An Effective Pd-Catalyzed Regioselective Hydroformylation of Olefins with Formic Acid

Article abstract of DOI:10.1021/jacs.6b10297

An effective palladium-catalyzed regioselective hydroformylation of olefins with formic acid is described. The ligand plays a crucial role in directing the reaction pathway. Linear aldehydes can be obtained in up to 93% yield with >20:1 regioselectivity using 1,3-bis(diphenylphosphino)propane (dppp) as the ligand. The reaction process is operationally simple and requires no syngas.

Full text of DOI:10.1021/jacs.6b10297

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Communication
An Effective Pd-Catalyzed Regioselective
Hydroformylation of Ole-fins with Formic Acid
Wenlong Ren, Wenju Chang, Jie Dai, Yuan Shi, Jingfu Li, and Yian Shi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b10297 • Publication Date (Web): 31 Oct 2016
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An Effective Pd-Catalyzed Regioselective Hydroformylation of Ole-
fins with Formic Acid
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Wenlong Ren,a Wenju Chang,a Jie Dai,a Yuan Shi,a Jingfu Li,a and Yian Shi*a,b
aState Key Laboratory of Coordination Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Center for Multi-
molecular Organic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China)
bDepartment of Chemistry, Colorado State University, Fort Collins, Colorado, 80523 (USA)
Supporting Information
O
O
ABSTRACT: An effective palladium-catalyzed regioselective hydro-
formylation of olefins with formic acid is described. The ligand plays a
crucial role in directing the reaction pathway. Linear aldehydes can be
obtained with up to 93% yield and >20:1 regioselectivity using dppp as
ligand. The reaction process is operationally simple and requires no
syngas.
HCOOH
Pd/L,
COOH
R
R
R
R
Pd
O
H
HCOOPh or Ac2O
1
10
3
2
CO2
H
O
H
O
R
Pd
11
Figure 1. Hydrocarbonylation with HCOOH.
Aldehydes are an important class of organic compounds and syn-
thetically versatile intermediates for pharmaceuticals and fine chemi-
cals. Hydroformylation provides a direct approach to aldehydes from
olefins (Scheme 1).1 Various transition metals such as Co, Rh, Ru, Ir,
Pd, have been used as catalysts. The reaction with Rh is probably the
most extensively studied.2 Hydroformylation is traditionally carried
out with syngas (CO/H2) (frequently at high pressure). The studies
and applications of the hydroformylation process are hindered for
laboratories that are not equipped for the handling of CO and H2.
Progress has been made in hydroformylation with syngas surrogates3
such as formaldehyde,4 alcohols.5 Formic acid has also been used for
the hydroformylation with Rh catalyst in the presence of CO.6 In this
case, formic acid served as hydrogen source for the reaction.
worth noting. In general, branched aldehydes2b, 2k-o, 2x are favored in
most of the hydroformylation processes with few exceptions,2p, 2v likely
due to the formation of a stabilized benzyl metal complex.
Styrene (1a) was used as the test substrate for the studies. Various
phosphine ligands were initially screened with 5 mol % Pd(OAc)2, 2.0
equiv HCOOH, and 1.0 equiv Ac2O in toluene at 80 C for 24 h. As
o
shown in Table 1, the reaction outcome was highly dependent on the
ligand used. Little aldehyde was observed with monodentate ligand
such as PPh3, (Table 1, entry 1). For the most of bidentate ligands
except dppp, little or only small amounts of aldehydes were detected
(Table 1, entries 2-8). In the case of dppp, aldehydes 2a and 2a’ were
formed in 42% crude yield (Table 1, entry 3). Encouraged by this
result, additional reaction conditions were further investigated with
dppp as ligand. Several Pd catalysts were subsequently tested for the
hydroformylation (see Supporting Information), the best result was
obtained with Pd(OAc)2. The solvent was also found to be an im-
portant factor for the competition between hydroformylation and
hydrocarboxylation (Table 1, entries 9-10)(for more solvent studies,
see Supporting Information). The formation of acids 3a and 3a’ were
suppressed when the reactions were carried out in DCE (Table 1, entry
10). Studies showed that the hydroformylation could be further im-
proved by the addition of small amounts of additive such as Bu4NI,
aldehyde 2 was formed 77% yield (l:b = >20:1) with 5 mol %
Pd(OAc)2, 10 mol % dppp, 2.0 equiv HCOOH, and 1.0 equiv Ac2O in
the presence of 2.5 mol % Bu4NI (Table 1, entry 11) (for more additive
studies, see Supporting Information). The amount of Bu4NI used
appeared to be important for the reaction. The yield of aldehyde 2a
was reduced to 35% when 10 mol % Bu4NI was used (Table 1, entry
12). The reaction was completely suppressed with 20 mol % Bu4NI
(Table 1, entry 13).11 The yield was also found to be dependent on the
amounts of HCOOH and Ac2O (Table 1, entries 14-15) and was in-
creased to 93% with 3.9 equiv HCOOH and 3.0 equiv Ac2O (Table 1,
entry 15). To further investigate the ligand effect on the hydroformyla-
tion, the reaction was reexamined with other ligand such as dppf under
Scheme 1. Transition-metal catalyzed hydroformylation of olefins.
Recently, we have shown that carboxylic acids can be obtained in
good yields via Pd-catalyzed hydrocarboxylation of olefins with formic
acid in the presence of catalytic amounts of HCOOPh7 or Ac2O.8,9 The
Pd complex 10 was proposed to be an intermediate for the formation of
carboxylic acid 3 (Figure 1). From this intermediate, we envisioned
that an aldehyde (2) could be generated under proper reaction condi-
tions via the loss of CO2 and a reductive elimination of the resulting Pd
hydride species 11 (Figure 1). To explore this possibility, various reac-
tion parameters were subsequently investigated. It was found that the
ligand has a dramatic effect on the pathway. We now report that the
envisioned hydroformylation process can be achieved with dppp as
ligand using HCOOH and Ac2O in the presence of Pd catalyst.10
A
variety of aryl and alkyl olefins can be effectively hydroformylated to
give the corresponding aldehydes without using syngas. The high
regioselectivity for linear aldehydes with aryl olefins is particularly
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Table 1: Studies on the reaction conditions.a
tion process, giving the aldehydes in 65-79% yield (Table 2, entries 17
and 18).
1
2
3
4
5
6
7
8
CHO
COOH
COOH
Pd(OAc)2 , ligand
HCOOH, Ac2O
A precise reaction mechanism is not clear at this moment, one of
Ph
Ph
Ph
2a
3a
plausible catalytic cycles is shown in Scheme 2. The Pd(0) was oxida-
tively inserted to HCOOAc (4) (generated from HCOOH and Ac2O)
to give palladium hydride complex 5, which rearranged to complex 6.
The olefin (1) was hydropalladated by 6 to generate alkyl palladium
complex 7, which underwent a migratory insertion to give acylpalladi-
um complex 8. The OAc group of 8 was subsequently replaced by the
iodide to give Pd-I complex 9, which reacted with HCOOH to form
complex 10. The Pd-H complex 11 was formed from complex 10 via
release of CO2. The reductive elimination of 11 led to aldehyde 2 with
the regeneration of Pd(0) catalyst.
+
Ph
additive, solvent
80 oC, 24 h
1a
Ph
CHO
2a'
3a'
yield (%)b
2a 2a’ 3a
entry ligand
solvent
additive
3a’
68
15
5
9
1
PPh3
dppe
dppp
dppb
dppf
binap
L1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
0
0
3
6
1
0
2
1
3
7
4
2
0
0
2
0
0
17
8
10
11
12
13
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2
4
3
36
2
30
69
56
36
The additive and ligand were crucial for the hydroformylation pro-
cess. Overall, the iodide could facilitate the acetate-formate exchange
(from 8 to 10) via Pd-I intermediate 9. However, the addition of excess
amounts of iodide relative to the Pd was found to be detrimental to the
hydroformylation process (Table 1, entries 12 & 13 vs entry 11), likely
due to the over coordination of the iodide to the Pd.11 Among various
ligands examined, only dppp was found to be effective for the current
hydroformylation process. Complex 10 served as a common interme-
diate for both acid 3 and aldehyde 2. The reductive elimination of 10
could give anhydride 12, which subsequently led to acid 3. It appeared
that the unique bite angle of dppp13,14 favored the CO2 releasing pro-
cess over the corresponding reductive elimination, thus favoring the
formation of the aldehyde (2) over the corresponding carboxylic acid
(3).
4
26
40
10
5
0
6
5
7
3
trace trace
8
L2
24
34
49
75
35
0
26
40
0
6
9
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppf
13
1
10
11
12c
13d
14e
15f
16f
DCE
DCE
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
0
0
DCE
0
0
DCE
0
0
DCE
83
93
0
0
0
DCE
0
0
Scheme 2. Proposed catalytic cycle for regioselective hydroformyla-
tion.
DCE
80
20
Pd(0) +
CO + AcOH
(Cy)2P
P(Cy)2
Ph2P
PPh2
OAc
R
L1
1
L2
H Pd Ln
OAc
PdLn
CO
O
CO
6
a The reactions were carried out with 1a (0.50 mmol), Pd(OAc)2 (0.025 mmol),
ligand (0.050 or 0.10 mmol, P/Pd = 4/1), HCOOH (1.0 mmol), Ac2O (0.50
mmol), and additive (0.0125 mmol) in toluene (0.50 mL) at 80 oC for 24 h
R
AcO PdLn
7
H
5
+
Ac2O
b
HCOOH
unless otherwise stated. The yield was determined from the crude reaction
c
mixture by 1H NMR with BnOCH3 as an internal standard. With 10 mol %
O
Bu4NI. d With 20 mol % Bu4NI. e With 3.0 equiv HCOOH and 2.0 equiv Ac2O.
HCOOAc
f
4
With 3.9 equiv HCOOH and 3.0 equiv Ac2O.
R
PdLn
OAc
I
COOH
Pd(0)Ln
R
8
3
CHO
R
2
O
O
O
AcO
the optimized reaction conditions (in the presence of 2.5 mol % Bu4NI
in DCE). In this case, acids were formed predominately (Table 1,
entry 16), illustrating the crucial role of dppp for the hydroformylation.
O
O
R
H
12
Pd
I
L
n
R
R
Pd
Ln
H
9
11
With the optimized reaction conditions in hand, the reaction gener-
ality was subsequently investigated. As shown in Table 2, the hydro-
formylation can be extended to a variety of styrenes, giving the corre-
sponding linear aldehydes in 67-93% yield (Table 2, entries 1-11).12
Various substituents on the phenyl groups were tolerated. The reac-
tion proceeded with high regioselectivity (l:b = >20:1) regardless of
the substituent on the phenyl group. The hydroformylation was also
effective for alkyl terminal olefins. The corresponding linear aldehydes
were isolated in 52-83% (Table 2, entries 12-15). The regioselectivity
was somewhat dependent on the alkyl group on the olefin with the l:b
ratio ranging from 7:1 to >20:1. The reaction also proceeded smoothly
with complex substrate such as sterol derivative 1p, giving the corre-
sponding aldehyde in 81% yield with >20:1 l:b ratio (Table 2, entry
16). Cycloalkenes were also effective substrates for the hydroformyla-
O
O
HCOO
CO2
I
H
R
Pd
Ln
O
10
To investigate if HCOOAc was involved in the reaction, isolated
anhydride HCOOAc (4) (prepared from AcCl and HCOONa)15 was
used. As shown in Scheme 3, aldehyde 2a was obtained in 87% yield
when the reaction was carried out with 3.0 equiv HCOOAc and 1.0
equiv HCOOH in the presence of 5 mol % Pd(OAc)2, 10 mol % dppp,
and 2.5 mol % Bu4NI. These results supported the involvement of
HCOOAc. When the reaction was carried out in the absence of
HCOOH, only trace amounts of the aldehyde were observed, showing
that HCOOH was also necessary for the reaction.
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Scheme 3. Hydroformylation with HCOOAc and HCOOH.
Table 2: Pd-catalyzed Hydroformylation of Olefins.a
1
HCOOH (1.0 equiv)
HCOOAc (3.0 equiv)
Pd(OAc)2 (5 mol %)
Pd(OAc)2 (5 mol %)
dppp (10 mol %)
2
3
4
5
6
7
R1
R2
CHO
R3
CHO
HCOOH
+
R2
R1
Bu4NI (2.5 mol %)
Ac2O (3.0 equiv)
dppp (10 mol %)
Bu4NI (2.5 mol %)
1
R3
2
4 Å MS, DCE, 80 o
C
1a
2a (87%)
4 Å MS, DCE, 80 o
C
entry substrate
product
yield (%)(l:b)b
8
9
CHO
X
Scheme 4. Deuterium-labeling experiments.
X
10
11
12
13
14
15
16
17
18
19
20
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60
Pd(OAc)2 (5 mol %)
dppp (10 mol %)
DCOOD (1.0 equiv)
40% D
a
O
c
1
2
3
4
5
2a
2b
2c
2d
2e
93 (> 20:1)
79 (> 20:1)
81 (> 20:1)
89 (> 20:1)
90 (> 20:1)
X = H, 1a
X = p-Cl, 1b
X = p-OMe, 1c
X = m-OMe, 1d
X = o-OMe, 1e
H (52% D)
b
DCOOAc (3.0 equiv)
MeO
60% D
MeO
Bu4NI (2.5 mol %)
4 Å MS, DCE, 80 o
C
1c
2c-d, (43%)
24% D
a
CHO
Pd(OAc)2 (5 mol %)
dppp (10 mol %)
H (17% D)
b
6
85 (> 20:1)
DCOOAc (1.0 equiv)
H(17% D)
1f
2f
MeO
MeO
DCE, 80 o
C
1c-d, (30%)
1c
CHO
7
88 (> 20:1)
To further probe the reaction mechanism, the hydrofomylation was
carried out with 1-methoxy-4-vinylbenzene (1c), DCOOAc, and
DCOOD in the presence of 5 mol % Pd(OAc)2, 10 mol % dppp, and
2.5 mol % Bu4NI (Scheme 4). The aldehyde (2c-d) was isolated in
43% yield with 40% D, 60% D, and 52% D at the three carbons, respec-
tively. When the reaction was carried out in the absence of DCOOD,
30% of unreacted olefin was recovered with 24% D and 17% D at the
two carbons. These results suggest that both linear and branched Pd
complexes 7 and 7’ were formed during the hydropalladation of the
olefin by Pd-H complex 6, and the reaction process was reversible
(Scheme 5). The linear aldehyde resulting from complex 7 was formed
predominately under the reaction conditions.
1g 2g
CHO
8
67 (> 20:1)
1h 2h
CHO
X
X
9
10
11
2i
2j
2k
78 (> 20:1)
86 (> 20:1)
80 (> 20:1)
X = H, 1i
X = p-Cl, 1j
X = p-Me, 1k
Scheme 5. The reversible hydropalladation.
CHO
12
65 (7:1)
4
1l 2l
OAc
OAc
4
OAc
PdLn
CO
+
+
R
H Pd Ln
PdLn
R
CHO
R
RO
RO
7
CO
7
CO
1
6
7
7'
13
14
2m
2n
52 (9:1)
65 (9:1)
R = Bn, 1m
R = TBDPS, 1n
O
MeO
MeO
CHO
CHO
L
Pd
n
R
R
15
16
83 (> 20:1)
2
OAc
8
1o 2o
OMe
OMe
CHO
In summary, we have developed an effective Pd-catalyzed regioselec-
tive hydroformylation of olefins with dppp as ligand using HCOOH-
Ac2O under mild reaction conditions. A wide variety of linear alde-
hydes have been obtained in good yields with high regioselectivity
without using flammable and toxic syngas. The hydroformylation
reaction is operationally simple, which could provide a useful method
for the preparation of linear aldehydes. It was found that the ligand
played a crucial role in directing the reaction pathway (hydroformyla-
tion vs hydrocarboxylation). Further efforts will be devoted to under-
standing the reaction mechanism, expanding the substrate scope, de-
veloping a reaction process for branched aldehydes.
81 (> 20:1)
MeO
1p
2p
CHO
n
n
17
18
2q
2r
79
65
n = 1, 1q
n = 2, 1r
a
Reactions were carried out with substrate 1 (0.50 mmol), Pd(OAc)2 (0.025
mmol), dppp (0.050 mmol), Bu4NI (0.0125 mmol), 4 Å molecular sieve (10
mg), HCOOH (1.95 mmol), Ac2O (1.50 mmol) in DCE (0.50 mL) at 80 oC for
24 h. b Isolated yield. The ratio of l/b was determined by 1H NMR analysis of
the crude reaction mixture.
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Lee, H. N.; Korneeva, G. A. J. Molecular Catal. A: Chem. 1999, 144, 295. (c)
ASSOCIATED CONTENT
Supporting Information
Rosales, M.; González, A.; González, B.; Moratinos, C.; Pérez, H.; Urdaneta, J.;
Sánchez-Delgado, R. A. J. Organometallic Chem. 2005, 690, 3095. (d) Makado,
G.; Morimoto, T.; Sugimoto, Y.; Tsutsumi, K.; Kagawa, N.; Kakiuchi, K. Adv.
Synth. Catal. 2010, 352, 299. (e) Cini, E.; Airiau, E.; Girard, N.; Mann, A.;
Salvadori, J.; Taddei, M. Synlett 2011, 199. (f) Ren, H.; Wulff, W. D. Org. Lett.
2013, 15, 242. (g) Morimoto, T.; Fujii, T.; Miyoshi, K.; Makado, G.; Tanimoto,
H.; Nishiyama, Y.; Kakiuchi, K. Org. Biomol. Chem. 2015, 13, 4632. (h)
Fuentes, J. A.; Pittaway, R.; Clarke, M. L. Chem. Eur. J. 2015, 21, 10645.
(5) For leading references on Rh-catalyzed hydroformylation of olefins via ex
situ generated syngas from alcohols via Ir-catalyzed dehydrogenative decar-
bonylation, see: (a) Verendel, J. J.; Nordlund, M.; Andersson, P. G. ChemSus-
Chem 2013, 6, 426. (b) Christensen, S. H.; Olsen, E. P. K.; Rosenbaum, J.;
Madsen, R. Org. Biomol. Chem. 2015, 13, 938.
1
2
3
4
5
6
7
8
Experimental procedures, characterization data, NMR spectra, and CIF
informations. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: Yian.Shi@colostate.edu
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Notes
The authors declare no competing financial interests.
(6) For leading references on hydroformylation of olefins with
HCOOH/CO, see: (a) Somasundcram, A.; Alper, H. J. Molecular Catal. 1994,
35. (b) Ali, B. E.; Vasapollo, G.; Alper, H. J. Molecular Catal. A: Chem. 1996,
112, 195.
ACKNOWLEDGMENT
(7) (a) Wang, Y.; Ren, W.; Li, J.; Wang, H.; Shi, Y. Org. Lett. 2014, 16, 5960.
(b) Dai, J.; Ren, W.; Wang, H.; Shi, Y. Org. Biomol. Chem. 2015, 13, 8429.
(8) Wang, Y.; Ren, W.; Shi, Y. Org. Biomol. Chem. 2015, 13, 8416.
(9) For leading references on metal-catalyzed hydrocarboxylation of alkynes
with HCOOH-Ac2O, see: (a) Hou, J.; Xie, J.-H.; Zhou, Q.-L. Angew. Chem.
Int. Ed. 2015, 54, 6302. (b) Fu, M.-C.; Shang, R.; Cheng, W.-M.; Fu, Y. ACS
Catal. 2016, 6, 2501. (c) Hou, J.; Yuan, M.-L.; Xie, J.-H,; Zhou, Q.-L. Green
Chem. 2016, 18, 2981.
(10) For leading references on Pd-catalyzed hydroformylation of olefins
with syngas, see: (a) Dekker, G. P. C. M.; Elsevier, C. J.; Vrieze, K.; van Leeu-
wen, P. W. N. M.; Roobeek, C. F. J. Organometallic Chem. 1992, 430, 357. (b)
Scheele, J.; Timmerman, P.; Reinhoudt, D. N. Chem. Commun. 1998, 2613. (c)
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2009, 15, 6383.
(11) Konya, D.; Leñero, K. Q. A.; Drent, E. Organometallics 2006, 25, 3166.
(12) The hydroformylation of α-methylstyrene with common chiral ligands,
such as (S)-BINAP, (S)-DTBM-SEGPHOS, (S)-DIOP, and (S,S)-BDPP (L2)
were also examined. No or little aldehydes were observed in most cases except
for (S,S)-BDPP (L2), where the aldehyde was isolated in 22% yield but with
only 5% ee.
(13) For a leading review on the bite angle effect, see: van Leeuwen, P. W. N.
M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chem. Rev. 2000, 100, 2741.
(14) For leading references on the bite angle effect, see: a) van der Veen, L.
A.; Boele, M. D. K.; Bregman, F. R.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Goubitz, K.; Fraanje, J.; Schenk, H.; Bo, C. J. Am. Chem. Soc. 1998, 120, 11616.
b) van der Veen, L. A.; Keeven, P. H.; Schoemaker, G. C.; Reek, J. N. H.; Kamer,
P. C. J.; van Leeuwen, P. W. N. M.; Lutz, M.; Spek A. L. Organometallics 2000,
19, 872. c) Bronger, R. P. J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Organ-
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Trans. 2003, 1890. e) Achord, P. D.; Kiprof, P.; Barker, B. J. Molecular Struc-
ture: THEOCHEM 2008, 849, 103.
We gratefully acknowledge the National Natural Science Foundation
of China (21472083) and Nanjing University for the financial support.
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Pd(OAc)2 (5 mol %)
dppp (10 mol %)
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R2
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HCOOH
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Ac2O (3.0 equiv)
4 Å MS, DCE
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up to 93% yield
l:b > 20:1
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