Palladium-Catalyzed Formylation of Aryl Iodides with HCOOH as CO Source

Article abstract of DOI:10.1021/acs.orglett.7b01882

A facile and practical method for the synthesis of aromatic aldehydes by palladium-catalyzed reductive carbonylation starting from aryl iodides and HCOOH is described. Compared to the known formylation procedure, HCOOH serves not only as the most convenient and environmental-friendly C1 source but also as the reviving agent in the reductive elimination process of a Pd-catalyst. Furthermore, this procedure is also applied successfully to the modification of natural products, such as vindoline, tabersonin, and vincamine, to obtain the corresponding products in good yields.

Full text of DOI:10.1021/acs.orglett.7b01882

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Formylation of Aryl Iodides with HCOOH as CO
Source
Guanglong Sun,‡,§,∥ Xue Lv,‡,§,∥ Yinan Zhang,† Min Lei,*,‡,§ and Lihong Hu*,†
†Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese
Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy,
Nanjing University of Chinese Medicine, Nanjing, P. R. China
‡Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China
§University of Chinese Academy of Sciences, Beijing 100049, P. R. China
S
* Supporting Information
ABSTRACT: A facile and practical method for the synthesis of aromatic
aldehydes by palladium-catalyzed reductive carbonylation starting from
aryl iodides and HCOOH is described. Compared to the known
formylation procedure, HCOOH serves not only as the most convenient
and environmental-friendly C1 source but also as the reviving agent in the
reductive elimination process of a Pd-catalyst. Furthermore, this
procedure is also applied successfully to the modification of natural products, such as vindoline, tabersonin, and vincamine,
to obtain the corresponding products in good yields.
romatic aldehyde is one of the critical synthetic blocks in
the consequent formation of various C−C and C−X
palladium-catalyzed formylation (Figure 1b), such as N-
formylsaccharin,8 9-methylfluorene-9-carbonyl chloride,9
CO2,10 paraformaldehyde,11 acetic formic anhydride,12 Fe-
(CO)5,13 and S-phenyl thioformate,14 extra reductants (e.g.,
silanes or metals reagents) are essential in most of the cases due
to the palladium redox cycle in the coupling reaction. The only
exceptional example also required acetic anhydride to generate
acetic formic anhydride in situ, which may cause an unnecessary
acetylation on the substrates with active function groups.15
Therefore, formylation procedures that are efficient and benign
to diverse function groups and the environment are still highly
requested. In recent years, formic acid as a carbonylation source
is reported.16 Since formic acid itself could play as a reducing
agent to the oxidative palladium, the finding of a trigger to
release carbon monoxide from formic acid would benefit the
formylation. Herein, we utilized I2 and triphenylphosphine to
promote the formic acid formylation (Figure 1c), which
circumvented the aforementioned drawbacks and provided
versatile functionalized aromatic aldehydes with high yields.
Initially, to exam whether I2 could promote HCOOH as a
CO provider, we carried out the formylation of 4-methoxy-
iodobenzene 1a with extra PPh3 and I2 in acetonitrile. After
refluxing for 2 h at 80 °C, the desired product 3a was formed in
57% yield. This result clearly indicated that HCOOH played
both formylating and reducing roles with the help of I2 (see
Scheme S1 in the Supporting Information (SI)). To further
improve the yield, a series of optimizationss were performed
and summarized in Table 1.
A
bonds. Its synthetic applications are widely distributed in the
areas of pharmaceuticals, food additives, pesticides, chemical
materials, and so on,1 thus receiving historic attention from
chemists.2 Electrophilic formylation is the conventional method
to access aromatic aldehydes, including Duff reaction and
Casiraghi reaction,1,3 Vilsmeier reaction,4 and Gattermann−
Koch reaction (Reimer−Tiemann reaction) (Figure 1a).5
Figure 1. Palladium-catalyzed reductive carbonylation of aryl halides.
Although the direct introduction of the fomyl group ensures
the highest synthetic efficiency, the requirement of electron-rich
aromatic systems as well as the incompatibility of plenty
function groups limits the scope of substrates.
Along with the discovery of palladium-catalyzed carbon-
ylzation,6 carbon monoxide became a powerful C1 source to
form aromatic aldehydes especially in industrial side.7 However,
laboratorial utilization of gaseous CO suffered from storage,
transportation, handling, and safety regulations. Even though a
series of C1 surrogates have been significantly explored in
Initially, to study the solvent effect, several solvents were
screened, and the results suggested that the solvent had a
Received: June 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Solvent and Catalyst Screening
Scheme 1. Reaction of Aryl Iodides with HCOOH
b
entry
solvent
[Pd] (equiv)
I2
PPh3 (equiv)
yield (%)
1
MeCN
THF
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdSO4
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.2
1.1
1.2
1.2
1.2
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.4
1.3
1.2
1.1
57
53
48
71
67
77
75
66
73
60
78
59
80
82
76
75
2
3
DMF
4
DCM
5
Py
6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
7
8
9
PdCl2
10
11
12
13
14
15
16
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
a
Reaction conditions: 1a (1 mmol), 2 (8 mmol), I2, PPh3, [Pd] (5 mol
b
%), Et3N (10 mmol), solvent (4 mL), 80 °C, 2 h. Yields were
determined by LC-MS.
significant impact on the yields of 3a and toluene displayed the
best yield at 77% (Table 1, entries 1−6 and Table S1 in SI).
Further examination of palladium sources proved Pd(OAc)2
was the best option in terms of efficiency, and the loading
amount was found to be as low as 3 mol % (Table 1, entries 6−
10 and Tables S3 and S4 in the SI). The optimal ratio of PPh3
and I2 was further investigated (Table 1, entries 11−16 and
Tables S7 and S8 in the SI), and the results revealed slightly
higher equivalences than the substrate were needed. After
extensive experimentation (see Tables S1−S10 in the SI), the
optimal conditions were established as HCOOH (4 equiv),
Pd(OAc)2 (3.0 mol %), I2 (1.2 equiv), PPh3 (1.2 equiv), and
Et3N (6 equiv) in toluene at 80 °C for 2−4 h. Moreover, an
83% yield was obtained on a 10 mmol scale, which proved the
potential practicality of this conversion. However, no improve-
ment took place with different leaving groups, such as Br−,
Cl−, TsO−, and TfO− (see Table S11 in the SI).
To explore the generality and scope of the formylation,
various aryl iodides were reacted under the optimal conditions
(Scheme 1). As shown in Scheme 1, the positions of
substitutions have little effect on the yield and all the ortho,
meta, and para aryl iodides underwent the formylation
smoothly with good yields in the range 68−92% (3a−l).
Traditional forbidden substrates (3m−p and 3t−w) with
electron-withdrawing substituents were tolerated in this
conversion, though the yields of para-nitro and para-cyano
dropped to a moderate level. It is also worth noting that the
desired formylating products were smoothly obtained from the
substrates with active functional groups (3r−u), which were
ineligible in the acetic anhydride promoted formylation.15
Furthermore, electron-donating and -withdraing hetereoaro-
matic aldehydes could also be achieved by HCOOH
formylation (3v−y).
a
Standard conditions: 1 (1 mmol), 2 (4 mmol), I2 (2.4 equiv), PPh3
(2.4 equiv), Pd(OAc)2 (3 mol %), Et3N (6 mmol), toluene (4 mL), 80
°C, 2 h. Isolated yields. The reaction proceeded for 4 h.
b
c
that the ortho-phthalaldehyde was sluggish to obtain, probably
due to the interference of palladium oxidative addition by the
neighboring carbonyl group (Scheme 2). Recently, modifica-
tion of indole alkaloids received wide attention.17 Therefore,
the formylation reaction was also examined on several alkaloid
natural products (Scheme 3). The results showed that
vindoline, tabersonin, and apovincamine were successfully
transferred to their formylated analogs (7−9a) through a
two-step conversion with 75%, 85%, and 68% yields,
respectively. During the process, no other byproducts were
clearly observed.
To further support its application, aryl di-iodides were used
as starting material to the formylation reaction. It was found
In order to determine the hydrogen source of the aldehyde
group, we carried out the reaction with isotopically labeled
B
DOI: 10.1021/acs.orglett.7b01882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
ab
,
Scheme 2. Reaction of Aryl Di-iodides with HCOOH
Scheme 4. Reaction of 1a with DCOOD
a
Standard conditions: 1 (1 mmol), DCOOD (4 mmol), I2 (1.2 equiv),
PPh3 (1.2 equiv), Pd(OAc)2 (3 mol %), Et3N (6 mmol), toluene (4
b
mL), 80 °C, 4 h. Isolated yields.
Scheme 5. Plausible Mechanism for Reductive
Carbonylation
a
Standard conditions: 4-6 (1 mmol), 2 (8 mmol), I2 (2.4 equiv), PPh3
(2.4 equiv), Pd(OAc)2 (6 mol %), Et3N (12 mmol), toluene (8 mL),
b
80 °C, 4 h. Isolated yields.
a b
,
Scheme 3. Reaction of Natural Products with HCOOH
arylpalladium formic acid complex D and released HI
simultaneously. Final decarboxylation furnished the reductive
elimination to regenerate Pd(II) that launched another catalytic
cycle. The elimination of carbon dioxide was confirmed by the
formation of CaCO3 after exporting the gas phase of the
reaction to a clear Ca(OH)2 solution.
In conclusion, we have developed a facile and practical
procedure for the synthesis of aromatic aldehydes by palladium-
catalyzed reductive fomylation starting from aryl iodides and
dual-role HCOOH. The products are obtained in moderate to
excellent yields avoiding the use of CO gas and additional
reductant. It is noteworthy that this protocol is also suitable for
the direct modification of natural products. The mild reaction
conditions, short reaction time, and compatibility with versatile
functional groups make our methodology a valid and alternative
contribution to the existing processes for the synthesis of
aromatic aldehydes.
a
Stndard conditions: 7−9 (1 mmol), 2 (4 mmol), I2 (1.2 equiv), PPh3
ASSOCIATED CONTENT
(1.2 equiv), Pd(OAc)2 (3 mol %), Et3N (6 mmol), toluene (4 mL), 80
°C, 2 h. Isolated yields.
■
b
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01882.
reagent D2-formic acid. As shown in Scheme 4, the result
clearly indicated the hydrogen source of the aldehyde group
derived from formic acid.
Based on the experimental results and previous reports, a
plausible reaction mechanism was proposed (Scheme 5).
Initially, I2 and PPh3 formed complex A, which helps to trigger
the release of CO from formic acid. Through a ligand exchange,
CO was captured by aryl palladium intermediate B generated
from a rapid oxidative addition of palladium to aryl iodide. After
CO insertion, the benzoylpalladium halide C converted to
Experimental procedures and spectral data for all
compound (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mlei@simm.ac.cn.
*E-mail: lhhu@simm.ac.cn.
C
DOI: 10.1021/acs.orglett.7b01882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(16) (a) Ren, W.; Chang, W.; Dai, J.; Shi, Y.; Li, J.; Shi, Y. J. Am.
Chem. Soc. 2016, 138, 14864. (b) Somasunderam, A.; Alper, H. J. Mol.
Catal. 1994, 92, 35. (c) El Ali, B. E.; Vasapollo, G.; Alper, H. J. Mol.
Catal. A: Chem. 1996, 112, 195.
(17) (a) Yang, Y.; Qiu, X.; Zhao, Y.; Mu, Y.; Shi, Z. J. Am. Chem. Soc.
2016, 138, 495. (b) Yang, Y.; Li, R.; Zhao, Y.; Zhao, D.; Shi, Z. J. Am.
Chem. Soc. 2016, 138, 8734. (c) Yang, Y.; Gao, P.; Zhao, Y.; Shi, Z.
Angew. Chem., Int. Ed. 2017, 56, 3966; Angew. Chem. 2017, 129, 4024.
Min Lei: 0000-0001-8696-9696
Author Contributions
∥G.S. and X.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (Grants 81473110, 81561148011),
Special Fund for Strategic Pilot Technology Chinese Academy
of Sciences (XDA12040303), the Science Foundation of
Shanghai (Grant 15431901100), and the Priority Academic
Program Development of Jiangsu Higher Education Institu-
tions.
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DOI: 10.1021/acs.orglett.7b01882
Org. Lett. XXXX, XXX, XXX−XXX