Dialkylhydrazides for directed orthometalations

Article abstract of DOI:10.1016/S0040-4039(00)00462-7

Dimethylhydrazides are shown to be excellent substrates for the directed orthometalation reaction. The advantage of using the hydrazide is that it is easily removed by treatment with H₅IO₆ or CuCl₂ to give the carboxylic acid under very mild conditions, in contrast to other amides that generally require harshly acidic conditions to achieve hydrolysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00462-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3559–3562
Dialkylhydrazides for directed orthometalations
Scott A. Pratt, Michael P. Goble, Michael J. Mulvaney and Peter G. M. Wuts ∗
Chemical Process Research and Development, 1500-91-201, Pharmacia and Upjohn, Kalamazoo, MI 49001, USA
Received 24 January 2000; accepted 8 February 2000
Abstract
Dimethylhydrazides are shown to be excellent substrates for the directed orthometalation reaction. The advan-
tage of using the hydrazide is that it is easily removed by treatment with H5IO6 or CuCl2 to give the carboxylic acid
under very mild conditions, in contrast to other amides that generally require harshly acidic conditions to achieve
hydrolysis. © 2000 Elsevier Science Ltd. All rights reserved.
The process of directed orthometalation is one of the better known methods for the construction of aryl
containing molecular frameworks.1 Among the many groups that have been used in the Dom reaction,
the dialkylamides appear to have taken center stage. The primary disadvantage of this group is that harsh
conditions are often required for its hydrolysis. The overall problem of hydrolysis of the directing group
has recently been addressed by Hawkins who has developed the neopentyl ester as a useful group for the
preparation of arylboronic acids, but the application to other derivatives was not described.2
During our work on approaches to the synthesis of new clinical candidates we became interested in an
approach to the basic furanopyridine skeleton that would rely on the orthofunctionalization of 2-furoic
acids. Initial studies with the t-Bu amide resulted in products that could not be hydrolyzed even in the
presence of a participating hydroxyl group.3
The problem with the hydrolysis of the amide stimulated our interest in the possibility of using a
dialkylhydrazide as an orthodirecting group,4 as well as a report that they could be oxidatively cleaved
under relatively mild conditions using reagents such as Pb(OAc)4, MnO2 and NaIO4.5 They also look
much like primary amides, which are excellent orthodirecting groups. Furthermore, chiral hydrazides
could be prepared and thus an asymmetric version of the Dom reaction was envisioned.
The concept was tested by preparing the N,N-dimethylhydrazide of benzoic acid and treating it with
s-BuLi and TMEDA in THF at −78°C followed by silylation with TMSCl (Scheme 1). We found that
the reaction proceeds smoothly giving the desired 2-trimethylsilylhdyrazide in excellent yield. n-BuLi
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00462-7
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was also tested, but it would not deprotonate the hydrazide at temperatures below −10°C which was
determined by reaction calorimetry.6 A brief survey of a number of standard electrophiles shows that
the generality of the process is consistent with the prior art on the use of simple amides. In the case of
aldehydes and ketones, lactonization often occurs during the isolation.7 This result augurs well for the
use of this chemistry in the elaboration of furans. A small solvent effect has been observed in the reaction
in that in some cases the use of ether results in better yields than when THF is used (Table 1).
Scheme 1.
Table 1
Dom reaction of hydrazides and their oxidative cleavage8
With the availability of Enders’ chiral hydrazines, we examined the possibility of inducing asymmetry
in a lactone synthesis. Unfortunately, when the hydrazide 5 was metalated and treated with anisaldehyde
only the racemic lactone 6 could be isolated from this reaction (Scheme 2).
Barton’s original work on the cleavage of the hydrazides utilized primarily Pb(OAc)4 for this type
of cleavage. Environmental concerns directed our attention to other oxidants such as periodic acid and

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Scheme 2.
Scheme 3.
CuCl2. The use of CuCl2 to cleave the dimethylhydrazide is new to this study and proceeds with excellent
efficiency as illustrated in Table 1.
With the viability of this reaction established, we began to explore the use of the furanyl hydrazides as
substrates (Scheme 3). A number of hydrazides were prepared and the regioselectivity of deprotonation
was examined by quenching the anions with TMSCl. The results of this study are outlined in Table 2.
The observed ratios are quite dependent upon the hydrazide and the base used to effect deprotonation.
Dimethyl and diisopropyl hydrazides favor deprotonation at the 5-position with increasing selectivity as
the steric bulk of the hydrazine increases. The SAMP hydrazide drives the selectivity more toward the
3-position, which may be a result of the coordinating methoxymethyl group. Currently, the best result
is obtained with the morpholine derivative which gives a reasonable 4.3:1 ratio favoring the 3-position
when BuLi is used as a base. Changing the base to LDA, which then leads to a 1:4.7 ratio favoring the
5-position, can effectively reverse this.
Table 2
Silylation of 2-furylhydrazides
Representative procedure: Dissolve 1a (1.0 g, 6.09 mmol) in diethyl ether (10 mL) under nitrogen,
cool to −78°C and add TMEDA (0.708 g, 6.09 mmol), then add s-BuLi (1.3 M, 11.7 mL, 15.22 mmol)
keeping the temperature below −74°C. After stirring for 3.5 hours, methyl disulfide (1.15 g, 12.18 mmol)

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was added. After stirring for 2 more hours, the reaction was allowed to warm to 22°C. Water (10 mL) was
added and the layers were separated. The aqueous phase was extracted with methylene chloride (2×10
mL). The organic phases were combined, and washed with water (1×10 mL). The organic phase was
1
dried with magnesium sulfate, filtered and concentrated to afford 1.16 g (90.5%) of the thioether. H
NMR (CDCl3, 400 MHz at 300 K) δ 2.47 (s, 3H, CH3), 2.73 (s, 6H, CH3), 6.92 (s, 1H, NH), 7.20 (t,
J=7.6, 1H), 7.29 (d, J=7.6, 1H), 7.38 (t, J=7.6, 1H), 7.51 (d, J=7.6, 1H); 13C NMR (CDCl3, 100 MHz,
300 K) δ 16.72, 47.46, 125.35, 127.29, 128.74, 130.67, 134.44, 136.36, 166.01. Mp: 125–126°C. HRMS
calcd for C10H14N2OS+H+: 211.0905. Found: 211.0909.
CuCl2 induced cleavage of dimethylhydrazides: To a 50 mL round-bottomed flask with a magnetic
stirrer was charged N,N-dimethyl-2-(methylthio)benzoic hydrazide (250 mg, 1.19 mmol), CuCl2 (480
mg, 3.56 mmol), water (10 mL), and dioxane (10 mL). The reaction was heated to 96°C for 24 hours.
The reaction was acidified to a pH of 2 with 10% (v/v) HCl. After adding 10 mL of CH2Cl2, the layers
were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The organic layers were
combined, and washed with water (2×10 mL). After drying the organic layer with MgSO4, and filtering,
the organic layer was evaporated by rotary evaporation to yield 170 mg (85%) of a white solid. 1H NMR
and 13C NMR analysis confirmed the product to be the known acid. All products of this cleavage were
compared to known standards by comparison with spectral data of known compounds.
References
1. Sniekus, V. Chem. Rev. 1990, 90, 879.
2. Caron, S.; Hawkins, J. M. J. Org. Chem. 1998, 63, 2054.
3. Carpenter, A. J.; Chadwick, D. J. J. Org. Chem. 1985, 50, 4362.
4. For a recent report on very similar chemistry which prompts the disclosure of our results, see: McCombie, W. W.; Lin,
S.-I.; Vice, S. F. Tetrahedron Lett. 1999, 40, 8767.
5. Oliveira Baptista, M. J. V.; Barrett, A. G. M.; Barton, D. H. R.; Girijavallabhan, M.; Jennings, R. C.; Kelly, J.; Papadimtriou,
V. J.; Turner, J. V.; Usher, N. A. J. Chem. Soc., Perkin Trans. 1 1977, 1477.
6. We wish to thank Don K. Knoechel for this determination.
7. For a similar lactonization with trimethylhydrazides, see: Chong, J. M.; Mar E. K. Tetrahedron Lett. 1990, 31, 1981.
8. Analytical data was obtained for all new compounds.