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A route to ortho-substituted benzyne precursors by deprotonation of 7-methyl-1-aminobenzotriazole derivatives
Tehahaxlmn Letters, Vol. 34, No. 43, pp. 6935-6938.1993 Primtedin Grclt Britain
oo404039/93 $6.00 + .cNl PcrgPress hl
lWiCbdA-dI?al?idW.~~ Department of Chemistry, University Park, Nottingham, NG7 2RD, UK MichaelRMitdleR SB Pharmaceuticals, The Old Powder Mills, Leigh, Tonbridge, Rent, TN11 9AN, UK.
Abstract:- Double
deprotonation
of E-Boc-‘I-methyl-I-aminobenzotriazole
TiUEDA-THF [-78°C -> O%] results in an essentially intermediate conditions
7. Trapping with alkylating
at the carbon-centred agents,
aldehydes
the 7-substituted-I-aminobenzotriazoks
quantitative anion
occurs
6 using nBuLi-
conversion
to the dianionic
selectively
under
suitable
and ketones to give good to excellent yields
8-16, precursors
of &-substituted
of
benzynes.
The classical and oldest approach to benzynes consists of dehydrohalogenation or bromobenzenes by treatment with a strong base. 1 Problems of regioselectivity
of chloroassociated
with this method can be overcome by using an appropriate 1,2dibromobenzene
and halogen-
metal
feature
rather
decomposition
than hydrogen-metal
exchange.
of a variety of other bifunctional
anthranilic acid, benzothiadiazole-S,S-dioxide
More
esoteric
approaches
or heteroaromatic
the
species, most notably
and 1-aminobenzotriazoles.
As recently stated
in a review:- “An important drawback of the aryne routes starting with bidentate or cyclic precursors can be the effort needed to prepare the precursor itself, especially for substituted arynes. However, these have the advantage that the arynic bond can be generated without positional ambiguity.“2 Although a number of relatively complex precursors to arynes have been reported,3 these are often derived from bromobenzenes wherein the array of substituents renders both their preparation and aryne generation unambiguous. No2
YN N'
\
NY
002Et
With this in mind, it occurred to us that appropriate derivatives of ‘I-methyl-l-amino benzotriazole
4 could be ideal for further functionalisation
using metallation
chemistry.
Compound 4 was prepared initially as outlined in the seminal papers by Campbell and Rees4
6935
describing
the generation
of benzynes from 1-aminobenzotriazoles,
conditions, using either lead(IV) acetate or N-bromosuccinimide.4 commercial trapped
2-methyl-6-nitroaniline
in situ
corresponding
however,
Thus, the amino group in
1 was diazotised and the resulting diazonium species
by diethyl malonate. aniline;
under notably mild
The resulting adduct 2 was then reduced to the
in our hands, the original
procedure
[lo%
Pd-C, H,,
MeOH14 gave relatively poor yields of rather impure material. These were much improved by using transfer diazotisation
hydrogenation
[lo%
Pd-C, cyclohexene,
then led smoothly to the benzotriazole
EtOH, reflux,
2-3h].5 A second
3 and finally to the required
amino
derivative 4, following hydrolysis using 6M HCl but with methanol as co-solvent, rather than neat as in the original method.4 The amino function in the heterocycle 4 appeared to be well positioned
to facilitate
deprotonation
of the adjacent methyl group, after appropriate
derivatisation.6 We chose to use a tbutoxycarbonyl function for this purpose, both because it would not be expected to undergo deprotonation7 and because it should be easy to remove. Treatment of the benzotriazole 4 with (BOC),O [Et,N, DMAP, CHzCI,, 0-2O”C, 4-5h] led not to the desired monoadduct 6 but rather to the bis-adduct 6 (89%); this was not a serious problem as one of these new groups could be removed in essentially quantitative yield by basic hydrolysis [NaOH, MeOH, 5O”C,
!;N N\
Q: 1;
Li+
7
6
5
Li 21 0
Oh
Subsequent reactions with a range of electrophiles proceeded smoothly; the results are collected in the following equivalents
Table. 8 Alkylations
of the electrophile;
were best carried out at -78°C using 1.1
at higher temperatures,
especially
if an excess of the
electrophile was used, competing N-alkylation became a serious problem. The 96% isolated yield of the adduct 8 from iodomethane indicates that the dianion 7 is formed in essentially quantitative yield. The excellent 90% return of adduct 9 from iodoethane is also significant as a number of carbanionic species, especially if sp2 centred,g tend to react poorly with this electrophile and its higher homologues presumably due to competing deprotonation and subsequent elimination. In general, sp3-centred anions are more nucleophilic and less basic;lO dianion 7 thus appears to conform to this pattern. A similar reaction with ally1
6937
bromide was also very efiicient, leading to an 85% isolated yield of the expected adduct 10. Similar yields of the adducts 11 and 12 were obtained when benzaldehyde or 2-furfural were used as the electrophiles. A more rigorous test is the reactions of dianion 7 with enolizable aldehydes and ketones. These gave consistently lower returns. Thus, the adducts 13 and 14 from n-hexanal and citral were isolated in yields of 55% and 53% respectively. In contrast, ketones reacted slightly more efficiently; the product Ma from acetone was formed in 70% yield while the corresponding cyclohexanone adduct Mb was isolated in 62% yield. TABIX:ReactiousofDianion7with
YkPC
I
yrHO$!Bm
NHBOC
8 [Mel; 95%]
10 [CH$CHCHzBr; 85%]
9 [Etl; 90%]
11; [PhCHO; 85%]
;a~;;;; Hx NHBoC H”cBoc H”x(Jc 15b; R’ = R2 = (CH& [Cyclohexanone; 620~1 12 [2-Futfural;81%] a The electrophiks
13 [n-Hexanal; 55%]
are given in brackets
beneath the product
14 [citral; 63%] structures;
yields
are isolated
but unoptimised.
Finally, each of the foregoing adducts 8-13 and 15 has been successfully deprotected by brief exposure to trifluoroacetic acid in dichloromethane. After baaification, the free l-aminobenzotriazoles 16 were isolated in 75-95% yields. CF&QH
*
‘;N N
CH2C12,2O”C, 0.5h
0-Q R’
2
NHBOC R2
a-13,
R’ 15
No evidence for dehydration,
\ NH2
W) A
F? 16
even with the sensitive alcohols leg. 11 and 121 was
6938
observed. The one exception to this was the citral adduct 14 which decomposed under these conditions; the addition of cation scavengersll failed to alleviate this. The dianion 7 should therefore be of use in the elaboration of a wide variety of bensyne precursors; an illustration of the utility of this methodology is given in the following paper.
We are grateful to Dr Rob Giles (Tonbridge) for his help and encouragement and to SB Pharmaceuticals and the SERC for financial support through the CASE Scheme.
1.
Hoffmann, R. W. “Dehydrobenxenes 1967; Rienecke,
and Cycloalkynes,”
M. G. Tetrahedron,
1983,
38,
Academic Press, New York,
427; Levine,
R. H. “Reactive
Intermediates,” Eds. Jones, M.; Moss, R. A., J. Wiley and Sons, New York, 1985,3,
1,
and references therein. 2.
Kessar,
S. V. “Nucleophilic
Coupling
with Arynes,”
Comprehensive
Organic
Synthesis, Eds. Trost, B. M.; Fleming, I., Pergamon Press, 1991,4,483. 3.
For a review of some recent examples, see Biehl, E. R.; Khanapure, 5. P. Act. Chem.
Res., l-,22,276. 4.
Campbell, C. D.; Rees, C. W. J. Chem. Sot, CC),1969,742 and 752.
5.
Entwistle, I. D.; Johnstone, R. A. W.; Povall, T. J. J. Chem. Sot., Perkin Trans. 1,
6. 7.
1975, 1300. See also Entwistle, I. D.; Jackson, A. E.; Johnstone, R. A. W.; Telford. R. P. J. Chem. Sot., Perkin Trans. 1,1977,443. For reviews, see Gschwend, H. W.; Rodriguez, H. R. Org. Reacts., 1979,26, 1; Snieckus, V. Chem. Rev., 1890,90,879. Fuhrer, W.; Gschwend, H. W. J. Org. Chem., 1879.45, 4798; Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M. Synthesis, 1991, 871, and references therein.
8. 9.
All yields refer to material showing correct analytical and spectroscopic data. Knight, D. W., “Alkylations of Vinyl Carbanions,” Comprehensive Organic Synthesis, Eds. Trost, B. M.; Fleming, I., Pergamon Press, 1991,3,241.
10. See, for example, Buttery, C. D.; Knight, D. W.; Nott, A. P. J. Chem. Sot., Perkin Trans.
I, 1984,2839, and references therein. 11. Masui, Y.; Chino, N.; Sawakibara,
S. Bull.
references therein.
(Receivedin UK 36 July 1993; accepted 27 August 1993)
Chem. Sot. Jpn., 1980,53,
464 and
oo404039/93 $6.00 + .cNl PcrgPress hl
lWiCbdA-dI?al?idW.~~ Department of Chemistry, University Park, Nottingham, NG7 2RD, UK MichaelRMitdleR SB Pharmaceuticals, The Old Powder Mills, Leigh, Tonbridge, Rent, TN11 9AN, UK.
Abstract:- Double
deprotonation
of E-Boc-‘I-methyl-I-aminobenzotriazole
TiUEDA-THF [-78°C -> O%] results in an essentially intermediate conditions
7. Trapping with alkylating
at the carbon-centred agents,
aldehydes
the 7-substituted-I-aminobenzotriazoks
quantitative anion
occurs
6 using nBuLi-
conversion
to the dianionic
selectively
under
suitable
and ketones to give good to excellent yields
8-16, precursors
of &-substituted
of
benzynes.
The classical and oldest approach to benzynes consists of dehydrohalogenation or bromobenzenes by treatment with a strong base. 1 Problems of regioselectivity
of chloroassociated
with this method can be overcome by using an appropriate 1,2dibromobenzene
and halogen-
metal
feature
rather
decomposition
than hydrogen-metal
exchange.
of a variety of other bifunctional
anthranilic acid, benzothiadiazole-S,S-dioxide
More
esoteric
approaches
or heteroaromatic
the
species, most notably
and 1-aminobenzotriazoles.
As recently stated
in a review:- “An important drawback of the aryne routes starting with bidentate or cyclic precursors can be the effort needed to prepare the precursor itself, especially for substituted arynes. However, these have the advantage that the arynic bond can be generated without positional ambiguity.“2 Although a number of relatively complex precursors to arynes have been reported,3 these are often derived from bromobenzenes wherein the array of substituents renders both their preparation and aryne generation unambiguous. No2
YN N'
\
NY
002Et
With this in mind, it occurred to us that appropriate derivatives of ‘I-methyl-l-amino benzotriazole
4 could be ideal for further functionalisation
using metallation
chemistry.
Compound 4 was prepared initially as outlined in the seminal papers by Campbell and Rees4
6935
describing
the generation
of benzynes from 1-aminobenzotriazoles,
conditions, using either lead(IV) acetate or N-bromosuccinimide.4 commercial trapped
2-methyl-6-nitroaniline
in situ
corresponding
however,
Thus, the amino group in
1 was diazotised and the resulting diazonium species
by diethyl malonate. aniline;
under notably mild
The resulting adduct 2 was then reduced to the
in our hands, the original
procedure
[lo%
Pd-C, H,,
MeOH14 gave relatively poor yields of rather impure material. These were much improved by using transfer diazotisation
hydrogenation
[lo%
Pd-C, cyclohexene,
then led smoothly to the benzotriazole
EtOH, reflux,
2-3h].5 A second
3 and finally to the required
amino
derivative 4, following hydrolysis using 6M HCl but with methanol as co-solvent, rather than neat as in the original method.4 The amino function in the heterocycle 4 appeared to be well positioned
to facilitate
deprotonation
of the adjacent methyl group, after appropriate
derivatisation.6 We chose to use a tbutoxycarbonyl function for this purpose, both because it would not be expected to undergo deprotonation7 and because it should be easy to remove. Treatment of the benzotriazole 4 with (BOC),O [Et,N, DMAP, CHzCI,, 0-2O”C, 4-5h] led not to the desired monoadduct 6 but rather to the bis-adduct 6 (89%); this was not a serious problem as one of these new groups could be removed in essentially quantitative yield by basic hydrolysis [NaOH, MeOH, 5O”C,
!;N N\
Q: 1;
Li+
7
6
5
Li 21 0
Oh
Subsequent reactions with a range of electrophiles proceeded smoothly; the results are collected in the following equivalents
Table. 8 Alkylations
of the electrophile;
were best carried out at -78°C using 1.1
at higher temperatures,
especially
if an excess of the
electrophile was used, competing N-alkylation became a serious problem. The 96% isolated yield of the adduct 8 from iodomethane indicates that the dianion 7 is formed in essentially quantitative yield. The excellent 90% return of adduct 9 from iodoethane is also significant as a number of carbanionic species, especially if sp2 centred,g tend to react poorly with this electrophile and its higher homologues presumably due to competing deprotonation and subsequent elimination. In general, sp3-centred anions are more nucleophilic and less basic;lO dianion 7 thus appears to conform to this pattern. A similar reaction with ally1
6937
bromide was also very efiicient, leading to an 85% isolated yield of the expected adduct 10. Similar yields of the adducts 11 and 12 were obtained when benzaldehyde or 2-furfural were used as the electrophiles. A more rigorous test is the reactions of dianion 7 with enolizable aldehydes and ketones. These gave consistently lower returns. Thus, the adducts 13 and 14 from n-hexanal and citral were isolated in yields of 55% and 53% respectively. In contrast, ketones reacted slightly more efficiently; the product Ma from acetone was formed in 70% yield while the corresponding cyclohexanone adduct Mb was isolated in 62% yield. TABIX:ReactiousofDianion7with
YkPC
I
yrHO$!Bm
NHBOC
8 [Mel; 95%]
10 [CH$CHCHzBr; 85%]
9 [Etl; 90%]
11; [PhCHO; 85%]
;a~;;;; Hx NHBoC H”cBoc H”x(Jc 15b; R’ = R2 = (CH& [Cyclohexanone; 620~1 12 [2-Futfural;81%] a The electrophiks
13 [n-Hexanal; 55%]
are given in brackets
beneath the product
14 [citral; 63%] structures;
yields
are isolated
but unoptimised.
Finally, each of the foregoing adducts 8-13 and 15 has been successfully deprotected by brief exposure to trifluoroacetic acid in dichloromethane. After baaification, the free l-aminobenzotriazoles 16 were isolated in 75-95% yields. CF&QH
*
‘;N N
CH2C12,2O”C, 0.5h
0-Q R’
2
NHBOC R2
a-13,
R’ 15
No evidence for dehydration,
\ NH2
W) A
F? 16
even with the sensitive alcohols leg. 11 and 121 was
6938
observed. The one exception to this was the citral adduct 14 which decomposed under these conditions; the addition of cation scavengersll failed to alleviate this. The dianion 7 should therefore be of use in the elaboration of a wide variety of bensyne precursors; an illustration of the utility of this methodology is given in the following paper.
We are grateful to Dr Rob Giles (Tonbridge) for his help and encouragement and to SB Pharmaceuticals and the SERC for financial support through the CASE Scheme.
1.
Hoffmann, R. W. “Dehydrobenxenes 1967; Rienecke,
and Cycloalkynes,”
M. G. Tetrahedron,
1983,
38,
Academic Press, New York,
427; Levine,
R. H. “Reactive
Intermediates,” Eds. Jones, M.; Moss, R. A., J. Wiley and Sons, New York, 1985,3,
1,
and references therein. 2.
Kessar,
S. V. “Nucleophilic
Coupling
with Arynes,”
Comprehensive
Organic
Synthesis, Eds. Trost, B. M.; Fleming, I., Pergamon Press, 1991,4,483. 3.
For a review of some recent examples, see Biehl, E. R.; Khanapure, 5. P. Act. Chem.
Res., l-,22,276. 4.
Campbell, C. D.; Rees, C. W. J. Chem. Sot, CC),1969,742 and 752.
5.
Entwistle, I. D.; Johnstone, R. A. W.; Povall, T. J. J. Chem. Sot., Perkin Trans. 1,
6. 7.
1975, 1300. See also Entwistle, I. D.; Jackson, A. E.; Johnstone, R. A. W.; Telford. R. P. J. Chem. Sot., Perkin Trans. 1,1977,443. For reviews, see Gschwend, H. W.; Rodriguez, H. R. Org. Reacts., 1979,26, 1; Snieckus, V. Chem. Rev., 1890,90,879. Fuhrer, W.; Gschwend, H. W. J. Org. Chem., 1879.45, 4798; Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M. Synthesis, 1991, 871, and references therein.
8. 9.
All yields refer to material showing correct analytical and spectroscopic data. Knight, D. W., “Alkylations of Vinyl Carbanions,” Comprehensive Organic Synthesis, Eds. Trost, B. M.; Fleming, I., Pergamon Press, 1991,3,241.
10. See, for example, Buttery, C. D.; Knight, D. W.; Nott, A. P. J. Chem. Sot., Perkin Trans.
I, 1984,2839, and references therein. 11. Masui, Y.; Chino, N.; Sawakibara,
S. Bull.
references therein.
(Receivedin UK 36 July 1993; accepted 27 August 1993)
Chem. Sot. Jpn., 1980,53,
464 and