Palladium-catalyzed decarboxylative 1,2-addition of carboxylic acids to aldehydes or imines

Article abstract of DOI:10.1039/c002052d

The first example of palladium-catalyzed decarboxylative 1,2-addition of carboxylic acids to aldehydes or imines under mild conditions is described.

Full text of DOI:10.1039/c002052d

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Palladium-catalyzed decarboxylative 1,2-addition of carboxylic acids to
aldehydes or iminesw
Yong Luoa and Jie Wu*ab
Received 29th January 2010, Accepted 19th March 2010
First published as an Advance Article on the web 13th April 2010
DOI: 10.1039/c002052d
The first example of palladium-catalyzed decarboxylative
1,2-addition of carboxylic acids to aldehydes or imines under
mild conditions is described.
stoichiometric amounts of costly organometallic reagents
would be avoided.
Since Miyaura and co-workers reported the rhodium-catalyzed
1,2-addition in 1998,1 using transition metal complexes of
rhodium, palladium, nickel, copper and platinum as catalysts
for 1,2-addition reactions of organoboronic acids to aldehydes
or imines has become established as a universal tool for
C–C bond formation.2–5 Typically, stoichiometric amounts
of costly organoboron compounds had to be utilized in such
transformation. Meanwhile, recently increasing interest
has been paid to the palladium-catalyzed decarboxylative
cross-coupling reactions,6–10 since it provides an important
alternative route for carbon–carbon bond formation. Compared
to the conventional transition metal-catalyzed cross-coupling
reactions and the direct arylation through C–H activation, this
method has several advantages as highlighted by Baudoin6
concerning the regioselectivity with atom and step economy
issues. And currently, it is well-recognized that this approach
combines the key benefit of regiospecificity as well as broad
availability, low cost, and easy handling of carboxylate
substrates. In the last two years, breakthroughs have been
achieved in the development of palladium-catalyzed decarbox-
ylative cross-coupling reactions.
Scheme 1 Proposed route for palladium-catalyzed decarboxylative
1,2-addition of carboxylic acids to aldehydes or imines.
With these considerations in mind and to verify the
practicability of the projected route as shown in Scheme 1,
we approached the search for an effective catalyst system using
as a model reaction, the decarboxylative 1,2-addition of
carboxylic acid 1a to aldehyde 2a. A few key experiments
selected from our investigation of various palladium catalysts,
additives, and conditions are displayed in Table 1. Initially, the
reaction was performed in the presence of PdCl2 (10 mol%) as
catalyst in toluene at 80 1C. However, no reaction occurred.
The result could not be improved when the reaction temperature
was increased to 120 or 160 1C. Subsequently, we shifted our
focus on other palladium catalysts. After screening different
palladium catalysts and solvents, we identified that Pd(OTf)2
was the most effective catalyst in DMSO–DMF (1 : 20 v/v)
and the desired product 3a was isolated in 73% yield (Table 1,
entry 6). This result was similar to the previous report,7c in
which the rate of decarboxylation in an mixture of DMF and
DMSO was much faster. Based on this result, we conceived
that Pd(OTf)2 might be generated in situ by combination of
It is well known that the synthesis of diarylmethyl amines or
diaryl methanols is of great importance because they are
present in a variety of pharmacologically active structures.11
Prompted by the advancement of 1,2-addition reactions of
organoboronic acids to aldehydes or imines and the palladium-
catalyzed decarboxylative cross-coupling reactions, we conceived
that carboxylic acids might be a good substrate as a replacement
for organoboron compound in the transition-metal catalyzed
1,2-addition reactions (Scheme 1), due to their easy availability
and low cost. In addition, employing carboxylic acids in such
transformations would greatly contribute to the creation of
environmentally benign processes. As mentioned above for the
decarboxylative cross couplings, the carboxylic acid would
convert into a carbon nucleophile by extrusion of CO2
and directly couple with carbon electrophiles. Moreover,
Table 1 Initial studies for palladium-catalyzed decarboxylative 1,2-
addition of carboxylic acid 1a to aldehyde 2a
Entry [Pd]
Additive Solvent
T/1C Yielda (%)
1
2
3
4
5
6
7
8
9
PdCl2
PdCl2
PdCl2
Pd(OTf)2
Pd(OTf)2
Pd(OTf)2
PdCl2
—
—
—
—
—
—
AgOTf
AgOTf
AgOTf
Toluene
Toluene
Toluene
Toluene
DMF
DMSO–DMF
DMSO
DMF
80
120
160
80
80
80
80
80
80
NR
NR
NR
Trace
Trace
73
58
Trace
87
a Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cnc;
Fax: 86 21 6564 1740; Tel: 86 21 6510 2412
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China
w Electronic supplementary information (ESI) available: General
experimental and characterization data for compounds 3 and 4. See
DOI: 10.1039/c002052d
PdCl2
PdCl2
DMSO–DMF
a
Isolated yield based on 4-nitrobenzaldehyde 2a.
ꢀc
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Chem. Commun., 2010, 46, 3785–3787 | 3785

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PdCl2 and AgOTf. Thus, the reaction was tested in the
presence of PdCl2 (10 mol%) and AgOTf (20 mol%). To
our delight, the corresponding product 3a was obtained in
87% yield in DMSO–DMF (1 : 20 v/v) at 80 1C (Table 1, entry 9).
Lower yield was observed when the catalyst amount was
reduced to 5 mol%. Inferior results were also observed when
the reaction was conducted at 50 1C.
other benzoic acids are not effective in the reactions. It seems
that the scope of the process is presently clearly limited to
electron-rich aryl carboxylic acids and electron-poor aryl
aldehydes/imines.
Using the optimized palladium-catalyzed conditions [PdCl2
(10 mol%), AgOTf (20 mol%), DMSO–DMF (1 : 20 v/v),
80 1C], the scope of this reaction was then investigated
(Table 2). For the decarboxylative 1,2-addition reactions
of 2,6-dimethoxybenzoic acid 1a, various aldehydes were
examined.z From Table 2, it was found that reactions of
aldehydes with electron-withdrawing groups attached to the
aromatic backbone proceeded smoothly to afford the desired
products in moderate to good yields. Moreover, different
functional groups such as nitro, trifluoromethyl and ester
groups could be tolerated under the conditions. However, no
reaction occurred when benzaldehydes with electron-donating
groups attached on the aromatic ring were utilized as substrates
(data not shown in Table 2), which might be due to their lower
electrophilicity. Aliphatic aldehydes and ketones were also
examined as substrates. However, no reactions occurred under
the standard conditions (data not shown in Table 2). This
decarboxylative 1,2-addition reaction was also extended to
imines. As expected, the benzoic acids reacted with aldimines
leading to the desired amines in good yields (Table 2,
entries 9–19).
Scheme 2 Palladium-catalyzed decarboxylative reaction of carboxylic
acid 1b with benzaldehydes.
In conclusion, the method disclosed herein clearly demonstrates
the concept of decarboxylative 1,2-addition of carboxylic acids
to aldehydes or imines, which opens a new avenue for carbon–
carbon bond formation. Although this reaction currently has
scope limitations we believe that this environmentally benign
process combined with the mild conditions would be attractive
and beneficial for its further development.
Financial support from the National Natural Science
Foundation of China (No. 20772018) and the Science &
Technology Commission of Shanghai Municipality (No.
09JC1404902) is gratefully acknowledged.
Notes and references
Other carboxylic acids were also tested in the decarboxylative
1,2-addition reactions of aldehydes. Interestingly, when 2,4,6-
trimethoxybenzoic acid 1b was employed in the reactions with
aldehydes under the standard conditions, triarylmethanes 4
were produced in the transformation (Scheme 2). However,
z General procedure for palladium-catalyzed decarboxylative 1,2-
addition of carboxylic acids to aldehydes or imines: Carboxylic acid
1 (0.24 mmol) and aldehyde or imine 2 (0.20 mmol) were added to a
mixture of PdCl2 (10 mol%, 3.6 mg) and AgOTf (20 mol%, 10.3 mg)
in DMF (2.0 mL) and DMSO (0.1 mL). The reaction was stirred at
80 1C. After completion of reaction as indicated in TLC, the mixture
was diluted by EtOAc (20 mL), washed with saturated brine
(2 ꢁ 20 mL), and dried by Na2SO4. Evaporation the solvent followed
by purification on silica gel provided the product 3. Data of selected
examples: (2,6-Dimethoxyphenyl)(4-nitrophenyl)methanol 3a. White
solid, mp 136–137 1C. 1H NMR (400 MHz, CDCl3): d 8.12 (d, J =
7.8 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.26 (m, 1H), 6.60 (d, J =
8.3 Hz, 2H), 6.38 (s, 1H), 4.31 (br, 1H), 3.80 (s, 6H). 13C NMR
(100 MHz): d 157.5, 152.6, 146.6, 129.6, 126.2, 123.1, 118.3, 104.5,
67.8, 55.8. IR (thin film): n/cmꢂ1 3536, 1597, 1518, 1476. HRMS (ESI)
calc. for C15H15NO5 [M + Na]+ requires 312.0848, found 312.0848.
4-Methyl-N-((4-nitrophenyl)(2,4,6-trimethoxyphenyl)methyl)benzene-
sulfonamide 3j. White solid, mp 138–139 1C. 1H NMR (400 MHz,
CDCl3): d 8.03 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.43 (d,
J = 8.7 Hz, 2H), 7.04 (d, J = 8.2 Hz, 2H), 6.37 (d, J = 10.5 Hz, 1H),
6.15 (d, J = 10.5 Hz, 1H), 5.9 (s, 2H), 3.74 (s, 3H), 3.62 (s, 6H), 2.31
(s, 3H). 13C NMR (100 MHz): d 161.3, 157.6, 149.4, 146.6, 142.8,
137.2, 128.8, 127.1, 126.8, 123.1, 107.7, 90.4, 55.5, 55.3, 51.0, 21.3. IR
(thin film): n/cmꢂ1 3317, 1597, 1518, 1495. HRMS (ESI) calc. for
C23H24N2O7S [M + Na]+ requires 495.1202, found 495.1209. Anal.
Calc. for C23H24N2O7S: C, 58.46; H, 5.12; N, 5.93; Found: C, 58.76;
H, 4.96; N, 5.88 (for details see ESIw).
Table 2 Palladium-catalyzed decarboxylative 1,2-addition of carboxylic
acids to aldehydes or imines
Entry
R1
R2
X
Yielda (%)
1
2
3
4
5
6
7
8
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,4,6-(OMe)3 (1b)
2,6-(OMe)2 (1a)
2,4,6-(OMe)3 (1b)
2,6-(OMe)2 (1a)
2,4,6-(OMe)3 (1b)
2,4,6-(OMe)3 (1b)
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,6-(OMe)2 (1a)
2,4,6-(OMe)3 (1b)
4-NO2
2,4-Cl2
2-Cl
2-Br-4-F
4-CF3
2-NO2
4-CO2Me
2-Br-5-F
4-NO2
4-NO2
2,4-Cl2
2,4-Cl2
2-Br-4-F
2-Br-4-F
2-Cl
O
O
O
O
O
O
O
O
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
87 (3a)
68 (3b)
57 (3c)
53 (3d)
57 (3e)
41 (3f)
50 (3g)
60 (3h)
62 (3i)
77 (3j)
60 (3k)
60 (3l)
70 (3m)
65 (3n)
68 (3o)
62 (3p)
51 (3q)
57 (3r)
73 (3s)
9
10
11
12
13
14
15
16
17
18
19
1 (a) M. Sakai, M. Ueda and N. Miyaura, Angew. Chem., Int. Ed.,
1998, 37, 3279; (b) M. Ueda and N. Miyaura, J. Org. Chem., 2000,
65, 4450Reviews: (c) K. Fagnou and M. Lautens, Chem. Rev.,
2003, 103, 169; (d) T. Hayashi and K. Yamasaki, Chem. Rev., 2003,
103, 2829.
2-NO2
2-Br-5-F
4-CF3
2 For examples of rhodium-catalyzed addition of organoboronic
acids to aldehydes, see: (a) A. Furstner and H. Krause, Adv. Synth.
¨
Catal., 2001, 343, 343; (b) M. Ueda and N. Miyaura, J. Org.
Chem., 2000, 65, 4450; (c) R. B. C. Jagt, P. Y. Toullec, J. G. de
Vries, B. L. Feringa and A. J. Minnaard, Org. Biomol. Chem.,
2006, 4, 773; (d) C. Pourbaix, F. Carreaux and B. Carboni, Org.
4-CF3
a
Isolated yield based on aldehyde or imine 2.
ꢀc
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3786 | Chem. Commun., 2010, 46, 3785–3787

View Article Online
Lett., 2001, 3, 803; (e) H.-F. Duan, J.-H. Xie, W.-J. Shi, Q. Zhang
and Q.-L. Zhou, Org. Lett., 2006, 8, 1479; (f) A. F. Trindade, P. M.
P. Gois, L. F. Veiros, V. Andre, M. T. Duarte, C. A. M. Afonso,
S. Caddick and F. G. N. Cloke, J. Org. Chem., 2008, 73, 4076;
(g) P. M. P. Gois, A. F. Trindade, L. F. Veiros, V. Andre,
M. T. Duarte, C. A. M. Afonso, S. Caddick and F. G. N. Cloke,
Angew. Chem., Int. Ed., 2007, 46, 5750.
3 For examples of palladium-catalyzed addition of organoboronic
acids to aldehydes, see: (a) C. Qin, H. Wu, J. Cheng, X. Chen,
M. Liu, W. Zhang, W. Su and J. Ding, J. Org. Chem., 2007, 72,
4102; (b) T. Yamamoto, T. Ohto and Y. Ito, Org. Lett., 2005, 7,
4153; (c) P. He, Y. Lu, C.-G. Dong and Q.-S. Hu, Org. Lett., 2007,
9, 343; (d) S. Liu and X. Lu, J. Org. Chem., 2007, 72, 9757;
(e) M. Kuriyama, R. Shimazawa and R. Shirai, J. Org. Chem.,
2008, 73, 1597; (f) M. Kuriyama, R. Shimazawa, T. Enomoto and
R. Shirai, J. Org. Chem., 2008, 73, 6939.
4 For examples of other metal-catalyzed addition of organoboronic
acids to aldehydes, see: (a) Y. Yamamoto, K. Kurihara and
N. Miyaura, Angew. Chem., Int. Ed., 2009, 48, 4414;
(b) H. Zheng, Q. Zhang, J. Chen, M. Liu, S. Cheng, J.
Ding, H. Wu and W. Su, J. Org. Chem., 2009, 74, 943;
(c) Y.-X. Liao, C.-H. Xing, P. He and Q.-S. Hu, Org. Lett.,
2008, 10, 2509.
5 For transition metal-catalyzed addition of organoboronic acids to
imines, see: (a) T. Hayashi, M. Kawai and N. Tokunaga, Angew.
Chem., Int. Ed., 2004, 43, 6125; (b) R. B. C. Jagt, P. Y. Toullec,
D. Geerdink, J. G. deVries, B. L. Feringa and A. J. Minnaard,
Angew. Chem., Int. Ed., 2006, 45, 2789; (c) T. Hayashi and
M. Ishigedani, J. Am. Chem. Soc., 2000, 122, 976;
(d) M. Kuriyama, T. Soeta, X. Hao, Q. Chen and K. Tomioka,
J. Am. Chem. Soc., 2004, 126, 8128; (e) N. Tokunaga, Y. Otomaru,
K. Okamoto, K. Ueyama, R. Shintani and T. Hayashi, J. Am.
Chem. Soc., 2004, 126, 13584; (f) D. J. Weix, Y. Shi and
J. A. Ellman, J. Am. Chem. Soc., 2005, 127, 1092;
(g) M. Beenen, D. J. Weix and J. A. Ellman, J. Am. Chem. Soc.,
2006, 128, 6304; (h) Z.-Q. Wang, C.-G. Feng, M.-H. Xu and
G.-Q. Lin, J. Am. Chem. Soc., 2007, 129, 5336; (i) M. Ueda and
N. Miyaura, J. Organomet. Chem., 2000, 595, 31; (j) Y. Otomaru,
N. Tokunaga, R. Shintani and T. Hayashi, Org. Lett., 2005, 7, 307;
(k) Y. Bolshan and R. A. Batey, Org. Lett., 2005, 7, 1481;
(l) H.-F. Duan, Y.-X. Jia, L.-X. Wang and Q.-L. Zhou, Org. Lett.,
2006, 8, 2567; (m) H. Nakagawa, J. C. Rech, R. W. Sindelar and
J. A. Ellman, Org. Lett., 2007, 9, 5155; (n) H. Dai and X. Lu,
Tetrahedron Lett., 2009, 50, 3478; (o) G.-N. Ma, T. Zhang and
M. Shi, Org. Lett., 2009, 11, 875.
Chem. Soc., 2005, 127, 10323; (d) M. Nilsson, Acta Chem. Scand.,
1966, 20, 423.
8 (a) L. J. Gooben, W. R. Thiel, N. Rodrı
B. Melzer, Adv. Synth. Catal., 2007, 349, 2241; (b) L. J. Gooben,
F. Rudolphi, C. Oppel and N. Rodrıguez, Angew. Chem., Int. Ed.,
´
guez, C. Linder and
´
2008, 47, 3043; (c) L. J. Gooben, B. Zimmermann and T. Knauber,
Angew. Chem., Int. Ed., 2008, 47, 7103; (d) A. G. Myers,
D. Tanaka and M. R. Mannion, J. Am. Chem. Soc., 2002, 124,
11250; (e) D. Tanaka, S. P. Romeril and A. G. Myers, J. Am.
Chem. Soc., 2005, 127, 10323; (f) P. Forgione, M. C. Brochu,
M. St-Onge, K. H. Thesen, M. D. Bailey and F. Bilodeau, J. Am.
Chem. Soc., 2006, 128, 11350; (g) L. J. Gooben, N. Rodrı
B. Melzer, C. Linder, G. Deng and L. M. Levy, J. Am. Chem. Soc.,
2007, 129, 4824; (h) L. J. Gooben, N. Rodrıguez and C. Linder,
´
guez,
´
J. Am. Chem. Soc., 2008, 130, 15248; (i) R. Shang, Y. Fu, J.-B. Li,
S.-L. Zhang, Q.-X. Guo and L. Liu, J. Am. Chem. Soc., 2009, 131,
5738; (j) Z. Duan, S. Ranjit, P. Zhang and X. Liu, Chem.–Eur. J.,
´
2009, 15, 3666; (k) L. J. Gooben, C. Linder, N. Rodrıguez and
P. P. Lange, Chem.–Eur. J., 2009, 15, 9336; (l) L. J. Gooben,
G. Deng and L. M. Levy, Science, 2006, 313, 662.
9 (a) D. Tanaka and A. G. Myers, Org. Lett., 2004, 6, 433;
(b) J. S. Dickstein, C. A. Mulrooney, E. M. O’Brien,
B. J. Morgan and M. C. Kozlowski, Org. Lett., 2007, 9, 2441;
(c) J. Moon, M. Jeong, H. Nam, J. Ju, J. H. Moon, H. M. Jung and
S. Lee, Org. Lett., 2008, 10, 945; (d) M. Nakano, H. Tsurugi,
T. Satoh and M. Miura, Org. Lett., 2008, 10, 1851; (e) P. Hu,
J. Kan, W. Su and M. Hong, Org. Lett., 2009, 11, 2341;
(f) J.-M. Becht, C. Catala, C. L. Drian and A. Wagner, Org. Lett.,
2007, 9, 1781; (g) J.-M. Becht and C. L. Drian, Org. Lett., 2008, 10,
3161; (h) L. J. Gooben and B. Melzer, J. Org. Chem., 2007, 72,
7473; (i) J. Moon, M. Jang and S. Lee, J. Org. Chem., 2009, 74,
1403; (j) L. J. Gooben, N. Rodrıguez and K. Gooben, Angew.
´
Chem., Int. Ed., 2008, 47, 3100; (k) H. Kim and P. H. Lee, Adv.
Synth. Catal., 2009, 351, 2827; (l) L. J. Gooben, B. Zimmermann,
´
C. Linder, N. Rodrıguez, P. P. Lange and J. Hartung, Adv. Synth.
Catal., 2009, 351, 2667; (m) M. Miyasaka, K. Hirano, T. Satoh and
M. Miura, Adv. Synth. Catal., 2009, 351, 2683.
10 (a) Z. Wang, Q. Ding, X. He and J. Wu, Org. Biomol. Chem., 2009,
7, 863; (b) Z. Wang, Q. Ding, X. He and J. Wu, Tetrahedron, 2009,
65, 4635.
11 For examples, see: (a) M. J. Bishop and R. W. McNutt, Bioorg.
Med. Chem. Lett., 1995, 5, 1311; (b) C. M. Spencer, D. Foulds and
D. H. Peters, Drugs, 1993, 46, 1055; (c) S. Sakurai, N. Ogawa,
T. Suzuki, K. Kato, T. Ohashi, S. Yasuda, H. Kato and Y. Ito,
Chem. Pharm. Bull., 1996, 44, 765; (d) N. Plobeck, D. Delorme,
Z.-Y. Wei, H. Yang, F. Zhou, P. Schwarz, L. Gawell, H. Gagnon,
B. Pelcman, R. Schmidt, S.-Y. Sue, C. Walpole, W. Brown,
E. Zhou, M. Labarre, K. Payza, S. St-Onge, A. Kamassah,
P.-E. Morin and D. Projean, J. Med. Chem., 2000, 43, 3878.
6 O. Baudoin, Angew. Chem., Int. Ed., 2007, 46, 1373.
7 (a) A. G. Myers, D. Tanaka and M. R. Mannion, J. Am. Chem.
Soc., 2002, 124, 11250; (b) D. Tanaka and A. G. Myers, Org. Lett.,
2004, 6, 433; (c) D. Tanaka, S. P. Romeril and A. G. Myers, J. Am.
ꢀc
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Chem. Commun., 2010, 46, 3785–3787 | 3787