1,4-Diazabicyclo[2.2.2]octane-Promoted Aminotrifluoromethylthiolation of α,β-Unsaturated Carbonyl Compounds: N-Trifluoromethylthio-4-nitrophthalimide Acts as Both the Nitrogen and SCF3 Sources

Article abstract of DOI:10.1021/acs.orglett.5b03116

A novel difunctionalization reaction is described. It uses N-trifluoromethylthio-4-nitrophthalimide as the reagent, which serves as both the nitrogen and SCF₃ sources. In the presence of DABCO (1,4-diazabicyclo[2.2.2]octane), the nitrogen and SCF₃ groups can be incorporated into α,β-unsaturated carbonyl compounds easily and give versatile β-amino ketones and esters in good yields. This difunctionalization reaction features mild reaction conditions, high atom-economy, and efficient access to α-SCF₃ amino acids.

Full text of DOI:10.1021/acs.orglett.5b03116

Letter
pubs.acs.org/OrgLett
1,4-Diazabicyclo[2.2.2]octane-Promoted
Aminotrifluoromethylthiolation of α,β-Unsaturated Carbonyl
Compounds: N-Trifluoromethylthio-4-nitrophthalimide Acts as Both
the Nitrogen and SCF3 Sources
Qing Xiao, Qijie He, Juncheng Li, and Jun Wang*
Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: A novel difunctionalization reaction is described. It
uses N-trifluoromethylthio-4-nitrophthalimide as the reagent,
which serves as both the nitrogen and SCF3 sources. In the
presence of DABCO (1,4-diazabicyclo[2.2.2]octane), the nitro-
gen and SCF3 groups can be incorporated into α,β-unsaturated
carbonyl compounds easily and give versatile β-amino ketones
and esters in good yields. This difunctionalization reaction features mild reaction conditions, high atom-economy, and efficient
access to α-SCF3 amino acids.
reintroduced by Rueping, Shen, and Lu),9 and SCF3-saccharine 6
here has been a resurgence of interest in organofluorine
Tchemistry over the past several years. Among various developed by Shen.10 Substrates of keto-esters and β-diketones,
1
as well as some related asymmetric reactions, were investigated.
α-Bromoketones,11 oxindoles,7b,9c,12 and α-diazoesters13 are also
applicable substrates for the formation of the corresponding α-
SCF3 carbonyl compounds. Nevertheless, under the reported
reaction conditions, these reagents serve only as the −SCF3
source, while the other counterpart is regarded as the side
product. In fact, it would be attractive if both components of this
reagent could be used in atom-economical synthetic chemistry.
Difunctionalization reactions of alkenes are particularly
important, as they can be used to produce highly complex
molecular architectures. There has been no example reported
concerning the difunctionalization of a carbon−carbon double
bond only with a SCF3-phthalimide reagent. β-Amino ketones
and esters are important structural motifs in a number of
biologically active compounds, and many synthetic approaches
to this class of compounds have been developed in recent years.14
Herein we report our efforts in developing an effective reagent
and protocol for facile access to the α-SCF3-β-amino carbonyl
skeleton from α,β-unsaturated carbonyl compounds by a
difunctionalization reaction. This method provides a highly
atom-economical preparation of α-SCF3-β-amino acids and their
corresponding peptides.
established fluoroalkyl groups, much attention is devoted to the
trifluoromethanesulfenyl group (−SCF3) due to its unique
features: remarkable electron-withdrawing character2 and
excellent lipophilicity (cf. Hansch hydrophobic parameter, π =
1.44).3 Indeed, this −SCF3 group is exceptionally useful in
isostere-based drug design. Thus, methods for assembling this
fluorinated moiety into organic molecules are always needed for
drug discovery in pharmaceutical and agrochemical industries.
The development of a useful SCF3-containing reagent and a
straightforward protocol for the incorporation of the −SCF3
group to organic molecules have recently emerged.4 In particular,
methods for integrating the −SCF3 group to the α-position of
carbonyl compounds are very valuable to a wide range of
bioactive and natural compounds. Expedient examples of
electrophilic trifluoromethylthiolation reagents have been
reported for these transformations (Figure 1), for instance,
Billard’s SCF3 reagent 1a,5 Shen and Lu’s SCF3 reagent 2,6 SCF3-
ether 3 reported by Buchwald, Shen, and Lu,7 Shibata’s SCF3-
iodonium ylide 4,8 Munavalli’s SCF3-phthalimide 5a (recently
We embarked upon this investigation using phenyl vinyl
ketone 7a as the benchmark substrate and SCF3-phthalimide 5a
as the trifluoromethylthiolation reagent (Table 1). Commonly
used DBU (1,8-diazabicyclo[5.4.1]undec-7-ene), an activator of
N-haloimides in difunctionalization of carbon−carbon multiple
bonds,15 only gave a trace amount of expected product (entry 1).
To our delight, DABCO (1,4-diazabicyclo[2.2.2]octane) was
Figure 1. Examples of electrophilic trifluomethylthiolation reagents of
carbonyl compounds.
Received: October 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03116
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction mixtures, and no desired product was identified as
judged by GC-MS analysis. With the initial result of SCF3-
phthalimide 5a in hand, we intended to prepare a more reactive
reagent. We employed a strategy of using a strong electron-
withdrawing group attached to the arene to make the SCF3-
phthalimide reagent more easily activated. With the newly
developed reagent 5b, the product yield of 8ab was increased to
84%. It should be noted that this electrophilic reagent features
high moisture and air stability.
Under the optimized reaction conditions, a range of various
α,β-unsaturated ketones 7a−q were examined with SCF3-4-
nitrophthalimide 5b (1.5 equiv) in acetonitrile at room
temperature (Scheme 2). The reactions proceeded well to afford
Table 1. Optimization of Aminotrifluoromethylthiolation of
Vinyl Phenyl Ketone 7a with SCF3-phthalimide 5a
a
b
entry
base
solvent
yield (%)
1
2
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
trace
75
DABCO
3
DMAP
59
4
i-Pr2NEt
NR
52
5
4-methylmorpholine
(S)-sparteine
K2CO3
c
6
39
Scheme 2. Aminotrifluoromethylthiolation of α,β-
Unsaturated Ketone 7 with SCF3-4-nitrophthalimide 5b
7
trace
52
ab
,
8
DABCO
9
DABCO
CH2Cl2
dioxane
DCE
47
10
11
12
DABCO
32
DABCO
41
DABCO
toluene
MeCN
37
d
13
DABCO
61
a
Reaction conditions: 7a (0.1 mmol), 5a (0.15 mmol), and base (0.05
mmol) in solvent (0.3 mL) were stirred at room temperature for 40 h
b
c
under air. Yield of isolated products. There was essentially no ee
value observed. With 0.2 equiv of base. NR = no reaction.
d
found to be an efficient promotor to give the product 8aa in 75%
yield (entry 2). In addition to DABCO, DMAP (4-
dimethylaminopyridine), 4-methylmorpholine, and sparteine
were surveyed, albeit in lower product yield (entries 3, 5, and
6). Solvents such as THF, DCM, DCE, dioxane, and toluene
resulted in poor yields (entries 8−12). When the reaction was
carried out in 0.2 equiv DABCO, the yield was decreased from 75
to 61% (entry 2 vs 13).
Besides SCF3-phthalimide 5a, the efficacy of other known
stable electrophilic N-SCF3 sources was tested (Scheme 1). A
Scheme 1. SCF3 Reagent Screening for DABCO-Promoted
Aminotrifluoromethylthiolation of Phenyl Vinyl Ketone 7a
a
Reaction conditions: 7a−q (0.15 mmol), 5b (0.225 mmol), and
DABCO (0.075 mmol) in MeCN (0.5 mL) were stirred at room
temperature for 40 h under air. Yield of isolated products.
b
the corresponding α-SCF3-β-phthalimide ketones 8ab−8qb in
good to high yields. No significant electronic effect was observed
on ketone substrates toward the efficiency of the reaction.
Naphthyl ketone 7l and furyl ketone 7m were also suitable
substrates. A slight decrease in product yields was observed when
aliphatic ketone substrates were employed (i.e., 8nb−8qb). No
desired products were obtained for α- or β-substituted enones.
significant electronic effect of R1 and R2 groups on amine part
was observed. N-SCF3-aniline 1b presumably is not electrophilic
enough to react with phenyl vinyl ketone 7a. To our surprise,
SCF3-saccharine 6, which always has superior reactivity, did not
give the expected product. Yet, only byproduct 9 was obtained in
92% yield (Scheme 1). SCF3-succinimide 10 gave complex
B
DOI: 10.1021/acs.orglett.5b03116
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Organic Letters
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To extend the substrate scope, acrylates, acrylonitrile, and
acrylamide were tested (Scheme 3). Further optimization
32% yield.16 Indeed, this method provided a new and practical
approach for the synthesis of novel SCF3-substituted β-amino
acids.
A proposed mechanism is shown in Scheme 5.17 The
nucleophilic promoter DABCO activates the SCF3-4-nitro-
Scheme 3. Aminotrifluoromethylthiolation of α,β-
Unsaturated Carbonyl Compounds 11a−g with SCF3-
a b
,
phthalimide 5a,b
Scheme 5. Plausible Mechanism of the Reaction
phthalimide to generate a more nucleophilic nitrogen source A
and a more electrophilic SCF3 species B. The first step proceeds
through the 1,4-addition of phthalimide anion A to the α,β-
unsaturated ketone to generate the enolate C. In the second step,
the enolate adds to electrophilic SCF3 species B. Consequently,
SCF3-4-nitrophthalimide functions as both the electrophilic
SCF3 and nitrogen sources. Although we were not able to
separate and confirm the active SCF3 intermediate B at this time,
the 19F NMR study showed the existence of new SCF3 species
under the current system (see the Supporting Information).
In conclusion, we have developed a novel DABCO-promoted
aminotrifluoromethylthiolation of α,β-unsaturated carbonyl
compounds with N-trifluoromethylthio-4-nitrophthalimide as
both the nitrogen and SCF3 sources. This protocol features mild
conditions, a relatively broad scope, and high atom-economy in
generating an array of α-SCF3-β-amino ketones and esters with
high efficiency. Remarkably, it provides a versatile approach for
the synthesis of new SCF3-containing β-amino acids and their
corresponding peptides. Further investigations are underway to
probe the mechanism and to extend the scope of the
aminotrifluoromethylthiolation reactions.
a
Reaction conditions: 11a−i (0.15 mmol), 5b (0.225 mmol), and
DABCO (0.075 mmol) in 0.45 mL of DCM/dioxane (1:1) were
stirred at room temperature for 40 h under air. Yield of isolated
product.
b
disclosed that the addition of SCF3-4-nitrophthalimide 5b to
α,β-unsaturated esters performed better in the mixed solvent
(DCM/dioxane = 1:1). Aryl acrylate esters 11a,b performed
similarly well despite their activity which was weaker than that of
ketones, affording the corresponding α-SCF3-β-amino esters in
71−80% yields. When aliphatic acrylate esters 11c−g were used
as substrates, decreased yields (45−79%) were obtained.
Acrylonitrile resulted in a relatively sluggish reaction and
provided the expected product 12hb in 36% yield. Attempted
investigation of α,β-unsaturated amide gave no desired product
essentially.
We attempted to use α-SCF3-β-N-phthaloylamino acid ester
to transform to the β-amino acid (Scheme 4). The acid group was
deprotected by hydrogenation with triethylsilane, then removal
of the phthaloyl group on 12cb by treatment with sodium
borohydride gave α-SCF3-β-alanine hydrochloride (13·HCl) in
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03116.
Experimental procedures and characterization/HPLC
data of products (PDF)
AUTHOR INFORMATION
Scheme 4. Synthesis of α-SCF3-β-alanine
■
Corresponding Author
*E-mail: wang.j@sustc.edu.cn.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b03116
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(c) Wang, Q.; Qi, Z.; Xie, F.; Li, X. Adv. Synth. Catal. 2015, 357, 355.
(d) Xu, C.; Shen, Q. Org. Lett. 2015, 17, 4561.
(11) (a) Huang, Y.; He, X.; Li, H.; Weng, Z. Eur. J. Org. Chem. 2014,
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ACKNOWLEDGMENTS
■
We gratefully thank the startup fund and faculty research grant
(FRG-SUSTC1501A-58) from South University of Science and
Technology of China for financial support.
(12) (a) Zhu, X.-L.; Xu, J.-H.; Cheng, D.-J.; Zhao, L.-J.; Liu, X.-Y.; Tan,
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