Regioselective palladium-catalyzed intramolecular oxidative aminofluorination of unactivated alkenes

Article abstract of DOI:10.1039/c3cc44711a

A novel Pd-catalyzed regioselective intramolecular aminofluorination of unactivated alkenes has been developed, which is an efficient method for the synthesis of a variety of monofluoromethylated nitrogen-containing heterocycles.

Full text of DOI:10.1039/c3cc44711a

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Regioselective palladium-catalyzed intramolecular
oxidative aminofluorination of unactivated alkenes†
Cite this: Chem. Commun., 2013,
49, 8707
Tao Wu, Jiashun Cheng, Pinhong Chen and Guosheng Liu*
Received 23rd June 2013,
Accepted 27th July 2013
DOI: 10.1039/c3cc44711a
www.rsc.org/chemcomm
A novel Pd-catalyzed regioselective intramolecular aminofluorination
of unactivated alkenes has been developed, which is an efficient
method for the synthesis of a variety of monofluoromethylated
nitrogen-containing heterocycles.
The challengeable transition metal-catalyzed C–F bond formation
has received much attention during the last decade.1 Recent studies
demonstrated that C–F bond could be easily generated from the
reductive elimination of high-valent palladium centers.2,3 However,
these processes were generally accompanied by other competitive
reductive elimination pathways.4 Thus, the development of catalytic
methods for direct fluorination achieved little success.
Scheme 1 Pd-catalyzed regioselective aminofluorination of alkenes.
heterocycles might be expected.9,10 Herein, we reported this
Recently, our group5 and Gagne demonstrated that oxidative study, and we found that addition of HFIP (hexafluoroisopropyl
fluorination of alkenes could be achieved by using transition metal, alcohol) is essential for highly selective fluorination of primary
in which a secondary Csp3–M bond was effectively fluorinated. However, Csp3–Pd bond (right, PG = C(O)NR2, Scheme 1).
6a
´
the fluorination of a primary Csp3–M complex is quite challenging due to
In order to test this hypothesis, a variety of substrates bearing
´
other competitive reactions. For example, Gagne reported that treatment different chelating protecting groups on nitrogen atoms were initially
of primary Csp3–Pt complexes by NFSI afforded amination products, investigated. We are delighted to find that substrate 1a with a urea
rather than fluorination products.6b Toste found that the reaction protecting group underwent exo-cyclization, and gave fluorinated pro-
of primary Csp3–Au bonds with XeF2 yielded b-hydride elimination duct 2a in 13% yield in CH3CN, without any endo-cyclization product.
products.7a Until recently, Sanford reported successful fluorination of However, aminooxygenation product 3a was obtained as a major
Pd complexes with primary Csp3–Pd bonds without b-H by using strong product (26%, Table 1, entry 1). A similar result was obtained in the
PyF+.7b But the related catalytic fluorination is quite rare.
EtOAc solvent. The preference for formation of C–O bonds compared to
In previous Pd-catalyzed aminofluorination, the reason for selec- C–F bonds is possible, resulting from the nucleophilic attack of
tive formation of the endo-product is that the reaction possibly carboxylate at the primary carbon centre of the Pd(IV) intermediate. If
involves reversible aminopalladation (AP) and oxidation of inter- so, this process is favoured in polar solvent, and employment of
mediate I due to higher electron density of the PdII centre than II nonpolar solvent should be helpful to suppress C–O bond formation.
(left, PG = tosyl, Scheme 1).8 In regard to the chelating effect, replacing Gratifyingly, benzene, toluene and xylene were demonstrated to be
a tosyl group on nitrogen by a chelating protecting group could good solvents to improve the yield of fluorination product 2a, but still
generate a primary Csp3–Pd species II from kinetically favoured exo- with a significant amount of product 3a (around 20–30%, entries 3–5).
aminopalladation (AP). We speculated that if a PhI(OPiv)2–AgF system Catalyst investigation showed that both Pd(OAc)2 and Pd(dba)2 pre-
can be applied to achieve selective fluorination of primary Csp3–Pd sented good reactivities (entries 5–8). No aminofluorination reaction
bonds, the regioselective formation of monofluoromethylated occurred in the absence of a palladium catalyst, even in the presence of
Brønsted acid (HO2CCF3) or Lewis acid (BF3ÁEt2O) (entry 9).11 More
efforts were devoted to improving the yield of fluorination product 2a:
addition of NaOPiv yielded a poor result; HOPiv just improved
the yield of the oxygenation product 3a (entries 10 and 11); tert-
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: gliu@mail.sioc.ac.cn
butyl alcohol gave aminofluorination product 2a in slightly
better yield (entry 12). Surprisingly, addition of fluorinated
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc44711a
c
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Table 1 Optimization of the reaction conditionsa
Table 2 Pd-catalyzed aminofluorination of alkenesa
Yieldb (%)
Entry
[Pd] (5 mol%)
Additive (equiv.)
Solvent
2a
3a
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(MeCN)2
PdCl2(PhCN)2
Pd(dba)2
—
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
—
—
—
—
—
—
—
CH3CN
EtOAc
Benzene
Toluene
Xylene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
13
19
49
51
46
44
34
50
0
13
45
60
62
73
81
26
30
21
17
23
18
13
16
0
12
34
13
9
—
10
11
12
13
14
15c
NaOPiv (1)
HOPiv (1)
HOBut (1)
TFE (2.5)
HFIP (2.5)
HFIP (2.5)
6
Trace
Trace
a
Reaction conditions: 1a (0.1 mmol), [Pd] (5 mol%), Phl(OPiv)2
(3 equiv.), AgF (3 equiv.), solvent (0.5 mL), at r.t. for 24 h. b 1H NMR
yield with CF3–DMA as internal standard. 2-MeOBQ (1 equiv.).
c
alcohol, such as HFIP (hexafluoroisopropyl alcohol) and TFE
(trifluoroethanol), significantly enhanced chemo-selectivity and
HFIP gave the best yield (entries 13 and 14). Finally, we found
that 2-methoxy-1,4-benzoquinone (2-MeOBQ) was a good addi-
tive to further improve the yield of 2a to 81% (entry 15).12
With the optimal reaction conditions in hand, the scope of alkenes
was further investigated (Table 2). For different substituents on urea
a
All the reactions were conducted at the 0.2 mmol scale; reaction
b
conditions are the same as those in entry 15 in Table 1. Isolated yield.
c
Diastereoselectivity.
protecting groups, the reactions of 1a and 1b afforded aminofluorina- between amides and alkenes were also investigated. Substrate 4i
tion products in good yields (entries 1 and 2). Next, the substrates - exhibited excellent reactivity to give the six-membered product in
1c–1e bearing dimethyl groups on the carbon chain provided the 80% yield (entry 9). Upon introducing a methyl group at the allylic
corresponding products in moderate yields (entries 3–5). Mono- position, the reaction of 4j exhibited excellent diastereoselectivity to
fluoromethylated spiro-pyrrolidines 2f and 2g were also produced in yield trans-5j as a single isomer (entry 10). In contrast, substrate 4k
this transformation with acceptable yields (entries 6 and 7). Substrate with a phenyl group at the homoallylic position gave poor diastereo-
1h with one phenyl group at b-carbon provided 2h in moderate yield selectivity (entry 11). It is worth noting that excellent chemoselectivities
but with poor diastereoselectivity (entry 8). Furthermore, due to steric were observed in all the above reactions to give fluorination products.
hindrance, 1,1-disubstituted alkene 1i exhibited slightly low reactivity
In regard to the reaction mechanism, deuterium-labelled
to form desired product 2i in 33% yield (entry 9). However, for an diene trans-d-4l was subjected to standard conditions to give
internal alkene substrate, the reaction did not afford the desired single isomer d-5l in 30% yield. This result indicated that an
aminofluorination product.
initial trans-aminopalladation step is involved in the catalytic
With the above results in hand, we turned our attention to the cycle. The subsequent process included alkene insertion, oxi-
synthesis of monofluoromethylated imidazolidines. Initial studies dative fluorination to afford the desired product (eqn (1)).
focused on the reaction of substrate 4a. We are delighted to find that
substrate 4a could be smoothly transformed into 5a in 61% yield.
Further optimization of reaction conditions indicated that the best
yield (75%) was obtained by using Pd(O2CCF3)2 as catalyst (Table 3,
entry 1). Other substrates were then subjected to the modified
(1)
reaction conditions. Urea substrates 4b–4f with different substituents
on nitrogen atoms gave the corresponding products in moderate to
good yields (entries 2–6). When a methyl group was introduced at the
allylic position, substrate 4g presented slightly lower reactivity and
selectivity (entry 7). In addition, 1,1-disubstituted substrate 4h showed
a similar reactivity to give the product in 56% yield (entry 8).
Furthermore, substrates bearing one more carbon atom tethered
During this process, combination of PhI(OPiv)2 and AgF pre-
sented a good system to achieve fluorination.5 In addition, only the
c
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Table 3 Pd-catalyzed aminofluorination of alkenesa
yield (entry 6). But CsOPiv was ineffective for this transformation.
These results suggested that ArIF2 may act as a true oxidant to
achieve C–F bond formation.
In summary, we have developed a Pd-catalyzed regioselective
intramolecular aminofluorination of unactivated alkenes, in which a
primary Csp3–Pd bond was selectively fluorinated by AgF/PhI(OPiv)2 in
the presence of HFIP. Preliminary mechanistic studies demonstrated
that PhI(OPiv)2 and/or PhIF2 might act as a real active oxidant. This
methodology is an efficient route to synthesize a variety of mono-
fluoromethylated nitrogen-containing heterocycles.
We are grateful for financial support from the 973 program
(No. 2011CB808700), NSFC (No. 2125210, 21202185, 20923005, and
21121062), STCSM (11JC1415000), and the CAS/SAFEA International
Partnership Program for Creative Research Teams.
Notes and references
1 For some recent reviews on the transition metal-catalyzed fluorination,
see: (a) V. V. Grushin, Acc. Chem. Res., 2010, 43, 160; (b) T. Furuya,
A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470; (c) A. Vigalok, Organo-
metallics, 2011, 30, 4802; (d) C. Hollingworth and V. Gouverneur, Chem.
Commun., 2012, 48, 2929; (e) G. Liu, Org. Biomol. Chem., 2012, 10, 6243.
2 For the stoichiometric reactions of high-valent Pd complexes, see:
(a) T. Furuya, H. M. Kaiser and T. Ritter, Angew. Chem., Int. Ed., 2008,
47, 5993; (b) N. D. Ball and M. S. Sanford, J. Am. Chem. Soc., 2009,
131, 3796; (c) T. Furuya, D. Benitez, E. Tkatchouk, A. E. Strom, P. Tang,
W. A. Goddard III and T. Ritter, J. Am. Chem. Soc., 2010, 132, 3793.
3 (a) K. L. Hull, W. Q. Anani and M. S. Sanford, J. Am. Chem. Soc., 2006,
128, 7134; (b) X. Wang, T.-S. Mei and J.-Q. Yu, J. Am. Chem. Soc.,
2009, 131, 7520; (c) K. S. L. Chan, M. Wasa, X. Wang and J.-Q. Yu,
Angew. Chem., Int. Ed., 2011, 50, 9081; (d) K. B. McMurtrey,
J. M. Racowski and M. S. Sanford, Org. Lett., 2012, 14, 4094.
a
Reaction conditions: 4 (0.2 mmol), Pd(O2CCF3)2 (5 mol%), Phl(OPiv)2
(3 equiv.), AgF (3 equiv.), 2-MeO-BQ (1 equiv.), (CF3)2CHOH (3 equiv.) in
toluene (1.0 mL) at r.t. for 24 hours. Isolated yield. Diastereoselec-
tivity. Only trans-isomer detected.
b
c
d
4 In the case of a highly valent R–PdIV(F)N(SO2Ph)2 complex, its reductive
elimination afforded the amination product, rather than the fluorination
´
´
´
product. For details, see: (a) A. Iglesias, R. Alvarez, A. R. de Lera and
a
Table 4 Pd-catalyzed aminofluorination with ArIF2
˜
K. Muniz, Angew. Chem., Int. Ed., 2012, 51, 2225; (b) E. L. Ingalls,
P. A. Sibbald, W. Kaminsky and F. E. Michael, J. Am. Chem. Soc., 2013,
135, 8854; (c) P. A. Sibbald and F. E. Michael, Org. Lett., 2009, 11, 1147.
5 T. Wu, G. Yin and G. Liu, J. Am. Chem. Soc., 2009, 131, 16354.
´
6 (a) N. A. Cochrane, H. Nguyen and M. R. Gagne, J. Am. Chem. Soc., 2013,
´
135, 628; (b) S.-B. Zhao, J. J. Becker and M. R. Gagne, Organometallics, 2011,
`
30, 3926; (c) A. Simonneau, P. Garcia, J.-P. Goddard, V. Mouries-Mansuy,
M. Malacria and L. Fensterbank, Beilstein J. Org. Chem., 2011, 7, 1379.
7 (a) N. P. Mankad and F. D. Toste, Chem. Sci., 2012, 3, 72; (b) J. M. Racowski,
J. B. Gary and M. S. Sanford, Angew. Chem., Int. Ed., 2012, 51, 3414.
8 A similar pathway in Pd-catalyzed aminochlorination of alkenes was
reported. For details, see: (a) G. Yin, T. Wu and G. Liu, Chem.–Eur. J.,
2012, 18, 451. The reversible aminopalladation also reported by
Stahl, see: (b) P. B. White and S. S. Stahl, J. Am. Chem. Soc., 2011,
133, 18594.
9 For the synthesis of monofluoromethylated compounds from alkenes
via an alternative fluoropalladation pathway, see: S. Qiu, T. Xu, J. Zhou,
Y.-L. Guo and G. Liu, J. Am. Chem. Soc., 2010, 132, 2856.
10 Very recently, synthesis of monofluoromethylated heterocycles was
reported through a silver-catalyzed radical process, see: Z. Li,
L. Song and C. Li, J. Am. Chem. Soc., 2013, 135, 4640.
Entry
[Pd]
[O]/F
Additive
2a
3a
1
2
3
4
5
6
Pd(OAc)2
—
Pd(OAc)2
Pd(OAc)2
—
ArlF2
ArlF2
ArlF2/AgOPiv
ArlF2/AgOPiv
ArlF2/AgOPiv
ArlF2/AgF
—
—
—
HFIP
HFIP
HFIP
0
0
13%
45%
0
0
0
0
0
0
0
Pd(OAc)2
27%
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (5 mol%), ArlF2 (2 equiv.),
b
AgOPiv (2 equiv.), additive (2 equiv.) in toluene (1 mL) at r.t. NMR yield.
11 Metal-free aminofluorination of alkenes, see: (a) Q. Wang,
W. Zhong, X. Wei, M. Ning, X. Meng and Z. Li, Org. Biomol. Chem.,
2012, 10, 8566; (b) W. Kong, P. Feige, T. de Haro and C. Nevado,
Angew. Chem., Int. Ed., 2013, 52, 2469; (c) H. T. Huang, T. C. Lacy,
B. Błachut, G. X. Ortiz and Q. Wang, Org. Lett., 2013, 15, 1818;
(d) Y. Kishi, H. Nagura, S. Inagi and T. Fuchigami, Chem. Commun.,
2008, 3876; (e) G. Verniest, K. Piron, E. V. Hende, J. W. Thuring,
G. Macdonald, F. Deroose and N. de Kimpe, Org. Biomol. Chem.,
2010, 8, 2509. However, these reaction conditions in ref. 11a and b
are not compatible for the substrates 1 and 4.
I(III) reagent could deliver fluorination products. Thus, it is possible
that high-valent iodine reagent PhIF2, generated in situ, might act
as a true oxidant. In order to address the possibility, ArIF2 (Ar =
2,4-xylenyl) was independently synthesized and subjected to stan-
dard conditions (see Table 4).13 Unfortunately, the reaction of ArIF2
failed to give fluorination product 2a in the presence or absence of a
palladium catalyst (entries 1 and 2). Interestingly, the reaction
occurred in the presence of AgOPiv to give fluorination products 12 The role of 2-MeOBQ is possible to promote reductive elimination of
Pd(IV) complexes. For details, see: (a) K. L. Hull and M. S. Sanford,
J. Am. Chem. Soc., 2009, 131, 9651; (b) X. Chen, J.-J. Li, X.-S. Hao,
C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006, 128, 78.
as single products in albeit low yield (entry 3). And addition of HFIP
could significantly enhance the yield to 45% (entry 4). Besides
AgOPiv, the additive AgF also provided the desired product in 27% 13 C. Ye, B. Twamley and J. M. Shreeve, Org. Lett., 2005, 7, 3961.
c
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Chem. Commun., 2013, 49, 8707--8709 8709