One-pot synthesis of aldehydes or ketones from carboxylic acids via in situ generation of Weinreb amides using the Deoxo-Fluor reagent

Article abstract of DOI:10.1016/j.tetlet.2006.06.121

A one-pot, high yield conversion of carboxylic acids to the corresponding aldehydes and ketones is described. The highlight of this methodology is the in situ generation of Weinreb amides with the Deoxo-Fluor reagent, which undergo nucleophilic reaction with DIBAL-H and Grignard reagents.

Full text of DOI:10.1016/j.tetlet.2006.06.121

Tetrahedron Letters 47 (2006) 6289–6292
One-pot synthesis of aldehydes or ketones from
carboxylic acids via in situ generation of Weinreb amides
using the Deoxo-Fluor reagent
Cyrous O. Kangani,a,* David E. Kelleya and Billy W. Dayb
aDepartment of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
bDepartment of Pharmaceutical Sciences and of Chemistry, University of Pittsburgh, Pittsburgh, PA 15213, USA
Received 2 June 2006; revised 21 June 2006; accepted 22 June 2006
Available online 10 July 2006
Abstract—A one-pot, high yield conversion of carboxylic acids to the corresponding aldehydes and ketones is described. The high-
light of this methodology is the in situ generation of Weinreb amides with the Deoxo-Fluor reagent, which undergo nucleophilic
reaction with DIBAL-H and Grignard reagents.
Ó 2006 Elsevier Ltd. All rights reserved.
In recent years, the transformation of carboxylic acids
into aldehydes1 and ketones2 has received considerable
attention because of their significance in synthetic
organic chemistry.3 Extensive efforts have been made
toward an efficient synthesis of these functional groups.
There are many different synthetic routes to ketones
reported in the literature, with the reaction of organo-
metallic reagents with acyl chlorides4 or Weinreb
amides5 being the most commonly used.
been detected from a wide variety of sources, for exam-
ple, insect pheromones, soil waxes, snake skin, and aero-
sols.10 Recently it has been shown that fatty ketones
may serve as therapeutic agents in the treatment of sleep
disorders and pain by targeting fatty acid amide hydro-
lase (FAAH), the enzyme responsible for the degrada-
tion of the chemical messengers, oleamide and
anandamide.11
A current practical method for the preparation of
ketones involves treatment of acyl chloride with Grignard
reagents in the presence of a catalytic amount of metal
halide. We decided to employ this procedure, but
instead used an acyl fluoride (generated in situ) for con-
version to the ketone. Although the desired ketones were
obtained by this procedure, the yields and purities were
poor. Using the recently reported procedure by Wang
et al.,12 reaction of an in situ generated acyl fluoride
and Grignard reagents in the presence of bis[2-(N,N-
dimethylamino)ethyl]ether resulted in a ketone but in
extremely low yield13 (<7% by GC–MS) (Scheme 1).
Although the above methods are well documented, the
direct addition of Grignard reagents to carboxylic acids
to form ketones is an approach that has been largely
unsuccessful.6 To date, ketones are synthesized by multi-
step synthesis involving derivatization of carboxylic
acid into acyl chlorides,4 Weinreb amides,5a thiol esters,7
imidazolides,8 and esters,9 followed by reaction with
organometallic reagents. To avoid multi-step syntheses
of ketones from carboxylic acid, an efficient one-pot
reaction has to be devised.
As part of our program to develop new analytical meth-
ods to quantify free fatty acids, we discovered a highly
efficient conversion of carboxylic acids to related
ketones and aldehydes by a one-pot synthesis using
Deoxo-Fluor reagent. Long chain fatty ketones have
Weinreb amides are very selective in their reactions with
organometallic reagents, giving ketones or aldehydes
exclusively in high yields. The efficiency of this process
has been attributed to the formation of a stable tetra-
hedral intermediate even in the presence of excess organo-
metallic reagents.5a,d We hypothesized that in situ
generated Weinreb amides could be used for direct syn-
thesis of ketones from carboxylic acids via nucleophilic
*
Corresponding author. Tel.: +1 412 647 6796; fax: +1 412 692
2165; e-mail: kanganic@msx.dept-med.pitt.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.121

6290
C. O. Kangani et al. / Tetrahedron Letters 47 (2006) 6289–6292
O
O
O
O
iPr2NEt, 0 oC
Deoxo-Fluor
MeMgBr
CuI, THF/-78 oC
R1
R2
R1
OH
OH
R1
F
F
(less than 15%)
O
O
iPr2NEt, 0 oC
Deoxo-Fluor
MeMgBr
THF/-60 oC
O
R1
R1
R1
R2
(less than 7%)
N
N
Scheme 1.
HN(OMe)Me
iPr2NEt, 0 oC - rt
O
O
O
Grignard reagents
THF/-40 oC- 0 oC
OMe
R1
OH
R1
N
R1
R2
Deoxo-Fluor
Scheme 2.
reactions of organometallic reagents (Grignard or lith-
ium reagents) (Scheme 2).
mixture (containing the in situ formed Weinreb amide)
was cooled to À40 °C and methylmagnesium bromide
was added. After stirring the reaction for 2 h at 0 °C,
the reaction was quenched with saturated aqueous
NH4Cl and the ketone was isolated in 93% yield. To
the best of our knowledge, this is the first example of
a one-pot method for the efficient generation of ketones
from carboxylic acids. The generality of our method was
tested using various carboxylic acids. Aliphatic, aro-
matic, and unsaturated (cis and trans geometry) carb-
oxylic acids could be converted into the corresponding
methyl or phenyl ketones in good to excellent yields.
A number of functional groups, including electron
withdrawing groups (i.e., nitro), are tolerated under
the reaction conditions. In most cases, 6 equiv of the
organometallic reagents (Grignard reagents) were found
to give the best yields and reaction times. The reaction
of phenylmagnesium bromide with various carboxylic
acids required more time than did that of methylmagne-
sium bromide (3 h) to give phenyl ketones (Table 1,
Recently, we have demonstrated an efficient method for
the one-pot direct synthesis of amides from carboxylic
acid.14 To extend this method to the synthesis of Wein-
reb amides, we reacted palmitic acid and N,O-di-
methylhydroxyamine at 0 °C with the Deoxo-Fluor
reagent.15 After 15 min at room temperature, TLC
examination showed the reaction to be complete. The
reaction was quenched with saturated sodium bicarbon-
ate followed by extraction with n-heptane and then dried
over MgSO4, filtered, and concentrated. GC analysis
showed >98% conversion. Delighted by this result, we
next examined direct synthesis of ketones from carb-
oxylic acids via in situ generation of Weinreb amides
using the Deoxo-Fluor reagent. A mixture of palmitic
acid and N,O-dimethylhydroxyamine in THF/CH2Cl2
(5:1) was treated dropwise at 0 °C with the Deoxo-Fluor
reagent. After 15 min at room temperature, the reaction
Table 1. One-pot synthesis of ketones from carboxylic acids via in situ generated Weinreb amides
1) HN(OMe)Me,iPr2NEt, 0 oC
O
O
2) Deoxo-Fluor reagent
3) Grignard reagents/ -40 oC - 0 oC
R1
OH
R1
R2
Entry
Carboxylic acid
Grignard reagent (equiv)a
Compound number
Yieldb (%)
1
2
3
4
5
6
7
8
9
Palmitic acid
Linoleic acid
Elaidic acid
Benzoic acid
p-Toluic acid
p-Nitrobenzoic acid
Palmitic acid
Linoleic acid
Elaidic acid
Benzoic acid
p-Toluic acid
p-Nitrobenzoic acid
MeMgBr (6)
MeMgBr (6)
MeMgBr (6)
MeMgBr (6)
MeMgBr (6)
MeMgBr (6)
PhMgBr (7)
PhMgBr (7)
PhMgBr (7)
PhMgBr (7)
PhMgBr (7)
PhMgBr (7)
1
2
92 2, n = 3
90 4, n = 3
90 2, n = 3
90 2, n = 3
94 5, n = 3
92 4, n = 3
85 2, n = 3
85 2, n = 3
80 3, n = 3
90 2, n = 3
95 3, n = 3
86 5, n = 3
3
4
5
6
7
8
9
10
11
12
10
11
12
a Equivalents of Grignard reagent relative to carboxylic acid.
b Refers to isolated yield of purified product SD. The purity of all products was determined to be 97–99% by 1H and 13C NMR spectroscopy and
GC–MS analysis.

C. O. Kangani et al. / Tetrahedron Letters 47 (2006) 6289–6292
6291
Table 2. One-pot synthesis of aldehydes from carboxylic acids via
in situ generation of Weinreb amides
Supplementary data
A description of the general methods used to prepare,
and spectroscopic data (1H and 13C NMR) for all
products are given in the Supplementary data. Supple-
mentary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.06.121.
1) HN(OMe)Me,iPr2NEt, 0 oC
O
O
2) Deoxo-Fluor reagent
3) DIBAL-H/ -78 oC
R1
OH
R1
H
Entry Carboxylic acid
Compound number Yielda (%)
1
2
3
4
5
6
Palmitic acid
Linoleic acid
Elaidic acid
Benzoic acid
p-Toluic acid
13
14
15
16
17
83
79
73
90
86
91
References and notes
1. (a) Mosettig, E. Org. React. 1954, 8, 218–257; (b) Cha, J.
S.; Kim, J. E.; Kim, Y. S. Tetrahedron Lett. 1987, 28,
6231–6234; (c) Corriu, R. J. P.; Lanneau, G. F.; Perrot, M.
Tetrahedron Lett. 1987, 28, 3941–3944; (d) Brown, H. C.;
Cha, J. S.; Nazer, B.; Yoon, N. M. J. Am, Chem. Soc.
1984, 106, 8001–8002.
p-Nitrobenzoic acid 18
a Yield of pure isolated products, characterized by GC–MS, 1H NMR,
and 13C NMR.
2. (a) O’Neill, B. T. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Schreiber, S. L., Eds.; Pergamon
Press: Oxford, 1991; Vol. 1, pp 399–407; (b) Sibi, M. P.
Org. Prep. Proceed. Int. 1993, 25, 15–40; (c) Mentzel, M.;
Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339, 517–524;
(d) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt.
Chem. 1997, 339, 517–524.
entries 6–12). The reaction of unsaturated carboxylic
acids (linoleic acid and elaidic acid) with methylmagne-
sium bromide as well as phenylmagnesium bromide gave
the corresponding ketones in very good yields (Table 1,
entries 2, 3, 8, and 9).
3. Dieter, R. K. Tetrahedron 1999, 55, 4177–4236, and
references cited therein.
Given the encouraging results, we next examined con-
version of carboxylic acids into the corresponding alde-
hydes. Reduction of in situ formed Weinreb amide with
DIBAL-H generated the aldehyde in very good yield.
The Deoxo-Fluor reagent was added dropwise to a mix-
ture of palmitic acid and N,O-dimethylhydroxyamine at
0 °C, stirred for 15 min at room temperature (resulting
in formation of the Weinreb amide) and then cooled
to À78 °C, followed by dropwise addition of DIBAL-
H (7 equiv). After stirring for 1 h, the reaction was
quenched with saturated aqueous NH4Cl and the alde-
hyde was isolated in 83% yield (Table 2, entry 1). Other
representative results are listed in Table 2. The reaction
worked very well with both aliphatic and aromatic carb-
oxylic acids.
´
4. (a) Thibonnet, J.; Vu, V. A.; Berillon, L.; Knochel, P.
Tetrahedron 2002, 58, 4787–4799; (b) Dieter, R. K.;
Sharma, R. P.; Yu, H.; Gore, V. K. Tetrahedron 2003,
59, 1083–1094; (c) Kondo, J.; Inoue, A.; Shinokubo, H.;
Oshima, K. Tetrahedron Lett. 2002, 43, 2399–2402; (d)
Malanga, C.; Aronica, L. A.; Lardicci, L. Tetrahedron
Lett. 1995, 36, 9185–9188.
5. (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815–3818; (b) Kuethe, J. T.; Comins, D. L. Org. Lett.
2000, 2, 855–857; (c) Davis, F. A.; Chao, B. Org. Lett.
2000, 2, 2623–2625; (d) Smith, A. B., III; Beauchamp, T.
L.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto,
H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000,
122, 8654–8664; (e) Taillier, C.; Bellosta, V.; Cossy, J. Org.
Lett. 2004, 6, 2145–2147; (f) Ghosh, A.; Gong, G. J. Am.
Chem. Soc. 2004, 126, 3704–3705.
In conclusion, we have developed an operationally
simple, one-pot, two-step method for the synthesis of
aldehydes and ketones by addition of, DIBAL-H and
Grignard reagents, respectively, to in situ generated
Weinreb amides. The notable advantages of this proce-
dure are its (a) operational simplicity, (b) general appli-
cability to aromatic and aliphatic (both saturated and
unsaturated) carboxylic acids, (c) reaction conditions
that are tolerant to a variety of sensitive functional
groups, (d) elimination of the need to isolate the inter-
mediate, and (e) high yields. We believe that this proto-
col provides a practical alternative to the existing
methods available for the synthesis of aldehydes and
ketones from their corresponding carboxylic acids.
6. (a) Wakefield, B. J. Organomagnesium Methods in Organic
Synthesis; Academic Press: San Diego, 1995; (b) Suga, K.;
Watanabe, S.; Yamaguchi, Y.; Tohyama, M. Synthesis
1970, 189–190; (c) Watanabe, S.; Suga, K.; Fujita, T.;
Saito, N. Aust. J. Chem. 1970, 30, 427–431.
7. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fuku-
yama, T. Tetrahedron Lett. 1998, 39, 3189–3192.
8. Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti,
G.; Ricci, A.; Varchi, G. Synlett 1998, 1013–1015.
´
9. (a) Barluenga, J.; Baragana, B.; Concellon, J. M. J. Org.
˜
Chem. 1995, 60, 6696–6699; (b) De Luca, L.; Giacomelli,
G.; Porcheddu, A. Org. Lett. 2001, 3, 1519–1521.
10. (a) Jamieson, G. R.; McMinn, A. L.; Reid, E. H. J.
Chromatogr. 1978, 161, 327–334, and references cited
therein; (b) Cheng, Y.; Li, S.-M. Int. J. Environ. Anal.
Chem. 2004, 84, 367–378.
11. Boger, D. L.; Sato, H.; Lerner, A. E.; Hedrick, M. P.;
Fecik, R. A.; Miyauchi, H.; Wilki, G. D.; Austin, B. J.;
Patricelli, M. P.; Cravatt, B. F. Proc. Natl. Acad.
Sci. U.S.A. 2000, 97, 5044–5049, and references cited
therein.
12. Wang, X.-J.; Zhang, L.; Sun, X.; Krishnamurthy, D.;
Senanayake, C. H. Org. Lett. 2005, 7, 5593–5595.
13. The low yield might be due to difference in the reaction
mechanism between acyl fluorides and acyl chlorides. See:
Acknowledgments
This investigation was supported by funding from
National Institutes of Health, NIDDK, (DK046204)
and by the University of Pittsburgh Obesity and Nutri-
tion Research Center (DK46204). We thank Professor
Dennis P. Curran for reviewing the manuscript.

6292
C. O. Kangani et al. / Tetrahedron Letters 47 (2006) 6289–6292
Carpino, L. A.; Beyermann, M.; Wenschuh, H.; Bienert,
M. Acc. Chem. Res. 1996, 29, 268–274.
14. Kangani, C. O.; Kelley, D. E. Tetrahedron Lett. 2005, 46,
15. (a) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.;
Cheng, H. J. Org. Chem. 1999, 64, 7048–7054; (b) Lal, G.
S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem.
Commun. 1999, 215–216.
8917–8920.