DIAD-mediated metal-free cross dehydrogenative coupling between tertiary amines and α-fluorinated sulfones

Article abstract of DOI:10.1039/c2nj40842b

A DIAD-mediated metal-free cross dehydrogenative coupling involving aliphatic tertiary amines and α-fluorinated sulfones leading to β-fluorinated amines was developed. This protocol represents the first direct fluoroalkylation of C-H bonds with hydrofluorocarbon derivatives (R _F-H).

Full text of DOI:10.1039/c2nj40842b

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DIAD-mediated metal-free cross dehydrogenative coupling between
tertiary amines and a-fluorinated sulfonesw
Weizhou Huang, Chuanfa Ni, Yanchuan Zhao and Jinbo Hu*
Received (in Montpellier, France) 17th September 2012, Accepted 16th October 2012
DOI: 10.1039/c2nj40842b
A DIAD-mediated metal-free cross dehydrogenative coupling
involving aliphatic tertiary amines and a-fluorinated sulfones
leading to b-fluorinated amines was developed. This protocol
represents the first direct fluoroalkylation of C–H bonds with
hydrofluorocarbon derivatives (RF–H).
ethers,10a and subsequently they reported the oxidative
trifluoromethylation of tetrahydroisoquinoline derivatives
promoted by benzoyl peroxide.10b And the modified oxidative
trifluoromethylation of tertiary amines includes CuI-catalyzed
oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)10c
and visible light-induced reaction catalyzed by Rose Bengal.10d,e
However, these reactions used silane reagents as fluoroalkyl
sources. On the other hand, the cross dehydrogenative coupling
(CDC) reaction has evolved as an effective strategy for
constructing new C–C bonds because of the high step- and
atom-economy.11 To our knowledge, there has been no report
on the CDC reaction between a-C–H bonds of tertiary amines
and C–H bonds adjacent to the fluorine in hydrofluorocarbons
and their derivatives (RF–H) (Scheme 1, eqn (2)). In this
communication, we report our preliminary results on the
CDC reaction between tertiary amines and a-fluorinated
sulfones for the synthesis of b-fluorinated amines under
metal-free conditions.
Fluorinated amines, especially b-fluorinated amines, have
received much attention in bioorganic and medicinal chemistry
research due to the profound change of the basicity of the
amine functionality imparted by fluorine substitution, which
has dramatic and beneficial influences on the bioavailability of
a target molecule.1,2 Among various methods for synthesizing
fluorinated amines, nucleophilic fluoroalkylation of CQN
bonds in imines, nitrones, hydrazones, iminium ions, and
azomethine ylides has been most intensively studied3,4 because
of the easy availability of many nucleophilic fluoroalkylation
reagents.5 Although direct C–H bond fluoroalkylation has
emerged as a potentially useful method for late-stage modifi-
cation of bioactive molecules,6 most research studies focused
on the fluoroalkylation of C–H bonds7 in p-systems such as
arenes, alkenes, and alkynes8 and the sp3-C–H bond adjacent
to electron-withdrawing groups such as carbonyl group9
(Scheme 1, eqn (1)).7–9 The direct fluoroalkylation of the
sp3-C–H bond in substrates such as amines is rare.10
In 2009, Qing et al. reported CuBr-catalyzed oxidative gem-
difluoroalkylation of tertiary amines with difluoroenol silyl
a-Fluorinated sulfones, featured by the activation of the
sulfonyl groups and their versatile transformations under mild
conditions, have been widely applied for introducing difluoro-
methylene, difluoromethyl, and fluoromethyl moieties into
various molecules.5b–d Considering that carbon acids with
electron-withdrawing groups are usually used as one of the
CDC partners,11 we envisioned that di- and monofluoromethyl
sulfones may undergo oxidative coupling reactions with
tertiary amines (Table 1).
At the onset of our study, we chose amine 1a and
fluorobis(phenylsulfonyl)methane (2a)12 as the model compound
to search for suitable conditions for the coupling reaction. A
screening of the peroxides showed that tert-butyl peroxy-
benzoate (TBPB) can promote the reaction in DCM solvent.
Other solvents such as tBuOH, THF, and DMF were ineffective
for the reaction. Although it was found that the addition of an
inorganic base such as K2CO3 could promote the reaction
significantly, 1a and TBPB had to be used in large excess
(46 equiv.). In 2009, Li et al. reported a copper-catalyzed,
diethyl azodicarboxylate (DEAD)-mediated regioselective
alkynylation of tertiary amines, in which DEAD was proposed
to act as the oxidant to form the iminium cation intermediate
and CuI assisted the transfer of alkynyl groups from
alkynes to the iminium cation.13 Inspired by this trans-
formation, we examined our reaction using a more stable
Scheme 1 Two pathways for fluoroalkylation of C–H bonds.
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling
Road, Shanghai 200032, China. E-mail: jinbohu@sioc.ac.cn;
Tel: +86-21-54925174
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data for new compounds. See DOI: 10.1039/
c2nj40842b
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Table 1 Fluoromethylation of amine 1a under various conditionsa
1,4-hydrogen transfer and subsequent fragmentation to afford
an ion pair consisting of iminium cation 5 and nitrogen anion
6. In the presence of 2a, anion 6 acted as a base and abstracted
a proton from 2a affording the dihydrogenated DIAD (7) and
fluorinated sulfone anion 8. A further addition of anion 8 to
iminium cation 5 gave the coupling product 3aa.
Temp.
[1C]
Reaction
timeb [h]
Yieldc
[%]
With the optimized reaction conditions identified, various
tertiary amines were subjected to the fluoroalkylation reactions
with sulfone 2a, and representative results are shown in Table 2. In
addition to the simple aliphatic amines (entries 1–3), the protocol
could also be successfully applied in the fluoroalkylation of amines
with ether and hydroxyl functional groups (entries 4 and 5).
Moreover, all reactions showed very high regioselectivity—only
product arising from fluoromethylation of methyl was obtained
(entries 1–5). In the case of 2-benzyloxy-substituted amine 1d, the
moderate yield of the coupling product is probably due to the
Entry Solvent
Oxidant Base
1
2
3
4
5
6
7
8
CH2Cl2
tBuOH
THF
CH2Cl2
DMF
CH2Cl2
THF
THF
Et2O
Dioxane DIAD
TBPB
TBPB
TBPB
TBPB
TBPB
TBHP
DIAD
DIAD
DIAD
—
—
—
r.t.
50
r.t.
12
1
1
20
0
0
50
0
0
64
73
38
34
53
70
95
K2CO3 r.t.
K2CO3 50
K2CO3 r.t.
—
—
—
—
—
—
—
5
12
12
12
18
12
12
12
18
3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
9
10
11
12
13
DMF
DMF
DMF
DIAD
DIAD
DIAD
Table 2 The scope of DIAD-mediated fluoromethylation of tertiary
aminesa
a
For entries 1–6, reaction was conducted with 1a (1.0 mmol), TBPB
or TBHP (1.1 mmol), 2a (0.16 mmol) in solvent (3.0 mL) and K2CO3
(1.0 mmol) was added after the addition of 2a; for entries 7–13,
reaction was conducted with 1a (1.0 mmol), DIAD (1.1 mmol), 2a
b
(0.5 mmol) in solvent (3.0 mL). Reaction time after the addition
c
of 1a. Yield was determined by 19F NMR. TBPB = tert-butyl
peroxybenzoate; TBHP = tert-butyl hydroperoxide; DIAD =
diisopropanyl azodicarboxylate.
Entry Amine
Sulfone Product
Yieldb [%]
azocarboxylate—diisopropanyl azodicarboxylate (DIAD)—as
the oxidant to promote the reaction. After stirring the mixture
of amine 1a (2.0 equiv.) and DIAD (2.2 equiv.) in neat at rt for
1 h, solvent and sulfone 2a (1.0 equiv.) were added subse-
quently. The reaction conditions were optimized by screening
several
1
2a
94
2
3
4
2a
2a
2a
95
reaction parameters (solvent, temperature, and time). The
reaction in THF at room temperature gave the desired product
3a in a slightly higher yield than that in DMF; however, an
unidentified byproduct (19F NMR: d À151.7 ppm) was detected
in ca. 5% yield. When the reaction in DMF was performed at
an elevated temperature, the coupling product 3a was obtained
regioselectively in excellent yield. It is noteworthy that the
reaction proceeded smoothly without a copper catalyst.
Based on the previously reported DEAD-mediated alkynyl-
ation of tertiary amines,13,14 we proposed a plausible reaction
mechanism for the current cross dehydrogenative coupling
between 1a and 2a (as shown in Scheme 2). Firstly,
the nucleophilic addition of amine 1a to DIAD affords a
zwitterionic intermediate 4,15 which undergoes intramolecular
39c
66
5
6
2a
90
2b
2c
90
92
7
a
Tertiary amine (1.0 mmol), DIAD (1.1 mmol), sulfone (0.5 mmol),
b
DMF (3.0 mL) (see Experimental section). Isolated yield of analytically
c
pure product. A solution of Me3N (33 wt% in ethanol) was used.
Scheme 2 Proposed mechanism for the coupling reaction.
c
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when other fluorinated sulfones such as PhSO2CHF2 and
PhSO2CHFSPh were used as RF–H sources in the reaction,
no desired CDC reaction occurred probably due to the relatively
low RF–H acidity of these sulfones.
To demonstrate the synthetic utility of the obtained amines
3, the reductive desulfonylation was conducted with Na–Hg
amalgam. As is exemplified in Scheme 6, amine 3aa could
be smoothly transformed into b-fluorinated tertiary amine
15 in 82% yield.
Scheme 3 Fluoromethylation of N,N-dimethylbenzyl amine (1f).
In conclusion, we have developed a DIAD-mediated metal-free
fluoroalkylation of aliphatic tertiary amines with a-fluorinated
sulfones, which is efficient for the synthesis of b-fluorinated
tertiary amines. The protocol represents the first cross dehydro-
genative coupling reaction between a-C–H bonds of tertiary
amines and C–H bonds adjacent to the fluorine in hydrofluoro-
carbon derivatives (RF–H). Further research on the direct fluoro-
alkylation of various C–H bonds with hydrofluorocarbons is
underway in our laboratory.
Scheme 4 Possible pathway for the formation of 3ca.
Experimental
competitive formation of benzyloxy-substituted enamine by
b-dehydrogenation from the N,N-dimethyl iminium cation.15a
In the case of N,N-dimethylbenzyl amine 1f, the reaction
requires elevated temperature and prolonged reaction time,
and a mixture of 3fa and 3ca was given as the fluoroalkylated
products (Scheme 3). 3ca was supposed to arise from the
phenyl transfer in intermediate 9 (Scheme 4, eqn (1)).
Although the benzyl C–H bond of 1f is more reactive than
the methyl C–H bond, no fluoromethylation of benzyl was
observed (Scheme 4, eqn (2)). The absence of benzyl fluoro-
alkylation is probably due to the high steric sensitivity of the
addition reaction of the bulky fluoromethyl anion 8 with
iminium cation 12. When N,N-dimethyl-1-(naphthalen-2-yl)-
methanamine was used instead of 1f, 2-naphthaldehyde could
be isolated in 79% yield (based on 2a) after aqueous workup,
which supports our explanation.
Typical procedure for the coupling reaction between tertiary
amines and a-fluorinated sulfones
To a 25 mL Schlenk tube with N,N-dimethylcyclohexylamine
1a (150 mL, 1.0 mmol) was dropwise added DIAD (230 mL,
1.1 mmol) in 1–2 minutes at 0 1C. The mixture was stirred in
neat for 1 hour at room temperature. Then DMF (3 mL) and
fluorobisphenylsulfonylmethane 2a (157 mg, 0.5 mmol) were
successively added. The resulting mixture was stirred at 50 1C
for 3 hours. After cooling to room temperature, saturated
brine (20 mL) was added and the mixture was extracted with
ethyl acetate (15 mL Â 3). The combined organic phase was
dried with anhydrous MgSO4 and evaporated to almost dry-
ness under reduced pressure. Purification by flash column
chromatography on silica gel (200–300 mesh) with petroleum
ether–ethyl acetate (5: 1) as an eluent gave product 3aa (207 mg,
94% yield). White solid, M.p.: 140–142 1C. IR (KBr): 2935,
The reaction was also amenable to other fluorinated sulfones
such as 2b and 2c; and their coupling with 1a afforded the
desired products in excellent yields (Table 2, entries 6 and 7). It
is interesting that when tropine 1e was used as the tertiary
amine, the decarboxylated product 14 was obtained in one pot
in 91% yield (Scheme 5). However, it should be mentioned that
2858, 1583, 1447, 1340, 1150, 1080 cmÀ1. H NMR: d 7.96 (d,
1
J = 7.8 Hz, 4H), 7.69 (t, J = 7.2 Hz, 2H), 7.53 (t, J = 7.8 Hz,
4H), 3.62 (d, J = 24.0 Hz, 2H), 2.19–2.28 (m, 1H), 1.93 (s, 3H),
1.44–1.72 (m, 4H), 0.95–1.14 (m, 6H). 19F NMR: d À146.3 (t,
J = 24.8 Hz, 1F). 13C NMR: d 136.7, 134.8, 130.9, 128.5, 116.8
(d, J = 271.0 Hz), 64.3, 53.6 (d, J = 16.1 Hz), 37.0, 27.6, 26.0,
25.9. MS (ESI, m/z): 440.4 ([M + H]+). Anal. calcd for
C21H26FNO4S2: C, 57.38; H, 5.96; N, 3.19; found: C, 57.49;
H, 6.02; N, 3.11%.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (20825209, 20832008) and the National
Basic Research Program of China (2012CB821600,
2012CB215500).
Scheme 5 Fluoromethylation of tropine 1e with sulfone 2b.
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Scheme 6 Synthesis of b-fluorinated amine 15 from 3aa.
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