The reaction of o-amino aryl carboxylic acids with Grignard reagents. The unusual effect of the N-protecting group on aryl ketone formation

Article abstract of DOI:10.1016/S0040-4039(01)00160-5

The addition of Grignard reagents to the o-amino aryl carboxylic acids without any additive forms the tertiary carbinol as a major product. Unexpectedly, the aryl ketones are formed as the only isolated product if o-amino moiety of anthranilic acids is protected with Boc, trifluoroacetyl, and pivaloyl protecting groups.

Full text of DOI:10.1016/S0040-4039(01)00160-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2097–2099
The reaction of o-amino aryl carboxylic acids with Grignard
reagents. The unusual effect of the N-protecting group on aryl
ketone formation†
Puwen Zhang,* Eugene A. Terefenko and Joseph Slavin‡
Medicinal Chemistry I, Chemical Sciences, Wyeth-Ayerst Research, Radnor, PA 19087, USA
Received 28 November 2000; revised 16 January 2001; accepted 17 January 2001
Abstract—The addition of Grignard reagents to the o-amino aryl carboxylic acids without any additive forms the tertiary carbinol
as a major product. Unexpectedly, the aryl ketones are formed as the only isolated product if o-amino moiety of anthranilic acids
is protected with Boc, trifluoroacetyl, and pivaloyl protecting groups. © 2001 Elsevier Science Ltd. All rights reserved.
The reaction of a Grignard reagent with a carboxylic
acid is not a practical approach for synthesising
ketones. Often, the reaction is plagued by low yield of
ketones and the formation of tertiary alcohols.1–3 Solu-
tions to this problem have involved the addition of a
Grignard reagent to carboxylic acid derivatives such as
Weinreb amides and acyl hemiacetals.4 Other methods
to prevent the formation of alcohols include the use of
a pre-formed lithium carboxylate or a nickel catalyst.5–7
Although the above methods are well documented, the
direct addition of Grignard reagents to carboxylic acids
to form ketones is an area which has been largely
unsuccessful.
was formed in high yield instead of the expected ter-
tiary carbinol 3.
Apparently, the formation of ketone 2 was mediated by
the Boc protecting group. We have examined a number
of N-protected anthranilic acids as well as various
Grignard reagents in this reaction and now wish to
report that such a transformation is general in scope
among the reactions we examined.
The protecting groups employed in the study included
Boc, pivaloyl and trifluoroacetyl groups. The N-pro-
tected starting materials can be readily prepared from
corresponding anthranilic acids following literature
procedures.8
During our research, an expedient synthesis of carbinol
1 from anthranilic acids was sought. To this end,
methylmagnesium bromide was reacted with the 3-
fluoroanthranilic acid to yield the desired carbinol 1 in
good yield. Surprisingly, when the amino group of
3-fluoroanthranilic acid was protected with Boc group
and treated with the methyl Grignard reagent, ketone 2
The various substrates and a number of Grignard
reagents were examined as illustrated in Tables 1 and 2.
The results are given as the isolated yield of the
product.9 The only other material isolated from the
reactions was starting material.
O
OH
OH
NHBoc
NH2
NHBoc
F
F
F
2
1
3
Keywords: ketone formation; Grignard reagents; protecting groups.
* Corresponding author. Present address: 145R-2006, 145 King of Prussia Road, Radnor, PA 19087, USA. Tel.: (610) 341-3856, fax: (610)
989-4588; e-mail: zhangp@war.wyeth.com
†
Presented in preliminary form at the 220th National Meeting of the American Chemical Society, Washington, DC, August 20–24, 2000.
Undergraduate Summer Intern, Villanova University, PA 19087, USA.
‡
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00160-5

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P. Zhang et al. / Tetrahedron Letters 42 (2001) 2097–2099
Table 1. Boc mediated ketone formation
Among the Grignard reagents examined, aliphatic
Grignard reagents gave higher yields than did the vinyl
or aryl species (entries 2–4 vs 5–7). This result was not
surprising since the alkyl anions are considered to be
more nucleophilic than aryl or vinyl anions.
O
O
X
X
RMgBr,
OH
R
THF, 50 °C
NHBoc
NHBoc
Y
Y
Diethyl ether was also examined as a solvent and found
to be less desirable than THF as the reaction in diethyl
ether was slower and not as clean. To examine if esters
of N-protected o-amino aryl carboxylic acids form aryl
ketones when reacted with Grignard reagents, N-Boc
methyl anthranilate (methyl ester of entry 1) was
treated with methylmagnesium bromide and the carbi-
nol was formed in quantitative yield instead of aryl
ketone.
4
5
Entry
RMgBr
X
Y
Yield (%) of 5
1
2
3
4
5
6
7
Methyl
Methyl
Methyl
Isopropyl
Phenyl
Phenyl
Vinyl
H
H
F
H
H
F
H
F
H
F
F
H
F
B5
80 (82)a
66
89
29
27
27
Using a pre-formed lithium carboxylate5 compared to
the free N-protected anthranilic acid used in this study
offered no advantage. Comparable yields of aryl
ketones were obtained as illustrated from entries 2 and
8 of Tables 1 and 2. It has also been shown that the
2-tetrahydrofuranyl acyl hemiacetal ester4 of carboxylic
acids is converted to the ketone upon treatment with
Grignard reagents. When the carboxylic acid moiety of
6 (P=t-BuCO, X=H) was converted into its 2-tetra-
hydrofuranyl acyl hemiactetal ester4 and treated with
methyl Grignard reagent carbinol instead of ketone was
obtained as a major product.
H
a Yield in parenthesis was obtained by following the procedure of
Ref. 5.
Table 2. Pivaloyl and trifluoroacetyl mediated ketone for-
mation
O
O
X
X
RMgBr, THF
R
OH
NHP
NHP rt or 50°C , N2
7
6
In conclusion, an unusual reaction for the formation of
ketones directly from the N-protected anthranilic acids
and Grignard reagents was unveiled. This novel finding
provided an interesting insight into the effect of the
N-protecting group on the reaction outcome and repre-
sents another useful way to prepare o-amino aryl
ketones since the starting materials are readily available
and the N-protecting groups can be easily removed.8
Furthermore, o-amino aryl ketones are extremely useful
intermediates in the synthesis of a variety of the hetero-
cyclic ring systems, for example, benzodiazepines.10
Entry
P
X
R
Yield (%) of 7
8
9
10
11
12
13
t-BuCO
t-BuCO
t-BuCO
t-BuCO
CF3CO
CF3CO
H
H
Br
Br
H
Me
Ph
Me
Ph
Me
Me
52 (50)a
40
70
50
50
65
Br
a Yield in parenthesis was obtained by following the procedure of
Ref. 5.
As illustrated in Tables 1 and 2, aryl ketones were
formed mostly in good yield from the reaction of
Grignard reagents and three different N-protected
anthranilic acids. For the unsubstituted N-protected
anthranilic acids, the amide protecting groups worked
better than Boc and gave higher yields of ketone prod-
ucts (about 50% yield of ketones formed for pivaloyl
and trifluoroacetyl, entries 8 and 12 vs <5% for Boc,
entry 1). The aryl substituent (X or Y) significantly
affected the reactivity of the N-protected anthranilic
acids with Grignard reagents. Electron withdrawing
halogen moieties increased the formation of ketones
presumably because it increased the electrophilicity of
the carboxylic acid group. This finding was more evi-
dent for the Boc protecting group as demonstrated by
the first three examples in Table 1. The unsubstituted
Boc protected anthranilic acid only gave a trace
amount of ketone (entry 1) while its fluoro substituted
congeners afforded ketones in over 60% yield (entries 2
and 3).
Acknowledgements
Authors are very grateful to Dr. Jay Wrobel for helpful
discussions and suggestions in the preparation of
manuscript and to Professors Steve Burke and Michael
Jung and Drs. Andrew Fensome & John Yardley for
useful discussions.
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