Palladium-catalyzed decarbonylative cyanation of acyl fluorides and chlorides

Full text of DOI:10.1246/CL.200750

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Palladium-catalyzed Dacarbonylative Cyanation of Acyl Fluorides and Chlorides
Shun Sakurai and Mamoru Tobisu*
Advance Publication on the web November 12, 2020
doi:10.1246/cl.200750
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2020 The Chemical Society of Japan
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1
Palladium-catalyzed Dacarbonylative Cyanation of Acyl Fluorides and Chlorides
Shun Sakurai and Mamoru Tobisu*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
E-mail: tobisu@chem.eng.osaka-u.ac.jp
7
1
2
3
Decarbonylative cyanation of acyl fluorides can be
catalyzed by a Pd/Xantphos system. This protocol is also
applicable to the conversion of acyl chlorides.
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
source of cyanide. Thus, the reaction of 1a with 2 in the
8
presence of Pd
2
(dba)
3
ꞏCHCl (10 mol% [Pd]), Xantphos
3
(13 mol%) and NaI (1.5 equiv) in toluene at 180 °C in a
sealed tube resulted in the formation of nitrile 3a in 95%
4
5
Keywords: Cyanation, Decarbonylation, Acyl Fluorides,
Palladium
isolated yield (Entry 1, Table 1). Pd(OAc)
as a catalyst precursor in place of Pd (dba)
with a slightly lower yield (Entry 2). Regarding the ligand,
monophosphines, such as PPh and PCy , and other
bidentate phosphines, including dppe and dcype, were
ineffective, and Xantphos was needed for this conversion
(Entries 3 and 4). Addition of NaI (1.5 quiv) is essential for
an efficient conversion of 1a (Entry 5). Although the use of
NI instead of NaI decreased the yield of 3a (39%, Entry
NBr (62%, Entry 7) and Bu NCl (57%, Entry 8) also
promoted this decarbonylative cyanation. The reaction can
also proceed at lower temperature (160 °C, 70% yield, Entry
9).
2
can also be used
2
3
ꞏCHCl , albeit
3
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
Acyl fluorides, which are readily prepared from the
corresponding carboxylic acids, are unique reagents that can
be used in either fluorination or acylation reactions despite
3
3
1
,2
their greater stability toward nucleophiles such as water.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
Transition metal catalyzed cross-coupling reactions of acyl
fluorides have also been reported, and some of these
Bu
4
3
reactions involve decarbonylation to form non-carbonyl
6), Bu
4
4
products. In such decarbonylative cross-coupling reactions,
4
a
an
array
of
nucleophiles,
organosilicon,
including
hydride,
4
b,c,d,i,j
4e,f,h
4c,k,l
organoboron,
organostannanes
4
g
and (hetero)arene C-H bonds have been reported to
participate successfully (Scheme 1). Although these
significant advances have been made in the catalytic
decarbonylative cross-coupling of acyl fluorides, the method
has not been applied to cyanation reactions, despite the
recognized utility of nitriles in organic synthesis. Herein,
4
4
7
8
Table 1. Palladium-catalyzed Cyanation of Acyl Fluoride 1a by
Trimethylsilyl Cyanide 2
a
Pd2(dba)3·CHCl3
O
5
(10 mol% [Pd])
CN
6
Xantphos 13 mol%
F
+
Me Si CN
3
NaI (1.5 equiv)
we report on the first decarbonylative cyanation of acyl
fluorides.
2
toluene, 180 °C, 24 h
1a
3a
(
1.5 equiv) (in a sealed vessel)
"
standard conditions"
2
4
Scheme 1. Catalytic decarbonylative transformations of acyl fluorides.
Entry
Deviations from "standard conditions"
Yield (%)b
1
None
100 (95)
2c
Pd(OAc)2, instead of Pd2(dba)3·CHCl3
89
6
3
Without Xantphos
4d
0-8
PPh , PCy , dppe or dcype,
3
3
instead of Xantphos
5
6
7
8
Without NaI
23
39
62
57
Bu4NI, instead of NaI
Bu4NBr, instead of NaI
Bu4NCl, instead of NaI
9
At 160 °C, instead of 180 °C
70
4
5
9
0
a
Reaction conditions: 1a (0.45 mmol),
2
(0.68 mmol),
5
5
5
5
5
5
1
2
3
4
5
6
Pd
2
(dba) ꞏCHCl (0.023 mmol), Xantphos (0.059 mmol), NaI (0.68
3
3
mmol), and toluene (1.5 mL) in a screw-capped vial under atmosphere
b
of N
isolated yield. Pd(OAc)
and PCy
2
for 24 h.c GC yield based on 1a. Numbers in parentheses refer to
d
2
(0.045 mmol). Ligand (0.12 mmol) for PPh
3
3
.
5
5
7
8
Having the optimized conditions in hand, we next
explored the palladium-catalyzed cyanation of various acyl
2
5
2
2
2
2
6
7
8
9
In view of the many successful examples of palladium-
catalyzed cross-coupling reactions of acyl fluorides, we
initially examined the palladium-catalyzed cyanation of the
acyl fluoride 1a using trimethylsilyl cyanide (2) as a safe
59 fluorides (Table 2). Both electron-rich (i.e., 1b and 1c) and
60 electron-deficient (i.e., 1d and 1e) acyl fluorides underwent
61 decarbonylative cyanation to provide the corresponding
62 cyanated products in an efficient manner. Acyl fluorides
1

2
4
4
2
3
Table 3. Palladium-catalyzed Cyanation of Acyl Chlorides by
Trimethylsilyl Cyanide 2
1
2
3
4
5
6
7
8
9
0
1
2
3
4
bearing nitro (1f), ester (1g) and chloro (1h) groups were
cyanated, but only in low yields, presumably because these
functional groups can react to some extent with Pd(0) and/or
the co-generated TMSI under these conditions. In fact, in
the case of 1h, the dicyanated product was also formed in
50% yield. The reaction was also applicable to sterically
hindered substrates, as 1i. Moreover, -extended aromatic
(1j) and heteroaromatic (1k) substrates also successfully
participated in this reaction. Notably, acyl fluorides derived
from aliphatic acids, such as 1l, were cyantaed to give the
corresponding alkyl cyanide 3l in 44% yield, despite the fact
that the undesired -hydride elimination of an
alkylpalladium intermediate frequently complicates the
a
O
Pd2(dba)3·CHCl3
10 mol% [Pd])
Xantphos (13 mol%)
(
CN
Cl
R
+
R
Me3Si CN
toluene
180 °C, 24 h
2
4a-4n
(
1.5 equiv)
3a-3n
(
in a sealed vessel)
CN
CN
CN
CN
1
1
1
1
1
Me
MeO
F3C
3d 73%c
95%b,c
3b 90%c
3
a
3c 82%
CN
CN
CN
CN
9
MeO
reaction, especially at higher temperature.
NC
3e
O N
Cl
2
O
1
1
5
6
Table 2. Palladium-catalyzed Cyanation of Acyl Fluorides by
5%c
3f
3g
72%
3h 53%b
7
60%
a
Trimethylsilyl Cyanide 2
Me
CN
CN
CN
Me
CN
Pd2(dba)3·CHCl3
(
10 mol% [Pd])
O
Xantphos (13 mol%)
F
+
Me Si CN
CN
3
3i 95%c
3m 94%b,c
3n 91%c
R
F
NaI (1.5 equiv)
toluene, 180 °C, 24 h
(in a sealed vessel)
R
3j 84%
4
4
2
(
1.5 equiv)
3a-3l
45
1
a-1l
a
4
4
4
4
50
5
5
6
7
8
9
Reaction conditions: Acyl chlorides (0.45 mmol), 2 (0.68 mmol),
Pd (dba) (0.023 mmol), Xantphos (0.059 mmol), and toluene
(1.5 mL) in a screw-capped vial under N
120 °C. Determined by GC analysis due to the volatility of the
product.
2
3
ꞏCHCl
3
CN
CN
CN
CN
CN
b
2
at 180 °C for 24 h. At
c
Me
MeO
F3C
95%b
3b 88%b
3d 93%b
3h 23%
3l 44%
3
a
3c 87%
1
2
CN
CN
CN
One possible scenario that can account for the positive
53 effect of NaI in the palladium/Xantphos-catalyzed
54 decarbonylative cyanation of acyl fluorides is the in situ
generation of acyl iodides via nucleophilic acyl substitution,
and a relatively weak C-I bond would allow for a more
57 facile reaction than an acyl fluoride. However, this
MeO
NC
O2N
Cl
O
3
e 73%b
3f 35%
3g 35%
5
5
5
6
Me
CN
CN
CN
CN
O
5
5
8
9
possibility can be excluded based on our observation that
the thermal reaction of 1a with NaI (1.5 equiv) did not occur
3
i 87%b
3j 93%
3k 71%
1
1
7
8
19
13
a
60 at 180 °C, as evidenced by F and C NMR spectral data
Reaction conditions: Acyl fluorides (0.45 mmol), 2 (0.68 mmol),
Pd (dba) ꞏCHCl (0.023 mmol), Xantphos (0.059 mmol), NaI (0.68
mmol), and toluene (1.5 mL) in a screw-capped vial under N at 180 °C
for 24 h. Determined by GC analysis due to the volatility of the
product.
6
6
1
2
(Scheme 2a). The thermal reaction of 1a with 2 was also
examined. Whereas no products were observed in the
63 absence of an additive, benzoyl cyanide (6) was formed in
64 53% yield when NaI was added (Scheme 2b). The thermal
1
2
2
2
2
2
9
0
1
2
3
4
2
3
3
2
b
6
6
6
6
6
7
7
7
7
7
7
7
7
7
7
8
8
8
8
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
transformation of acyl fluorides to acyl cyanides has not
We next investigated the issue of whether the
palladium/Xantphos system would be applicable to the
decarbonylative cyanation of acid chlorides. Although it has
been reported that such a cyanation reaction of acid
been reported, except for one patent in which NaCN was
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
10
used, to the best of our knowledge. These results in
conjunction with reported catalytic decarbonylation of acyl
5a,11
cyanides
indicate that 6 can serve as an intermediate in
5
c
chlorides is catalyzed by nickel, the corresponding
palladium-catalyzed reactions have not been reported. The
desired cyanation, in fact, was found to proceed with a
Pd/Xantphos catalyst (Table 3). For example, the
Pd/Xantphos-catalyzed reaction of benzoyl chloride (4a)
with 2 delivered 3a in 95 % yield. Unlike the conditions
used for acyl fluorides, the addition of NaI was not
necessary. Functional groups, such as nitro (4f), ester (4g)
and chloro (4h) groups, were compatible, presumably
because TMSCl, a co-product that is produced in this
reaction, is less harmful to these functional groups than
TMSI. Aliphatic acid chlorides cannot be cyanated under
these conditions (see SI for details).
our Pd/Xantphos-catalyzed decarbonylative cyanation of
acyl fluorides. To verify the feasibility of this scenario, we
subsequently exposed 6 to the typical conditions for the
palladium/Xantphos-catalyzed decarbonylative cyanation of
acyl fluorides, and the results showed that decarbonylation
occurred with 3a being formed in 95% yield (Scheme 2c). It
therefore appears that the non-catalyzed formation of acyl
cyanides, followed by palladium-catalyzed decarbonylation
are involved as one of the pathways in these reactions of
acyl fluorides. However, C-F bond cleavage could also be
mediated by a palladium catalyst under the catalytic
conditions, because decarbonylation occurs, even in the
absence of NaI (Entry 5, Table 1), where acyl cyanides are
not formed. Interestingly, the Pd/Xantphos-catalyzed

3
1
2
3
4
5
6
7
8
9
decarbonylation of 6 proceeded at a lower temperature than
that required for the decarbonylative cyanation of acyl
fluorides (81% at 60 °C), indicating that heating at 180 °C is
required for the initial formation of 6. Acyl chlorides were
found to react more efficiently with 2 at 180 °C than acyl
fluorides (Scheme 2d), indicating that the palladium-
catalyzed decarbonylation of the thermally generated 6 is a
predominant pathway for acyl chloride substrates.
29 use of a palladium/Xantphos catalyst is essential. This
30 method is also amenable for use in the conversion of acyl
31 chlorides.
32
This work was supported by Scientific Research on
33 Innovative Area “Hybrid Catalysis” (18H04649) from
34 MEXT, Japan. We also thank the Instrumental Analysis
35 Center, Faculty of Engineering, Osaka University, for their
36 assistance with HRMS. MT thanks Iketani Science and
37 Technology Foundation for financial support. SS thanks
1
2
3
3
4
4
8
9
0
1
JSPS Research Fellowship for Young Scientists. We also
thank the Instrumental Analysis Center, Faculty of
Engineering, Osaka University, for their assistance with
HRMS.
1
0
Scheme 2. Mechanistic Studies
(a)
O
O
NaI
F
I
42
toluene
4
3
Supporting
Information
is
available
on
1
80 C, 24 h
1
a
(in a sealed vessel)
5 0%
>99% recovery of 1a)
44 http://dx.doi.org/10.1246/cl.
(
4
5
(b)
4
6 References and Notes
O
O
2
(1.5 equiv)
47
1
(a) N. Blanchard, V. Bizet, Angew. Chem., Int. Ed. 2019, 58, 6814.
(b) Y. Ogiwara, N. Sakai, Angew. Chem., Int. Ed. 2020, 59, 574.
(c) Y. Sakurai, Y. Ogiwara, N. Sakai, J. Synth. Org. Chem. Jpn.
2020, 78, 585. (d) Z. Wang, X. Wang, Y. Nishihara, Chem.–
Asian J. 2020, 15, 1234.
F
CN
4
8
toluene
1
80 C, 20 h
49
50
51
52
(in a sealed vessel)
6
1
a
without NaI
0% (74% recovery of 1a)
with NaI (1.5 equiv) 53% (23% recovery of 1a)
2
We recently reported an intriguing reaction, in which acyl
fluorides can serve both as acyl and fluoride source: H. Fujimoto,
T. Kodama, M. Yamanaka, M. Tobisu, J. Am. Chem. Soc. 2020,
142, 17323.
5
3
(c)
Pd2(dba)3·CHCl3
O
54
55
56
57
58
59
(10 mol% [Pd])
CN
Xantphos (13 mol%)
CN
toluene
3
4
H. Lu, T.-Y. Yu, P.-F. Xu, H. Wei, Chem. Rev.in press (doi:
10.1021/acs.chemrev.0c00153).
1
80 °C, 24 h
6
3a 95%
(in a sealed vessel)
9
8
3% (at 80 °C)
1% (at 60 °C)
(a) Y. Ogiwara, Y. Sakurai, H. Hattori, N. Sakai, Org. Lett. 2018,
20, 4204. (b) Y. Okuda, J. Xu, T. Ishida, C. Wang, Y. Nishihara,
ACS Omega, 2018, 3, 13129. (c) C. A. Malapit, J. R. Bour, C. E.
Brigham, M. S. Sanford, Nature, 2018, 563, 100. (d) L. Fu, Q.
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48, 94. (h) X. Wang, Z. Wang, Y. Nishihara, Chem. Commun.
2019, 55, 10507. (i) Z. Wang, X. Wang, Y. Nishihara, Chem.
Commun. 2018, 54, 13969. (j) C. A. Malapit, J. R. Bour, S. R.
Laursen, M. S. Sanford, J. Am. Chem. Soc. 2019, 141, 17322. (k)
X. Wang, Z. Wang, L. Liu, Y. Asanuma, Y. Nishihara, Molecules
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D. –Y. Wang, A. Zhang, Adv. Synth. Catal. 2020, 362, 776.
Transition-metal-catalyzed cyanation of other carboxylic acid
derivatives have been reported. Acyl cyanides: (a) A.
Chatupheeraphat, H. –H. Liao, S. C. Lee, M. Rueping, Org. Lett.
2017, 19, 4255. Phenyl esters: (b) K. Iizumi, M. B. Kurosawa, R.
Isshiki, K. Muto, J. Yamaguchi, Synlett in press (doi: 10.1055/s-
0040-1705943). Acid chlorides: (c) Z. Wang, X. Wang, Y. Ura, Y.
Nishihara Org. Lett. 2019, 21, 6779.
(d)
6
6
0
1
O
O
2
(1.5 equiv)
Cl
CN
62
toluene
6
3
1
80 C, 20 h
(in a sealed vessel)
6
81%
4% (at 120 °C)
7% (at 100 °C)
64
65
66
67
4
a
6
3
1
1
1
2
6
6
7
7
7
73
74
7
7
7
7
79
80
8
9
0
1
2
1
1
1
1
1
1
1
2
2
2
2
3
4
5
6
7
8
9
0
1
2
3
The relatively stable nature of an acyl fluoride functionality
allows for the synthesis of multifunctionalized arenes via a
tandem C-X/C(=O)-F transformation. For example, iodide
1o underwent Suzuki-Miyaura coupling with an acyl
fluoride moiety remaining intact to form 1p, which could
subsequently be cyanated by our Pd/Xantphos method
(Scheme 3). Since the corresponding acid chlorides are not
compatible with the conditions for Suzuki-Miyaura
reactions and the use of acyl fluorides is essential for this
type of application.
1
3
5
6
5
6
7
8
In addition to classical functional group interconversion, nitriles
can be derivatized via catalytic C-CN bond transformation.
Selected reviews and reports: (a) Y. Nakao, Bull. Chem. Soc. Jpn.
2012, 85, 731. (b) M. Tobisu, N. Chatani, Chem. Soc. Rev. 2008,
37, 300. (c) Y. Kita, M. Tobisu, N. Chatani, J. Synth. Org. Chem.
Jpn. 2010, 68, 1112. (d) Y. Kita, M. Tobisu, N. Chatani, Org. Lett.
2010, 12, 1864. (e) M. Tobisu, H. Kinuta, Y. Kita, E. Rémond, N.
Chatani, J. Am. Chem. Soc. 2012, 134, 115.
8
8
8
8
8
8
8
8
8
9
9
9
9
1
2
3
4
5
6
7
8
9
0
1
2
3
2
4
Scheme 3. Synthetic Application
7
(a) N. Chatani, T. Hanafusa, J. Org. Chem. 1986, 51, 4714. (b) M.
Sundermeier, S. Mutyala, A. Zapf, A. Spannenberg, M. Beller, J.
Organomet. Chem. 2003, 684, 50.
2
2
2
2
5
6
7
8
8
9
Piet W. N. M. van Leeuwen, Paul C. J. Kamer, Catal. Sci.
Technol. 2018, 8, 26.
Reviews: (a) Kambe, T. Iwasaki, J. Terao, Chem. Soc. Rev. 2011,
40, 4937. (b) R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev.
In summary, we report on
decarbonylative cyanation of acyl fluorides, in which the
a method for the
94

4
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
2011, 111, 1417. (c) J. Choi, G. C. Fu, Science 2017, 356,
eaaf7230. Selected examples in which -hydrogen containing
alkylmetal species can participate in cross-coupling reactions
even at high temperature (>120 °C) (d) M. Tobisu, R. Nakamura,
Y. Kita, N. Chatani, J. Am. Chem. Soc. 2009, 131, 3174. (e) M.
Tobisu, T. Takahira, T. Morioka, N. Chatani, J. Am. Chem. Soc.
2016, 138, 6711.
10 Patent: T. Shi, S. Lou, O. De Lucchi, P. Padovan, PCT Int. Appl.
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12 The reaction of aroyl chloride with 2 proceeds in the presence of a
Lewis acid promotor. For example, see: G. A. Olah, M.
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1
1
1
1
1
1
1