Catalytic C-H Arylation of Aliphatic Aldehydes Enabled by a Transient Ligand

Article abstract of DOI:10.1021/jacs.6b08478

The direct arylation of aliphatic aldehydes has been established via Pd-catalyzed sp³ C-H bond functionalization in the presence of 3-aminopropanoic acids as transient directing groups. The reaction showed excellent functional group compatibility and chemoselectivity in which a predominant preference for functionalizing unactivated β-C-H bonds of methyl groups over others was achieved. In addition, C-H bonds of unactivated secondary sp³ carbons can also be functionalized. The extreme popularity and importance of aliphatic aldehydes would result in broad applications of this novel method in organic chemistry and medicinal sciences.

Full text of DOI:10.1021/jacs.6b08478

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Communication
Catalytic C-H Arylation of Aliphatic Aldehydes Enabled by a Transient Ligand
Ke Yang, Qun Li, Yongbing Liu, Guigen Li, and Haibo Ge
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08478 • Publication Date (Web): 21 Sep 2016
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Catalytic C−H Arylation of Aliphatic Aldehydes Enabled by a Transi-
ent Ligand
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Ke Yang,†, ‡ Qun Li,† Yongbing Liu,‡ Guigen Li,*,†, § and Haibo Ge*,‡
† Institute of Chemistry & BioMedical Sciences, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing
University, Nanjing 210093, P. R. China
‡ Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis, Indiana
46202, USA
§ Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409ꢀ1061, USA
Supporting Information Placeholder
aminopyridine as the transient directing group.5 Besides, selective
ABSTRACT: The direct arylation of aliphatic aldehydes has
C(sp2)−H functionalizations of phenols, alcohols, anilines or sulꢀ
fonamides have also been realized with catalytic amount of phosꢀ
phinite ligands through reversible transesterification.6,7 Recently,
Mo and Dong showed that the addition of ketone αꢀC(sp3)−H
bonds to olefins can be performed by rhodium(I) catalysis with a
catalytic transient directing group.8 In the proposed catalytic cycle,
a rationally designed secondary amine containing a pyridine
moiety reacts with the ketone substrate to form an enamine, and
simultaneously coordinates the lowꢀvalent rhodium complex.
Thus, the ketone α sp3 C−H bond can be converted into a more
reactive sp2 C−H bond, while the insertion of the rhodium into
this C−H bond is facilitated by the directing group. Despite the
success in Rh(I)ꢀcatalyzed sp2 C−H activation reactions, the direct
functionalization of unactivated sp3 C−H bonds with transient
directing groups has remained a big challenge. In a very recent
report, Yu and coꢀworkers described the palladiumꢀcatalyzed
arylation of oꢀalkyl benzaldehydes and ketones with catalytic
amounts of natural amino acids, but aliphatic aldehydes failed in
their system.9
been established via the palladiumꢀcatalyzed sp3 C−H bond funcꢀ
tionalization in the presence of 3ꢀaminopropanoic acids as transiꢀ
ent directing groups. The reaction showed excellent functional
group compatibility and chemoselectivity in which predominant
preference of functionalizing unactivated βꢀC−H bonds of methyl
groups over others was achieved. In addition, C−H bonds of unacꢀ
tivated secondary sp3 carbons can also be functionalized. The
extreme popularity and importance of aliphatic aldehydes would
result in broad applications of this novel method in organic chemꢀ
istry and medicinal sciences.
Transition metalꢀcatalyzed carbonꢀhydrogen bond functionaliꢀ
zation is one of most efficient tools for selective carbonꢀcarbon
and carbonꢀheteroatom bond constructions in organic chemistry.
Towards the development of synthetically invaluable methods,
two principal challenges arise in this approach: the inert feature of
most C−H bonds and siteꢀselectivity in reactions with multiple
analogous C−H bonds. To address these issues, chemists have
typically relied on the use of substrates that contain various directꢀ
ing groups.1 The reactivity of the C−H bonds as well as the posiꢀ
tional selectivity can be greatly promoted by the close proximity
of C−H bonds to the metal centres. In the past decade, a great
progress on transition metalꢀcatalyzed selective activation of eiꢀ
ther C(sp2)−H or C(sp3)−H bonds have been achieved by using
directing groups on substrates,2,3 but this approach exist limitaꢀ
tions. Additional steps are required for the preꢀconstruction of the
substrates and for removal of the directing groups, which diminꢀ
ishes the efficiency and compatibility of the reactions.
Aliphatic aldehydes are ubiquitous structural units in biologiꢀ
cally active natural products and pharmaceuticals, and the key
intermediates in chemical synthesis.10 Therefore, the derivatizaꢀ
tion of aliphatic aldehydes has attracted much attention in organic
community. Methods for the functionalization at the ipsoꢀ and αꢀ
positions of C=O moieties have been well documented.11 The βꢀ
functionalization of aliphatic aldehydes relies primarily on the
addition of soft nucleophiles to α,βꢀunsaturated aldehydes which
often requires preꢀfunctionalization of the saturated precursors.12
But the direct βꢀfunctionalization of aliphatic aldehydes is rare. In
2011, Wang and coworkers reported the enantioselective βꢀ
functionalization of simple aldehydes in the presence of a simple
chiral amine catalyst and the nonꢀtoxic oxidant IBX, involving a
sequential enamine formation, oxidation, and nucleophilic addiꢀ
tion process (Scheme 1A).13 Very recently, MacMillan group
developed the direct functionalization of unactivated βꢀC−H
bonds of aliphatic aldehydes by merging the organocatalysis and
photoredox catalysis; and electron deficient (hetero)arenes and
Michael acceptors proven to be effective substrates in the process
(Scheme 1B).14 In our continuous efforts to develop efficient C−H
A promising solution to this problem would be to introduce a
wellꢀdesigned temporary directing group that binds reversibly to
the substrate and the metal centre. In the process, the desired siteꢀ
selective activation would be accomplished with a catalytic
amount of this transient directing group without changing the
substrate function after the catalysis is finished. Some early pioꢀ
neering strategies by utilizing reversibly formed covalent bonds
have proven successfully.4 Jun and coꢀworkers reported that Rhꢀ
catalyzed functionalization of aldehyde C−H bonds using 2ꢀ
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functionalization processes, here we report the palladiumꢀ
pling of 2ꢀmethylpentanal (1a) and iodobenzene (2a) in the presꢀ
catalyzed arylation of unactivated βꢀC−H bonds of aliphatic aldeꢀ
hydes with 3ꢀaminopropanoic acids as novel transient directing
groups (Scheme 1C).
ence of catalytic Pd(OAc)2 and stoichiometric amounts of AgTFA
with 3ꢀaminopropanoic acid (L1) as a transient directing group at
80 °C (Table 1). Initial solvent screening showed that the desired
arylated product 3a could be obtained in AcOH, TFE or HFIP
(entries 1ꢀ3). It was then noticed that the reaction was significantꢀ
ly improved with HFIP and AcOH as the coꢀsolvent at the volume
ratio of 5:1 (entries 4ꢀ6). Next, the effect on selected ligands toꢀ
wards the process was examined. It turned out that the reaction
failed with natural amino acid glycine (L2) as the ligand, indicatꢀ
ing a [5,5]ꢀbicyclic palladium intermediate is not suitable in this
process (entry 7). In contrast, all substituted 3ꢀaminopropanoic
acids L3ꢀL5 led to the formation of the desired arylated product
3a, albeit with lower efficiency compared with L1 (entries 8ꢀ10).
Then, the examination on different palladium catalysts revealed
that this reaction can also be catalyzed by PdCl2, Pd(TFA)2 or
Pd(acac)2 with moderate yields (entries 11ꢀ13). Following the
above investigation, the screening of silver salts was conducted,
and a low yield was observed with AgF, AgF2, or AgOAc (entries
14ꢀ16). Interestingly, a lower yield was observed with either inꢀ
creased or decreased loading of the ligand L1 (entries 17 and 18).
To our delight, the isolated yield was improved to 71% by inꢀ
creasing the reaction concentration from 0.1 M to about 0.14 M
(entry 19). It is noteworthy that no desired product 3a was obꢀ
tained in the absence of a silver salt or ligand was absent (entry 20
and 21).
Scheme 1. Direct βꢀfunctionalization of aliphatic aldehydes
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11
12
13
14
15
16
17
18
19
20
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60
Table 1. Optimization of reaction conditionsa
Table 2. Scope of aliphatic aldehydesa,b
CHO
CHO
L
cat. Pd, cat. , Additives
H
+
PhI
Ph
Solvent, 80 oC, 24 h, N2
2a
1a
3a
COOH
COOH
COOH
COOH
COOH
H2N
L2
H2N
H2N
H2N
L5
H2N
L1
L3
L4
Solvent
AcOH
entry Pd source Ligand(mol%) Additives
Yield(%)b
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(40)
(60)
(20)
(40)
(40)
-
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgF
16
6
2
TFE
3
HFIP
29
45
53
63
0
4
HFIP/AcOH (1/1, v/v)
HFIP/AcOH (3/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
HFIP/AcOH (5/1, v/v)
5
6
7
8
38
21
37
48
54
55
44
27
5
9
10
11
12
13
14
15
16
17
18
19c
20c
21c
Pd(TFA)2
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgF2
AgOAc
AgTFA
AgTFA
AgTFA
-
50
47
75(71)d
0
AgTFA
0
aReaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), Pd source
aReaction conditions: 1 (0.3 mmol), 2a (0.45 mmol), Pd(OAc)2
(0.03 mmol), AgTFA (0.45 mmol), L1 (0.12 mmol), HFIP (1.8
(0.03 mmol), ligand, additives (0.45 mmol), solvent (3 mL), 80
1
oC, N2, 24h. bYields are based on 1a, determined by HꢀNMR
o
b
c
c
mL), HOAc (0.36 mL), 80 C, N2, 24 h. Isolated yields. HFIP
using dibromomethane as the internal standard. HFIP (1.8 mL),
(2.25 mL), HOAc (0.75 mL). 2a (0.6 mmol). 36 h. fL4 (0.12
d
e
HOAc (0.36 mL). dIsolated yields.
mmol), 100 oC.
Very recently, our group discovered the palladiumꢀcatalyzed
direct γꢀarylation of primary amines with glyoxylic acid as a tranꢀ
sient directing group and acetic acid as the solvent.15 On the basis
of this study, we commenced our investigation on the cross couꢀ
Next, we carried out the substrate scope study of aliphatic aldeꢀ
hydes under the optimized reaction conditions. As shown in Table
2, αꢀmethylꢀαꢀalkyl substituted acetaldehyde derivatives provided
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the corresponding products in good yields with excellent siteꢀ
would not be excluded in this reaction.16 To clarify this, cross
coupling of methacrylaldehyde (4) and iodobenzene was examꢀ
selectivity (3aꢀg). In all cases, the functionalization of the βꢀC−H
bonds of αꢀmethyl groups is predominantly favored over γꢀ or δꢀ
C−H bonds of the methyl groups, indicating that the kinetic barriꢀ
er towards functionalizing the βꢀC−H bond is lower than γꢀ or δꢀ
C−H bond. It was also found that with isobutyraldehyde was emꢀ
ployed as the substrate, both βꢀmonoꢀ and β,β′ꢀdiphenyl substitutꢀ
ed products were generated (3d). This result suggests that the
reaction was performed with a great preference for functionalizing
the sp3 βꢀC−H bond of the methyl group over the relatively reacꢀ
tive benzylic βꢀC−H bond. In addition, cyclic sp3 C−H bonds
were functionalized with high siteꢀ and stereoꢀselectivity, providꢀ
ing the cisꢀisomers as the major products (3j and 3k). Furthermore,
selective functionalization of a βꢀC−H bond of a methylene group
was also achieved in the presence of a γꢀC−H bond of a methyl
group (3l). Moreover, unactivated methyl and methylene βꢀC−H
bonds of linear aliphatic aldehydes could also be arylated with
iodobenzene by using 3ꢀaminoꢀ3ꢀmethylbutanoic acid (L4) as a
transient directing group (3m and 3n).
ined
under
the
current
conditions.
2ꢀMethylꢀ3ꢀ
phenylacrylaldehyde (5) and 2ꢀbenzylꢀ3ꢀphenylacrylaldehyde (6)
were obtained in 13% and 45% yield, respectively, while the diꢀ
rect sp3 C−H arylation product (3d) was not observed. Notably,
the similar results were also obtained in the absence of ligand L1.
Additionally, we examined the reaction of isobutyraldehyde (1d)
and iodobenzene without ligand L1 under the current conditions,
and no desired products (3d) were observed. These outcomes
suggest that dehydrogenation of aliphatic aldehydes is not inꢀ
volved in the formation of the desired products. In order to further
illustrate the reaction mechanism, the bicyclic palladium intermeꢀ
diate 7 was captured from the reaction of 2ꢀmethylpentanal with
3ꢀaminopropanoic acid in the presence of stoichiometric amounts
of Pd(OAc)2 and one of equivalent pyridine.15,17 Next, the desired
arylated product 3a was isolated in 52% yield using the intermeꢀ
diate 7 and iodobenzene under the arylation conditions (Scheme
3).
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
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60
We then examined the substrate scope of aryl iodides. As
shown in Table 3, the great functional group compatibility was
observed in this catalytic process. Iodobenzene substituted with an
electronꢀdonating group (alkoxyl or alkyl) or moderate or strong
electronꢀwithdrawing group (ester or CF3) were all compatible
with the current catalytic system. In addition, halogens (F, Cl, or
Br) were well tolerated, enabling the further manipulation of the
initial products. It was also noticed that there is no an apparent
electronic effect in the process.
Scheme 2. Control experiments
O
(1.5 eq)
PhI
O
O
Pd(OAc)2 (10 mol%)
Ph
H
Ph
H
+
H
AgTFA (1.5 eq), HFIP/HOAc
80 oC, 24 h, N2
Ph
3d1
1d
3d2
L1
with
without
(40 mol%)
34%
0%
37%
L1
0%
O
O
O
Table 3. Scope of aryl iodidesa,b
same as above
Ph
H
3d
+
Ph
H
H
+
Ph
4
5
6
L1
with
(40 mol%)
L1
13%
15%
0%
0%
45%
40%
without
Scheme 3. Synthesis of bicyclic palladium intermediate 7 and
subsequent arylation
On the basis of the above results and the previous literature reꢀ
ports,9,15,18 a plausible reaction pathway of this process is proꢀ
posed as shown in Scheme 4. Condensation of aliphatic aldehyde
1 with the ligand 3ꢀaminopropanoic acid provides the imine inꢀ
termediate A. Coordination of the imine intermediate A to a palꢀ
ladium species produces the corresponding sixꢀmember cyclic
palladium complex B. Next, the cyclometalation gives rise to a
[5,6]ꢀbicyclic palladium intermediate C via a siteꢀselective C−H
bond activation process and oxidative addition of the intermediate
C with an aryl iodide generates the palladium (IV) species D.
Finally, reductive elimination of the palladium complex D folꢀ
lowed by the ligand dissociation and iodide abstraction processes
gives the βꢀimino acid F, which releases the desired product 3,
and ligand 3ꢀaminopropanoic acid.
aReaction conditions: 1a (0.3 mmol), 2 (0.45 mmol), Pd(OAc)2
(0.03 mmol), AgTFA (0.45 mmol), L1 (0.12 mmol), HFIP (1.8
o
b
mL), HOAc (0.36 mL), 80 C, N2, 24 h. Isolated yields. c105 oC,
36 h.
To provide some insights into the reaction mechanism, a series
of control experiments were carried out (Scheme 2). It has been
demonstrated that aliphatic carbonyl compounds could undergo
dehydrogenation to produce the corresponding α,βꢀunsaturated
derivatives. Therefore, a sequential oxidation/addition process
Scheme 4. Plausible reaction mechanism
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CHO
CHO
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Ar
H
R1
R1
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AgTFA
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N
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PdII
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X
E
B
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-HX
X = AcO- or TFA-
R1
R2
N
R1
N
PdII
O
PdIV
O
Ar
I
O
R2
O
D
C
ArI
2
In summary, a highly siteꢀselective arylation reaction of an aliꢀ
phatic aldehyde with an aryl iodide was developed via a palladiꢀ
umꢀcatalyzed sp3 C−H bond functionalization process with 3ꢀ
aminopropanoic acid as a novel transient directing group. A great
preference for functionalizing unactivated βꢀsp3 C−H bonds of
methyl groups over the unactivated βꢀmethylene, γꢀ or δꢀterminal
C−H bonds was observed. In addition, the cyclic aldehydes could
be functionalized in a diastereoselective manner by favoring the
cis products. Furthermore, the direct C−H functionalization of
unactivated secondary βꢀC−H bonds has also been achieved, albeꢀ
it with a lower efficiency. Moreover, a good functional group
compatibility was observed in the process, and both electronꢀrich
and electronꢀdeficient aromatic rings can be efficiently incorpoꢀ
rated into the aliphatic aldehydes at a highly siteꢀselective manꢀ
ner. Considering the vital importance of aliphatic aldehyde in
organic and pharmaceutical research, this reaction would have the
great potential for broad applications in organic and medicinal
chemistry. The detailed mechanistic studies and synthetic applicaꢀ
tions of this process are currently undergoing in our laboratory.
(8) Mo, F.; Dong, G. Science 2014, 345, 68.
(9) Zhang, F.ꢀL.; Hong, K.; Li, T.ꢀJ.; Park, H.; Yu, J.ꢀQ. Science 2016, 351, 252.
(10) For selected reviews, see: (a) Tatsuta, K. J. Antibiot. 2013, 66, 107. (b) Kim, H.
Y.; Walsh, P. J. Acc. Chem. Res. 2012, 45, 1533. (c) Dyachenko, V. D.; Karpov, E. N.
Russ. J. Org. Chem. 2011, 47, 1. (d) Moreau, A. P. X.; Campagne, J.ꢀM. Chem. Rev.
2006, 106, 911.
(11) For selected reviews, see: (a) Allen, A. E.; MacMillan, D. W. C. Chem. Sci.
2012, 3, 633. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471. For selected a example, see: (c) Terao, Y.; Fukuoka, Y.; Satoh, T.;
Miura, M.; Nomura, M. Tetrahedron Lett. 2002, 43, 101.
ASSOCIATED CONTENT
Supporting Information
(12) For a selected review, see: (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033. For selected examples, see: (b) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2006, 128, 9328. (c) Brown, S. P.; Goodwin, N. C.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2003, 125, 1192. (d) Austin, J. F.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 1172. (e) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2002, 124, 7894. (f) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001,
123, 4370.
Experimental details and compound characterizations. This mateꢀ
rial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(13) Zhang, S.ꢀL.; Xie, H.ꢀX.; Zhu, J.; Li, H.; Zhang, X.ꢀS. Li,; J.; Wang, W. Nat.
Commun. 2011, 2, 211.
*Eꢀmail: guigen.li@ttu.edu
*Eꢀmail: geh@iupui.edu
(14) (a) Terrett, J. A.; Clift, M. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2014,
136, 6858. (b) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C.
Science 2013, 339, 1593.
Notes
(15) Liu, Y.; Ge, H. Nat. Chem. 2016, DOI: 10.1038/NCHEM.2606.
(16) (a) Muzart, J. Eur. J. Org. Chem. 2010, 2010, 3779. (b) Terao, Y.; Kametani, Y.;
Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron 2001, 57, 5967.
(17) Pyridine might act as an additional ligand to generate a stable palladium interꢀ
mediate, see: Calleja, J.; Pla, D.; Gorman, T. W.; Domingo, V.; Haffemayer, B.;
Gaunt, M. J. Nature 2014, 510, 129.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We gratefully acknowledge NSF (CHEꢀ1350541) and Indiana
University Purdue University Indianapolis for financial support.
Ke Yang, Qun Li, and Guigen Li are also grateful for financial
support from NSFC: (No. 21332005) and Robert Welch Foundaꢀ
tion (USA).
(18) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127,
13154. (b) Arroniz, C.; Denis, J. G.; Ironmonger, A.; Rassias, G.; Larrosa, I. Chem.
Sci. 2014, 5, 3509. (c) Weibel, J.ꢀM.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149.
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