Carbofluorination via a palladium-catalyzed cascade reaction

Article abstract of DOI:10.1039/c2sc22198e

This article demonstrates the first examples of tandem C-C and C-F bond formation for the palladium-catalyzed carbofluorination of allenes. The intramolecular Heck-fluorination cascade provides monofluoromethylated heteroarenes, an important class of products in medicinal chemistry. We also describe an intermolecular variant for the three-component coupling of allenes, aryl iodides, and AgF. Mechanistic studies indicate that C-F bond formation occurs by outer sphere attack of fluoride on an allylpalladium fluoride intermediate.

Full text of DOI:10.1039/c2sc22198e

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Carbofluorination via a Palladium-Catalyzed Cascade Reaction
Marie-Gabrielle Braun,‡a Matthew H. Katcher‡a and Abigail G. Doyle*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
This article demonstrates the first examples of tandem C–C and C–F bond formation for the palladium-
catalyzed carbofluorination of allenes. The intramolecular Heck-fluorination cascade provides
monofluoromethylated heteroarenes, an important class of products in medicinal chemistry. We also
describe an intermolecular variant for the three-component coupling of allenes, aryl iodides, and AgF.
Mechanistic studies indicate that C–F bond formation occurs by outer sphere attack of fluoride on an
10 allylpalladium fluoride intermediate.
Ph
I
LnPd0
AgF
Introduction
Ph
R
+
•
+
R
R
F
F
Palladium-catalyzed
cascade
reactions
are
valuable
linear
branched
transformations in chemical synthesis that enable rapid and
efficient access to molecular complexity.1 Among these, cascades
15 initiated by the coupling of an aryl or vinyl halide with an olefin
(Heck reaction) have been used extensively to achieve olefin
LnPd0
difunctionalization,2
including
recent
examples
of
Ph
Ln
Pd
carbochlorination, carbobromination,3 and carboiodination.4
Notably, related carbofluorination reactions have yet to be
20 described.5 Since organofluorine derivatives have found
widespread application in nearly every facet of the chemical
industry,6 such a cascade reaction would be of great value as it
would permit access to these compounds by the modular
combination of an aryl halide, olefin, and fluoride source. Herein,
25 we report the development of an intramolecular Pd0-catalyzed
carbofluorination of allenes for the preparation of
monofluoromethylated heterocycles. Although the CH2F unit is
important to isostere-based drug discovery,7 current strategies for
the preparation of monofluoromethylated heterocycles suffer
30 from significant limitations in functional group compatibility or
R
•
R
AgF
I
A
B
Pd
I
Ln
productive
C–F
AgF
bond
formation?
Ph
Ln
Pd
•
R
± AgF
R
F
B'
A'
Pd
F
Ln
Scheme 1 Proposed carbofluorination of allenes
using AgF, and stoichiometric studies with a Pd(allyl)(Cl)
50 complex support an outer-sphere mechanism for C–F bond
formation.12,13 Recently, we questioned whether this mechanism
could enable the design of a carbofluorination reaction between
readily available allenes and aryl iodides. As outlined in Scheme
1, it was envisioned that exposure of an aryl iodide to Pd0 would
55 afford Pd(Ar)(I) A, which could readily engage an allene in a
Heck insertion.14 In accord with our earlier studies, we
anticipated that the resulting Pd(allyl)(I) intermediate B would
then undergo outer-sphere C–F bond formation with AgF to
deliver the desired carbofluorinated product. As an alternative
60 pathway, it is well-known that AgF readily reacts with Pd(Ar)(I)
complexes to give Pd(Ar)(F) species (A') by halide metathesis,15
and A' could also participate in Heck insertion with the allene to
furnish Pd(allyl)(F) B'. At the outset of our studies it was unclear
whether this neutral intermediate could participate in productive
65 C–F bond formation since most Pd-catalyzed allylic alkylations
with outer-sphere nucleophiles undergo reaction from cationic
starting
material
preparation.8
The
intramolecular
carbofluorination reported in this article offers a functional group
tolerant and flexible method for the synthesis of these motifs via
simultaneous heterocycle and C–F bond formation. Furthermore,
35 an intermolecular variant of the carbofluorination is described,
which delivers 2-substituted allylic fluorides in an efficient three-
component coupling reaction.9 Based on stoichiometric
experiments conducted on this intermolecular reaction, we report
a
key role for
a
PdII(allyl)(F) intermediate in the
40 carbofluorination.
Prior work has demonstrated that reductive elimination of a C–
F bond from PdII is challenging.10 For the synthesis of aryl
fluorides, inner-sphere C–F bond formation from PdII(Ar)(F)
complexes has only been demonstrated at temperatures near 100
45 ºC and with specialized ligands.11 By contrast, our laboratory has
reported mild conditions for Pd0-catalyzed allylic fluorination
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Table 1 Optimization of intramolecular carbofluorination
Table 2 Scope of intramolecular carbofluorination
CH2F
Pd2(dba)3 (5 mol%)
Pd2(dba)3 (5 mol%)
Conditions A or B or C
CH2F
I
I
ligand (20 mol%)
•
+
R
F
R
•
"F–" source (1.5 equiv)
N
Ts
AgF (1.5 equiv)
N
Ts
n
N
Ts
X
n
X
CH2Cl2, RT, 24 h
1: n= 0, 1, 2
2
(+/–)-3a
1a
2a
A: P(3,5-CF3-C6H3)3 (20 mol%), CH2Cl2, RT, 24 h
B: XPhos (20 mol%), toluene, 60 ˚C, 2–3 h
C: PPh3 (30 mol%), toluene, 40 °C, 48 h
Entry
Ligand
“F–” source Yield (%)a 2a:3ab
1c Trost DACH-naphthyl
AgF
AgF
AgF
7
20
9
ndd
1:1
45
2
3
4
5
6
7
8
9
PPh3
P(4-OMe-C6H4)3
XPhos
Substrate
Product
Conditions Yield (%)a
ndd
CH2F
AgF
AgF
AgF
CsF
36
53
80
0
0
0
>20:1
>20:1
>20:1
ndd
R
I
R
2a R=H, 71
•
P(2-furyl)3
2b R=Br, 82b
2c R=CF3, 67
2d R=OMe, 76
P(3,5-CF3-C6H3)3
P(3,5-CF3-C6H3)3
P(3,5-CF3-C6H3)3
P(3,5-CF3-C6H3)3
A
A
N
Ts
N
Ts
Et3NŸ3HF
ndd
1a–d
2a–d
TBATe
ndd
CH2F
I
a Combined yield of 2a and 3a, determined by HPLC using naphthalene
•
as a quantitative internal standard. b Determined by 19F NMR. c 10 mol%
5 ligand. d Not determined. e Tetrabutylammonium difluorotriphenylsilicate.
77
69
Me
N
Ts
N
Ts
Me
allyl complexes16 and ionization of a Pd–F bond is unfavorable
compared to that of a Pd–Cl or Pd–I bond.17
1e
2e
CH2F
MeO2C
I
MeO2C
•
A
B
N
Boc
N
Results and discussion
Boc
1f
2f
With these concerns in mind, we began our investigation by
10 examining the intramolecular carbofluorination of allene 1a with
a tethered aryl iodide (Table 1). Recognizing that ligand effects
would play an important role in achieving the desired reactivity
and regioselectivity (2a:3a), we initially surveyed ligands that
had been effective for allylic fluorination.12 With AgF as fluoride
15 source, carbofluorinations conducted with both the Trost DACH-
naphthyl ligand and triphenylphosphine provided the desired
product, albeit with low yield and regioselectivity. Although
reactions with electron-rich phosphines also resulted in poor
yields (entries 3–4), the use of electron-deficient monophosphines
20 led to improvements in reactivity and selectivity (entries 5–6).
The best outcome was obtained with P(3,5-CF3-C6H3)3, which
afforded 2a in 80% yield (entry 6).18 Notably, these conditions
(conditions A, Table 2) also provided complete regioselectivity
for the linear isomer presumably due in part to the preference for
25 aromaticity over cross-conjugation. As observed in our previous
studies, AgF was uniquely effective as a fluoride source (entries
7–9).
Following this optimization, we investigated the scope of the
intramolecular carbofluorination for the preparation of
30 monofluoromethylated heterocycles (Table 2). From easily
accessible allenes,19 various five-membered nitrogen-, oxygen-,
and sulfur-containing heteroarenes were synthesized. Using
conditions A, good to moderate yields were obtained for indoles
with a range of substitution patterns and functional groups,
35 including trifluoromethyl (2c), methoxy (2d), methyl (2e), N-Boc
(2f), and ester (2f). An aryl bromide (2b) was also well-tolerated,
potentially allowing for subsequent derivatization via distinct
cross-coupling protocols.20 Allene substrates bearing ether and
thioether tethers furnished benzofuran 2g and benzothiophene 2h
40 in slightly lower yields; for these substrates, the use of XPhos as
ligand was required to avoid competitive degradation of the
allene. XPhos was also optimal to minimize diene formation (vide
infra) in the conversion of a disubstituted allene into 1-
CH2F
I
•
2g X = O, 57
2h X=S, 58
X
X
1g–h
2g–h
Me
H
I
Me
F
•
A
C
72c
N
Ts
N
Ts
(+/–)-1i
(+/–)-2i
CH2F
•
I
62
CO2Et
CO2Et
CO2Et
EtO2C
1j
2j
CH2F
•
I
NPh
NPh
C
C
40
53
O
O
2k
1k
CH2F
•
F3C
I
F3C
N
Ts
N
Ts
1l
2l
a Isolated yields for reactions carried out on 0.3–1.0 mmol scale (average
of two runs). b [η3-C3H5PdCl]2 (5 mol%) was used as catalyst, 12 h. c
With [η3-C3H5PdCl]2 (5 mol%), XPhos (20 mol%).
fluoroethyl indole 2i.21,22
50
Given the importance of monofluoromethylated heterocycles
in medicinal chemistry,7 we sought to extend the scope of the
carbofluorination to the synthesis of 6- and 7-membered ring
products (Table 2). In these cases, higher temperatures were
required to induce cyclization. However, for the preparation of 2j,
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Table 3 Scope of intermolecular carbofluorination
AgF
Ph
PPh3
X
+
Me
Pd
•
Me
Ph
Ph3P
6
6
d8-toluene
50 ºC
F
•
R
Pd2(dba)3 (5 mol%)
PPh3 (30 mol%)
4
4d
8-F: X = F
8-I: X = I
(+/–)-7f
8-F: 23%a
8-I: 50%a
CH2F
R
R
+
+
AgF (1.5 equiv)
toluene, 50 °C, 24 h
8-F, without AgF: 34%b
I
F
6
(+/–)-7
Scheme 2 Mechanistic studies with stoichiometric Pd complexes.
30 Reactions conducted in the presence of dimethyl fumarate (1 equiv) to
complex Pd(0). Yield determined by 1H NMR, using methyl benzoate as a
quantitative internal standard. Branched:linear ratio >20:1 by 19F NMR. a
4d (1 equiv), 8-I or 8-F (1 equiv), AgF (3 equiv), 12 h. b 4d (1 equiv), 8-F
(1 equiv), 24 h.
5
Allene
Iodide
Product
Yield (%)a
63
CH2F
I
S
EtO2C
•
S
EtO2C
35 vinyl (5b) iodides were also competent coupling partners (Table
3). Notably, the regioselectivity of fluoride attack varied with the
structure of the allene. For products 6a, 6b, and 6c, the linear
isomer was observed due to the preference for conjugation with
the ester. In contrast, other substrates (4b, 4c) afforded products
40 with a slight excess of the branched isomer; this regiochemical
outcome is in accord with our previous work on allylic
fluorination.12b
The success of this intermolecular reaction provides a unique
opportunity to interrogate the intermediacy of a PdII(allyl)(F) (B',
45 Scheme 1) in Pd-catalyzed allylic fluorinations. To this end, we
prepared known PdII(Ph)(F) 8-F15 and subjected it to allene 4d in
the presence of AgF (Scheme 2).29 After 12 h at 50 ºC, the
desired carbofluorination product 7f was produced in 23% yield,
with the major byproduct of the reaction resulting from
50 elimination. Notably, when the analogous iodide complex 8-I was
subjected to the same conditions, carbofluorination also required
12 h to reach full conversion of 4d and 50% yield of 7f,30 but the
only PdII species detectable by 31P NMR after 30 min was 8-F.31
Furthermore, at temperatures below those required for
55 carbofluorination, halide exchange between 8-I and AgF occurred
readily. These findings demonstrate that A' is a kinetically viable
intermediate in the catalytic cycle and that allylic C–F bond
formation can proceed via PdII(allyl)(F) B' (Scheme 1).32
Surprisingly, a control experiment showed that AgF is not
60 required for stoichiometric carbofluorination, as the reaction of 8-
F with 4d in the absence of AgF also afforded 7f (34% yield,
Scheme 2). Taking into account our previous stereochemical
studies on allylic fluorination and the fact that a PdII–F bond is
unlikely to undergo inner-sphere C–F reductive elimination under
65 these conditions (vide supra), this stoichiometric reaction likely
proceeds via an outer-sphere pathway. “Naked” fluoride
generated from ionization of Pd–F B' could serve as the outer-
sphere nucleophile. However, this mechanism seems unlikely
given that the reactions are conducted in non-polar solvents in
70 which the concentration of free fluoride will be low.33 A more
likely possibility is that the outer-sphere nucleophile is a
palladium fluoride complex (A' or B') that delivers fluoride to a
distinct allylpalladium intermediate in a bimetallic mechanism.34
Mechanistic studies are underway in order to distinguish these
75 two scenarios; however, preliminary rate data suggest that the
Ag-free mechanism may not be relevant to the catalytic system.35
The result nevertheless highlights the attractive possibility that a
transition metal fluoride other than AgF can be identified for the
catalytic reaction.
4a
5a
6a
CH2F
O
O
EtO2C
I
60b
4a
4a
Me
Me Me
Me
5b
6b
CH2F
I
EtO2C
62
76
71c
5c
6c
•
5c
F
4b
7d:6d = 1.5:1.0
BzO
•
BzO
5c
F
4c
7e:6e = 2.0:1.0
a Product ratios were determined by 19F and 1H NMR. Combined isolated
yields of all isomers for reactions carried out on 0.5–1.0 mmol scale,
5 average of two runs. Ratio of olefin isomers > 20:1, linear:branched >
20:1, except where noted. b With Pd(dmdba)2 (10 mol%) and Xantphos
(10 mol%), Z:E = 1.3:1.0. c With Pd(dmdba)2 (10 mol%) as catalyst.
reactions under conditions B (60 ºC, XPhos as ligand) afforded
mainly diene (80%) via elimination, a common pathway in
10 nucleophilic fluorinations with substrates bearing β-hydrogens.23
We were pleased to find that use of PPh3 as ligand at 40 °C
reduced the formation of this undesired byproduct to 20%,
allowing for isolation of carbocycle 2j in 62% yield.22 With these
conditions, the reaction also provided access to isoquinolinone 2k
15 and 1,2-dihydroquinoline 2l. Despite their seeming simplicity,
none of the fluorinated products in Table 2 has been previously
reported,24 underscoring the lack of efficient strategies for the
preparation of these motifs in comparison with methods for the
synthesis of fluoro-25 trifluoromethyl-,26 and difluoromethyl-27
20 heterocycles.
We next pursued an intermolecular carbofluorination cascade
for the three-component coupling of commercial or readily
accessible aryl iodides, allenes, and AgF. Importantly, this
method allows access to allylic fluorides with 2-substitution,28
25 products that were difficult to access via our previous method due
to limitations in preparing the corresponding allylic chloride
substrates.12 In addition to aryl iodides (5c), heteroaryl (5a) and
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Jeong, S. T. Lim, M.-H. Sohn, Angew. Chem. Int. Ed., 2008, 47,
8404–8406; b) W. J. Middleton, J. Org. Chem., 1975, 40, 574–578;
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Conclusions
65
70
In summary, we have demonstrated the first examples of pal-
ladium-catalyzed intra- and intermolecular carbofluorination of
olefins.
Valuable
fluorinated
motifs,
including
5
monofluoromethylated heterocycles, can be efficiently
synthesized. Based on stoichiometric experiments, we propose
that a palladium fluoride, resulting from halide exchange with
AgF, is a key intermediate in the reaction. The implications of
this unexpected observation on the mechanism of C–F bond
4094–4097; for
a recent approach to monofluoromethylated
heterocycles, see: f) Y. Fujiwara, J. A. Dixon, F. O’Hara, E. D.
Funder, D. D. Dixon, R. A. Rodriguez, R. D. Baxter, B. Herlé, N.
Sach, M. R. Collins, Y. Ishihara, P. S. Baran, Nature, 2012, 492, 95–
99.
10 formation are the subject of further investigations in our
laboratory.
75 9 For a review on allylic fluorides, see: M. C. Pacheco, S. Purser, V.
Gouverneur, Chem. Rev., 2008, 108, 1943–1981.
10 a) T. Furuya, A. S. Kamlet, T. Ritter, Nature, 2011, 473, 470–477; b)
C. Hollingworth, V. Gouverneur, Chem. Commun., 2012, 48, 2929–
2942.
Acknowledgements
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17402–17404; b) M. H. Katcher, A. Sha, A. G. Doyle, J. Am. Chem.
Financial support provided by Merck, Princeton University, NSF
(CAREER-1148750), a fellowship to M.-G.B. from the Ecole
15 Polytechnique, and a fellowship from Eli Lilly to M.H.K. are
gratefully acknowledged. A.G.D. is an Alfred P. Sloan
Foundation Fellow, Eli Lilly Grantee, an Amgen Young
85
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13 For other examples of transition metal-catalyzed allylic fluorination,
see: a) C. Hollingworth, A. Hazari, M. N. Hopkinson, M. Tredwell,
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20 No carbofluorination was observed under a variety of conditions with
the bromide analog of 1a. Carbofluorination was observed for
anilines with more electron-rich protecting groups (e.g. methyl
carbamate), but the monofluoromethyl indole products were unstable
to various purification techniques.
Investigator, and
Awardee.
a Roche Early Excellence in Chemistry
90
20 Notes and references
a Department of Chemistry, Princeton University, Washington Rd,
Princeton, NJ 08544-1009, USA. Fax: (+1) 609-258-2558; Tel: (+1) 609-
258-1944; E-mail: agdoyle@princeton.edu
† Electronic Supplementary Information (ESI) available: Experimental
25 procedures, additional reaction optimization, details for stoichiometric
reactions, and spectroscopic data for all new compounds. See
DOI: 10.1039/b000000x/
95
‡ These authors contributed equally to this paper.
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110
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22 For further details, see the ESI.
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50
55
60
7
For examples, see: a) I. I. Gerus, A. A. Kolomeitsev, M. I.
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Patterson, R. B. Innis, V. W. Pike, J. Med. Chem., 2007, 50, 3256–
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27 a) J. Hu, W. Zhang, F. Wang, Chem. Commun,. 2009, 7465–7478; b)
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28 For the Pd-catalyzed synthesis of 2-substituted allylic fluorides
without substitution at the allyl termini, see ref. 13a.
29 For other stoichiometric reactions of Pd complexes with allenes, see:
T. Bai, L. Xue, P. Xue, J. Zhu, H. H.-Y. Sung, S. Ma, I. D. Wiliams,
Z. Lin, G. Jia, Organometallics, 2008, 27, 2614–2626.
125
8
Common methods for synthesizing monofluoromethylated
heterocycles include halide exchange with TBAF, deoxyfluorination
of benzylic alcohols with DAST, and substitution of
aryldiazomethanes with tetrafluoroboric acid. a) D. W. Kim, H.-J.
130
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30 The lower yield of 7f obtained starting from 8-F compared to 8-I is
likely due to the presence of an additional equivalent of fluoride in
the reaction, which leads to more elimination.
31 8-I and 8-F are also competent catalysts for the carbofluorination of
4d with 5c and AgF.
5
10
15
20
32 Allylpalladium fluoride intermediates have been proposed, but not
fully characterized, in several allylic alkylation reactions. See: a) U.
Burckhardt, M. Baumann, A. Togni, Tetrahedron: Asymmetry, 1997,
8, 155–159; b) A. Hazari, V. Gouverneur, J. M. Brown, Angew.
Chem. Int. Ed., 2009, 48, 1296–1299.
33 For a discussion of Pd–F ionization and the generation of “naked”
fluoride, see ref. 15 and: V. V. Grushin, Chem. Eur. J., 2002, 8,
1006–1014.
34 For recent examples where phosphine-Pd-fluoride complexes deliver
fluoride to an electrophile, see: a) D. Breyer, T. Braun, P. Kläring,
Organometallics, 2012, 31, 1417–1424; b) L. M. Martınez-Prieto, C.
́
Melero, D. del Rıo, P. Palma, J. Cámpora, E. Álvarez,
́
Organometallics, 2012, 31, 1425–1438.
35 Stoichiometric reactions without AgF required 24
h to reach
complete conversion of 4d, while those with AgF were complete
within 12 h.
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