Wenbin Yi,a,* Xin Huang,b Jerry P. Jasinski,c and Wei Zhangb,*
a
School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing
210094, Peopleꢀs Republic of China
E-mail: yiwb@njust.edu.cn
Department of Chemistry, University of Massachusetts Boston; 100 Morrissey Boulevard, Boston, MA 02125, USA
b
E-mail: wei2.zhang@umb.edu
Department of Chemistry, Keene State College; Keene, NH 03435-2001, USA
c
Received: April 12, 2016; Revised: June 15, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600392.
Abstract: 2,2-Difluoro-1,3-diketones are introduced
as gem-difluoroenolate precursors for the first ex-
ample of an organocatalytic asymmetric aldol addi-
tion with N-benzylisatins to form 3-difluoroalkyl-3-
hydroxyoxindoles.
semble 2,2-difluoro-3-hydroxy ketones I have attract-
ed more attention. a,a-Difluoroketones IIa,[8] a,a,a-
trifluoro-ketones IIb,[9] a,a-difluoro-b-ketone-gem-
diols IIc,[10] a,a-difluoro-a-(trimethylsilylacet)amides
IId,[11] and a,a-difluoro-b-ketoesters IIe[12] have been
developed as precursors for a,a-difluoroenolates III
(Scheme 1À). The a,a-difluoromethylsulfone anion
(RSO2CF2 ) derived from PhSO2CF2TMS or
PhSO2CF2H has also been reported for nucleophilic
additions.[13] Asymmetric nucleophilic additions of
a,a-difluoroenoxysilanes or a,a-difluoroenolates with
isatins 1 to prepare 3-hydroxy-3-difluoroalkyl-substi-
tuted oxindoles 3 have been documented (Scheme 2).
Keywords: difluoroalkylation; 2,2-difluoro-1,3-dike-
tones; difluoroenolates; enantioselectivity; organo-
catalysis
Special chemical and biological properties associated But so far only the organocatalytic reaction of difluor-
with fluorinated molecules have encouraged chemists oenol silyl ether IV reported by Zhouꢀs group is suc-
to develop new fluorination reactions, especially in an cessful.[6] The Fang and Wu groups developed an or-
asymmetric fashion.[1] The carbonyl a-position is an ganocatalytic aldol reaction of a-monofluoro-b-
important place for fluorine insertion.[2] Shown in ketone-gem-diols IIc’ for monofluorinated oxindoles
Figure 1 are representative biologically active oxin- 3’.[4a] But this failed for the reaction of IIc to afford
doles bearing hydroxy and alkyl groups at the C-3 po- difluorinated oxindoles 3. We have recently reported
sition.[3] Mono- and difluorination of the carbonyl a- the deacylation of 2-fluoro-1,3-dicarbonyls for making
position of such compounds is a topic of current inter- a-fluoro-a,b-unsaturated carbonyl compounds.[14] We
est.[4–6]
Compared to using a-fluorinated ketones as nucleo-
philes,[7] aldol additions using a,a-difluoroenoxysila-
nes[6a,b] or a,a-difluoroenolates as nucleophiles to as-
Scheme 1. Methods for the preparation of a,a-difluoroeno-
lates III.
Figure 1. Bioactive 3-hydroxy-3-alkyloxindoles.
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ments in yield and ee were obtained by running the
reactions in MeOH at lower temperature but with in-
creased time (entries 20–22). A 7.7 mmol (2 g)-scale
reaction of 2a gave a similar yield and ee as the
0.2 mmol-scale reaction, which demonstrates the scale
up capability of this reaction (entry 23). The absolute
configuration of product 3aa was determined by com-
parison with literature data and also by X-ray crystal-
lographic analysis (Table 1).[4a,6a]
With the optimized reaction conditions in hand, we
investigated the substrate generality using different
N-substituted isatins 1a–k and 2,2-difluoro-1,3-dioke-
tones 2a–j (Table 2). Reactions of N-benzylisatin 1a
with 2a–j afford the corresponding products 3aa–aj in
good to excellent yields (82–95%) and ee (66–92%)
(Table 2, entries 1–9). The position and electronic
property of the substituents on the phenyl rings have
no significant impact on the yield. The reaction of 2h,
which has a 2-fluorophenyl as R3, gave 3ah with a de-
creased ee (66%) (entry 8). The reaction of 2k, which
has Me instead of Ar as R3, gave 3ak in low yiled
Scheme 2. Asymmetric aldol additions towards fluorinated
oxindoles 3.
also found that readily available 2,2-difluoro-1,3-dike- (42%) and decreased ee (63%) (entry 11). The config-
tones 2 could be deacylated under basic conditions to uration of 3ak was confirmed by comparison with the
form a,a-difluoroenolates III.[15] We envisioned that literature data.[4a,19] Reactions of 2a with N-substituted
difluoro-1,3-diketones 2 could be a new synthon for isatins 1a–k were also conducted. Substitutions such
organocatalytic aldol reactions.
as halogen atoms and electron-donating MeO group
Results obtained from the initial reactions of N- on the aromatic ring of 1 are tolerated to give prod-
benzylisatin 1a with 2,2-difluoro-1,3-diones 2a in the ucts 3 in excellent yields (82–93%) with good ee (62–
presence of different Cinchona alkaloid-thiourea or- 98%) (Table 2, entries 12–19). Reactions of N-methyl-
ganocatalysts C-1 to C-5 are shown in Table 1.[16] isatin 1j and N-phenylisatin 1k also gave the corre-
Using CH2Cl2 as a solvent at room temperature reac- sponding compounds 3ja and 3ka in good yields (79%
tions catalyzed with C-1 and using AcOH or benzoic and 58%), but slightly low ee (79% and 58%) (en-
acid as an additive[4a] only gave a trace amount of tries 20 and 21).
product 3aa after 72 h (Table 1, entries 1 and 2).
Two control reactions were conducted to gain
When the additive was changed from acids to a base mechanistic insights of the aldol reaction of difluoroe-
(NH3), the reaction occurred at room temperature, nolates. The first one is a reaction of isatin 1a with
but had a poor ee (entry 3). Reactions at lower tem- monofluoro-1,3-diketone 4 under C-3 catalysis. Com-
perature and for longer reaction time did not increase pound 5 was obtained in 97% yield, but with neither
the ee, but significantly decreased the yields (entries 4 diastereoselectivity nor enantioselectivity (Scheme 3,
and 5). To our surprise, an acceptable yield (78%) A). This may suggest that the asymmetric aldol reac-
and ee (55%) were obtained from a reaction without tions of a-fluoro-1,3-diketones take a different path-
using an additive (entry 6). Screening of different cat- way from that of a-flourinated-b-ketone-gem-diols re-
alysts C1–C4 revealed that C-3 is the winner (en- ported in Fang and Wuꢀs work.[4a] The second control
tries 6–9). Further optimization of the conditions by reaction of difluoro-1,3-dione 2l which has two differ-
variation of solvent, reaction temperature and time ent substitution groups on the phenyl rings was con-
showed that the C-3 catalyzed reaction in MeOH for ducted to verify if two enolates could be generated
48 h at room temperature could afford 3aa in 91% from the deacylation of 2l. Indeed, the reaction of
yield and 92% ee (entry 15). The reaction with a fluo- 1.5 equiv. of 2l with 1a generated 3af and 3ad in 46%
rous organocatalyst C-5 gave a similar result as that and 43% yields, and 80% and 76% ee, respectively
with C-3 (entry 16).[17] Recyclable C-5 could be easily (Scheme 3, B).
isolated from the reaction mixture by fluorous solid-
Monitoring the reaction of 1a and 2g (Table 2,
phase extraction (F-SPE).[18] To evaluate the effect of entry 7) by 19F NMR allowed us to observe the pro-
MeOH on the catalysis process, reactions using cess of deacylation of 2g to form difluoroenolate 6g,
MeOH as an additive or a co-solvent were conducted as well as methyl 4-fluorobenzoate by-product (see
(entries 17–19). These reactions gave good yields and the Supporting Information). Based on our experi-
ee, albeit slightly lower than that from the reaction mental results and literature information,[6] a mecha-
using MeOH as a solvent (entry 15). No improve- nism for the organocatalytic aldol addition involving
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Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst [10 mol%] Additive [20 mol%] Solvent
Temperature [oC] Time [h] 3aa [%][b] ee [%][c]
1
2
3
4
5
6
7
8
C-1
C-1
C-1
C-1
C-1
C-1
C-2
C-3
C-4
C-3
C-3
C-3
C-3
C-3
C-3
C-5
C-3
C-3
C-3
C-3
C-3
C-3
C-3
AcOH
PhCOOH
NH3
NH3
NH3
–
–
–
–
–
–
–
–
–
–
–
MeOH 50 mol%
MeOH 300 mol%
–
–
–
NH3
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
PhMe
MeOH
DMF
iPrOH
MeOH
MeOH
CH2Cl2
CH2Cl2
25
25
25
0
72
72
24
72
72
72
72
72
72
72
72
72
72
72
48
48
72
72
48
24
72
72
48
trace
trace
83
32
trace
78
79
89
80
81
66
93
90
67
91
87
87
89
–
–
5
40
–
À20
25
25
25
25
25
25
25
25
25
25
25
25
25
55
49
75
62
73
58
89
71
82
92
90
77
81
84
88
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23[d]
CH2Cl2/MeOH=1/1 25
83
76
trace
46
93
MeOH
MeOH
MeOH
MeOH
25
0
0
40
90
25
[a]
Reaction of 1a (0.2 mmol), 2a (0.3 mmol) and catalyst (0.02 mmol).
Isolated yield.
Determined by chiral HPLC.
[b]
[c]
[d]
Scale-up reaction with a 2 g scale of 1a.
difluoroenolate is proposed in Scheme 4. The deacyla- nolate from the favorable Re face of isatin affords the
tion of 2a catalyzed with C-3 results in difluoroenlate (S)-enantiomer as the aldol addition product.[6,21]
6a.[20] It is then paired with the bridgehead amino
In conclusion, the first example of aldol addition of
group of C-3. The aldol reaction is activated by the difluoroenlates derived from 2,2-difluoro-1,3-dike-
hydrogen bonds between two hydrogens in the thiour- tones with isatins is introduced. The reactions are pro-
ea and two carbonyls in isatin. The transition state of moted with a Cinchona alkaloid-thiourea bifunctional
the complex is arranged in a way where the unfavora- organocatalyst to afford various 3-hydroxy-3-difluoro-
ble interaction between the isatin benzene ring and
ACHTUNGTRENaNGNU lkylated oxindoles in good yields and enantioselec-
the enolate could be avoided. Attack of the difluoroe- tivities. Readily available difluoroenlate precursors
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Table 2. Scope of the reactions with isatins 1 and 2.[a]
Entry
R1/R2
R3
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
H/Bn (1a)
H/Bn (1a)
H/Bn (1a)
H/Bn (1a)
H/Bn (1a)
H/Bn (1a)
H/Bn (1a)
H/Bn (1a)
H/Bn (1a)
H/Bn (1a)
H/Bn (1a)
4-Br/Bn (1b)
5-Me/Bn (1c)
5-OMe/Bn (1d)
5-Cl/Bn (1e)
5-F/Bn (1f)
6-Cl/Bn (1g)
6-Br/Bn (1h)
7-F/Bn (1i)
H/Me (1j)
H/Ph (1k)
Ph (2a)
48
48
48
48
36
48
36
36
36
36
36
48
48
48
48
48
48
48
48
48
48
91 (3aa)
87 (3ab)
82 (3ac)
80 (3ad)
89 (3ae)
95 (3af)
91 (3ag)
88 (3ah)
93 (3ai)
85 (3aj)
42 (3ak)
85 (3ba)
89 (3ca)
87 (3da)
85 (3ea)
82 (3fa)
90 (3ga)
88 (3ha)
89 (3ia)
87 (3ja)
93 (3ka)
92
75
88
74
86
82
79
66
88
77
63
70
89
70
84
98
90
92
62
79
58
4-MeC6H4 (2b)
3-MeC6H4 (2c)
4-t-BuC6H4 (2d)
4-ClC6H4 (2e)
4-BrC6H4 (2f)
4-FC6H4 (2g)
2-FC6H4 (2h)
4-CF3C6H4 (2i)
2-thienyl (2j)
Me (2k)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
9
10
11
12
13
14
15
16
17
18
19
20
21
[a]
Reaction of 1a (0.2 mmol), 2 (0.3 mmol, C-3 (0.02 mmol) in MeOH (1.5 mL).
Isolated yield.
Determined by HPLC.
[b]
[c]
Scheme 3. Control reactions.
Scheme 4. A proposed mechanism.
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centrated and purified by column chromatography to afford
the decarboxylative aldol products 3.
and scalability of the reaction make it a feasible
method for asymmetrical introduction of difluorome-
thene and hydroxy groups through the aldol addition.
Acknowledgements
Experimental Section
We acknowledge the financial support from the Natural Sci-
ence Foundation of China (21476116) and Jiangsu
(BK20141394), Priority Academic Program Development of
Jiangsu Higher Education Institutions, the Center for Ad-
vanced Materials and Technology in Nanjing University of
Science and Technology, and the University of Massachusetts
Boston (Joseph P. Healey grant).
General Information
All reactions were run using flame-dried glassware and mag-
netic stirring. Chemicals and solvents were purchased from
commercial suppliers and used as received. 1H, 19F and
13C NMR spectra were recorded on a 500 MHz Bruker
DRX 500 and tetramethylsilane (TMS) was used as a refer-
ence. Chemical shifts are reported in parts per million
(ppm), and the residual solvent peak was used as an internal
reference: proton (chloroform d=7.26, acetone d=2.09,
DMSO d=2.50), carbon (chloroform d=77.0, acetone d=
205.87, 30.60, DMSO d=40.45). GC-MS were performed on
an ISQ Trace 1300 (electrospray ionization: EI). For thin-
layer chromatography (TLC), Sorbent silica gel XHL TLC
plates (130815) were used, and compounds were visualized
with a UV light at 254 nm. Melting points were measured
on a melting point apparatus and are uncorrected. Mass
spectra were recorded on the Waters Q-Tof microTM (elec-
trospray ionization: ESI). HPLC analysis was performed on
an Agilent1200 instrument with a Daicel Chiralpak AD-H
column.
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Synthesis of 2,2-Difluoro-1,3-diones 2
Step A: To a suspension of ketone (10 mmol) in THF
(40 mL) was added NaH (0.8 g, 20 mmol, 60%). After the
reaction mixture was stirred at 08C for about 1 h, the ester
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These are not the final page numbers!

UPDATES
2,2-Difluoro-1,3-diketones as gem-Difluoroenolate
Precusors for Asymmetric Aldol Addition with N-
Benzylisatins
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Adv. Synth. Catal. 2016, 358, 1 – 7
Jinlong Qian, Wenbin Yi,* Xin Huang, Jerry P. Jasinski,
Wei Zhang*
Adv. Synth. Catal. 0000, 000, 0 – 0
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ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!