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A direct synthesis of primary amides from grignard reagents
PergemonPrear. Printed in Qrwt Britain.
TetrahedronLettem Ho. 12, pi 981 - 984, 19%
ADIRECT
f4!mTmsIsoPppMbBYMIDHIPBoMGBIGuABD~
Kathlyn A. Pulur* and E. Grant Gibboaml Metcelf lkeaeerch Laboretorlem,Brwn Uaiverelty, Providence,Rhode Inland 02912
(hoeid
in USI 31 October 1974; reoeived III1II[ for publioetiw 11 %bm
1975)
iave~tigetianof epproecheeto the total eynthemia of cerulonin (&I2 end
beptalldmy
related compouoda,vetiahedto
convert the temlnal acetylena~to theacetyleulc priauy mida
33 -a am2 1
100
siaplemethod forecbieving a comereionof
thetypeRC%H+RCZ-WNE2
quenceuhicb requirea the fntemedkcyof
the ecid cbloride&ia
of tbe tetrehydropyrmyl
group.
the methylester~ln
ether protectfng
4a
is hmm.
As-
iacap8tiblewith tbepremeace
Au akemmtBJe
ntbd,
the mly8f8
8 aolutioncapoeed of 30% liqa2d QlDoiL md 502 ethyl-
of
&cold
conteiaiaSe trece of XQ$Cl requ%ree 10 bour8 even et 7S".&
PCZ-COCl
P-Cz-CG2CE3
r Thereforewe soughterore
a fecile end ~relMthodof~colp~~pronccuboa
ption which would afford a prlnry emUa.
homolo-
Seconduy amidee (8J uy be convenientlypreparod by
treetmnt of a covelent isocyenete (I, with a GriSnad reagent &5
If tbeneturaof
the i8ocyr
nate aubetltueutB' were such that ft could eaeUy be rewved from the nitrogen in emide 3, this
Ho. 12
982
We have found that
Grfmard synthesiswould afford primary amides as well as secondary amides.
and chloroacetylisocyanate (7J)' are particularly
trimethylsilylisocyanate @'
suited
to this
approach to primary amides, that the tramformation is general for arometic and alipbatic as well as acetylanicGrignard reagauts,and that in the reactionwith trimethylsilylisocyanate.the conversion a '2
requires only one stapp, KC
a
2
1 a.
B’ - Si(~)3
b.
B' - CCm Cl 2
Ho \ =2
The addition of trimethyleilylisocyanatato a solutionof Grignard rugmt,
followed by
aqueous workup, afforded the amida 2 along with varying awunts of the substitutedsilane 10.' The product distributionia this reaction vu
fouud to be solvent deprrdaut. The proeence of
dioxme greatly increamed the addition reaction (& +a, action @ * 2).
to the exclusion of the substitutionre-
Uo silanu could be detwted in mixtures from thuo experimentsand the amides
could be isolated directly.
In atypical procedure,
a 0.9 g wlution of the GriIpurd rugsnt was prepared in ether or
tatrabydrofurauand added to a alight excess of trimethylrilylieocyanate
in 3 - 5 volumes of
dioxane. The reactioamixtore was stirred at 85-95. for 2 - 24 hours, allowed to cool to room twerature.
and quenchedwith aqueous Worn
chloride. Theproductwu
iaolatd from chloro-
fond~thar and recrystallized. Specific raeulto are recorded kr the Table. In the case of the reaction of a Grignard rugent with chloroacatylisocyuute, the initially isolated product is the imide 3.
Hydrolyticor reductiveremval of the cbloroacatylgroup
lffor& the unsubstitutedamide 2. follow. gMg Br
//O 1.c1Cg2c~lKC 2. E20
>
Kxpuimatal
proceduresfor each of theae transformations
no. 12
985
A 0.9 g solutionof the GrQnerd reagentvea prepued in tetrahydrofurea end wu 111owly edded to e eligbtexceemof ctkro&cetyliaocy&kete in 2 - 3 volumeaof tetrahydrofuxan et -70.. Afterstirring for 5 - 10 minute08t -70.. the cold beth vem remwed and wheu the reaction mixture reeched-30.,it wea quenchedwith aaturetedmilrm &waa
chloridesolution. The intermediate imide
ieoletedfrom cbloroform/etber aad recryetellizad (me Table). A
aa@e
of imide& wu treetedwith 1.5 equivalarta of sodim hydroxidein wthenol. Thin
layerchromatography indiutedthettbe reectionwu completein a feuminutea. The amide9_wea isoletedfrom chloroform/ether end recrystellised (aeoTeble). Alternatively, excem zinc dustvaa eddedto a methanolsolutionof imide&.
After 14
boura.the reectioomixturevu filteredend pertitiomed betworncblorofoafether end mter. Amide2 was isolatedend recrymtellized (seeTeble). Teble- 2%. Enectionsof GrigcurdEeegeutawith SubmtiutedIsocyautr:' Yieldaand MeltingPointaof Product8 B
sb (fromM
sb
C
9' (fromg (fr% 8b by hydrolyaia) by reduc&)
'6%
49% 125.5'
56X 52% 157.5-158.5. 126.5-128.
c6E5cIc-
48% 106.5-107.'
76% 145.5-147,s
,-c as
82% 127-128,
83% 90% 107.5-108.5. 102.5-104.5.
84x 67% 86% 106.5-107.5a 104.5-105.5. 100.5-102~ 50%
81.5-83.5°
-
e. All crudeyieldsere greetertheu 70%. Crudeproductawere recryatallimed from benzene/hew me. All productsheve ir cud nmr spectra consistent vith the lasi~md ltructurea.b. Yields era bued on C E r, C B CiCll, PC 5Br, and C61i5CE2Ck12Cli2Br, rerpectively.c. Yieldsere besedonthe d rz pen& imi&_. sa"l
l
Tbia methodcomplammtathe previously known1-cerbonhomolopetiona of GrQnerd r-gents.' Bfforteare uaderweyto applythis methodto the synthesisof caruleninand other functioneliaed emides. tiow1edEmalt &ImowledSmeotia nude to the donorsof The PetroleumReseercbPund,administered by the AmericanChemicalSociety,for pertielsupportof tbie reseerch.
80. 12
9aq
References 1. Browa UniversityUndergraduateUsearch Assietaat,3.973-74. 2. J. d'Agno10, I. 5. Rosenfeld.J. Awaya, S. (Inuta.and P. B. Vagelos;Biochm. Biophvs. Acta, 326. 155-166 (1973). 3. An extensive revfew of the synthesesof tides is by A. L. J. Beckx&tb fn The Chalstry of Amides, J. Zabrcky, ed., XUerscience Publishers,1970, pp 73-185. 4. a. 1. 0. V. Sonntag,Chem. Bev., 52, 237 (1953); b. B. 8. Woodward, Pure Appl. Chem., 22. 145 c1973). 5. B. B. Cerlfn and L. 0. Smith, Jr., J. Amar. Chew Sot., 6& Furry, J. Amer. Chem. Sot., 50, 1214 (1928).
2007 (1947); 8. Gilman and M.
6. Tha procedure of G. S. Forbes and lL H. Anderson, J. Amar. Chem. Sot., & 1222 (l%8), was modified. Xylene was used as a solvent and the product mixtu~c-vas fractionallydastilled. 7. A. J. Speaialeand L. R. Smith, Org. Sm., Coll. Vol. V, p 204 (1973). 8. The reactions of phenyllithi)rm and phenylmegneslumbromide with triphenyleilylieocyanateand triphenyle~yl tsotbtocyanstewere studied by Gilman and coworkers; see Ii.Gilmen, B. Eofferth,end EL W. Melvin, J. Amer. m. Sot., 72, 3045,cl950). The trtiethylsilyl. compoundax are more readfly avatiable than the triphenylsflylrompounds and trWthylsilano1 ti more easily separablethan trtphenylsilanolfrom &e products. 9. Other Grignard reacttonswhich result in one-carbonhomologationeafford esters, alcohols, acids, and titrttea. Soma representativereferencesare F. C. Whitmore and D. J. Loder, Org. Syn u p. 282 ($943);J. liouben,Chew Ber.\z, 2087 (l903);A. Schaap, L. Brand& and 3. F. Areas, Xecl. Trav. Chim. Pays-Bee,84. 1200 (1965); Ii.Gilman and Ri Ii.Kirby, Org. Svn Coll. Vol. r, p.361 (1941);V. Grignard and Ch. Courtot, u. sot. chim., nemoZres~'i28(1915).
TetrahedronLettem Ho. 12, pi 981 - 984, 19%
ADIRECT
f4!mTmsIsoPppMbBYMIDHIPBoMGBIGuABD~
Kathlyn A. Pulur* and E. Grant Gibboaml Metcelf lkeaeerch Laboretorlem,Brwn Uaiverelty, Providence,Rhode Inland 02912
(hoeid
in USI 31 October 1974; reoeived III1II[ for publioetiw 11 %bm
1975)
iave~tigetianof epproecheeto the total eynthemia of cerulonin (&I2 end
beptalldmy
related compouoda,vetiahedto
convert the temlnal acetylena~to theacetyleulc priauy mida
33 -a am2 1
100
siaplemethod forecbieving a comereionof
thetypeRC%H+RCZ-WNE2
quenceuhicb requirea the fntemedkcyof
the ecid cbloride&ia
of tbe tetrehydropyrmyl
group.
the methylester~ln
ether protectfng
4a
is hmm.
As-
iacap8tiblewith tbepremeace
Au akemmtBJe
ntbd,
the mly8f8
8 aolutioncapoeed of 30% liqa2d QlDoiL md 502 ethyl-
of
&cold
conteiaiaSe trece of XQ$Cl requ%ree 10 bour8 even et 7S".&
PCZ-COCl
P-Cz-CG2CE3
r Thereforewe soughterore
a fecile end ~relMthodof~colp~~pronccuboa
ption which would afford a prlnry emUa.
homolo-
Seconduy amidee (8J uy be convenientlypreparod by
treetmnt of a covelent isocyenete (I, with a GriSnad reagent &5
If tbeneturaof
the i8ocyr
nate aubetltueutB' were such that ft could eaeUy be rewved from the nitrogen in emide 3, this
Ho. 12
982
We have found that
Grfmard synthesiswould afford primary amides as well as secondary amides.
and chloroacetylisocyanate (7J)' are particularly
trimethylsilylisocyanate @'
suited
to this
approach to primary amides, that the tramformation is general for arometic and alipbatic as well as acetylanicGrignard reagauts,and that in the reactionwith trimethylsilylisocyanate.the conversion a '2
requires only one stapp, KC
a
2
1 a.
B’ - Si(~)3
b.
B' - CCm Cl 2
Ho \ =2
The addition of trimethyleilylisocyanatato a solutionof Grignard rugmt,
followed by
aqueous workup, afforded the amida 2 along with varying awunts of the substitutedsilane 10.' The product distributionia this reaction vu
fouud to be solvent deprrdaut. The proeence of
dioxme greatly increamed the addition reaction (& +a, action @ * 2).
to the exclusion of the substitutionre-
Uo silanu could be detwted in mixtures from thuo experimentsand the amides
could be isolated directly.
In atypical procedure,
a 0.9 g wlution of the GriIpurd rugsnt was prepared in ether or
tatrabydrofurauand added to a alight excess of trimethylrilylieocyanate
in 3 - 5 volumes of
dioxane. The reactioamixtore was stirred at 85-95. for 2 - 24 hours, allowed to cool to room twerature.
and quenchedwith aqueous Worn
chloride. Theproductwu
iaolatd from chloro-
fond~thar and recrystallized. Specific raeulto are recorded kr the Table. In the case of the reaction of a Grignard rugent with chloroacatylisocyuute, the initially isolated product is the imide 3.
Hydrolyticor reductiveremval of the cbloroacatylgroup
lffor& the unsubstitutedamide 2. follow. gMg Br
//O 1.c1Cg2c~lKC 2. E20
>
Kxpuimatal
proceduresfor each of theae transformations
no. 12
985
A 0.9 g solutionof the GrQnerd reagentvea prepued in tetrahydrofurea end wu 111owly edded to e eligbtexceemof ctkro&cetyliaocy&kete in 2 - 3 volumeaof tetrahydrofuxan et -70.. Afterstirring for 5 - 10 minute08t -70.. the cold beth vem remwed and wheu the reaction mixture reeched-30.,it wea quenchedwith aaturetedmilrm &waa
chloridesolution. The intermediate imide
ieoletedfrom cbloroform/etber aad recryetellizad (me Table). A
aa@e
of imide& wu treetedwith 1.5 equivalarta of sodim hydroxidein wthenol. Thin
layerchromatography indiutedthettbe reectionwu completein a feuminutea. The amide9_wea isoletedfrom chloroform/ether end recrystellised (aeoTeble). Alternatively, excem zinc dustvaa eddedto a methanolsolutionof imide&.
After 14
boura.the reectioomixturevu filteredend pertitiomed betworncblorofoafether end mter. Amide2 was isolatedend recrymtellized (seeTeble). Teble- 2%. Enectionsof GrigcurdEeegeutawith SubmtiutedIsocyautr:' Yieldaand MeltingPointaof Product8 B
sb (fromM
sb
C
9' (fromg (fr% 8b by hydrolyaia) by reduc&)
'6%
49% 125.5'
56X 52% 157.5-158.5. 126.5-128.
c6E5cIc-
48% 106.5-107.'
76% 145.5-147,s
,-c as
82% 127-128,
83% 90% 107.5-108.5. 102.5-104.5.
84x 67% 86% 106.5-107.5a 104.5-105.5. 100.5-102~ 50%
81.5-83.5°
-
e. All crudeyieldsere greetertheu 70%. Crudeproductawere recryatallimed from benzene/hew me. All productsheve ir cud nmr spectra consistent vith the lasi~md ltructurea.b. Yields era bued on C E r, C B CiCll, PC 5Br, and C61i5CE2Ck12Cli2Br, rerpectively.c. Yieldsere besedonthe d rz pen& imi&_. sa"l
l
Tbia methodcomplammtathe previously known1-cerbonhomolopetiona of GrQnerd r-gents.' Bfforteare uaderweyto applythis methodto the synthesisof caruleninand other functioneliaed emides. tiow1edEmalt &ImowledSmeotia nude to the donorsof The PetroleumReseercbPund,administered by the AmericanChemicalSociety,for pertielsupportof tbie reseerch.
80. 12
9aq
References 1. Browa UniversityUndergraduateUsearch Assietaat,3.973-74. 2. J. d'Agno10, I. 5. Rosenfeld.J. Awaya, S. (Inuta.and P. B. Vagelos;Biochm. Biophvs. Acta, 326. 155-166 (1973). 3. An extensive revfew of the synthesesof tides is by A. L. J. Beckx&tb fn The Chalstry of Amides, J. Zabrcky, ed., XUerscience Publishers,1970, pp 73-185. 4. a. 1. 0. V. Sonntag,Chem. Bev., 52, 237 (1953); b. B. 8. Woodward, Pure Appl. Chem., 22. 145 c1973). 5. B. B. Cerlfn and L. 0. Smith, Jr., J. Amar. Chew Sot., 6& Furry, J. Amer. Chem. Sot., 50, 1214 (1928).
2007 (1947); 8. Gilman and M.
6. Tha procedure of G. S. Forbes and lL H. Anderson, J. Amar. Chem. Sot., & 1222 (l%8), was modified. Xylene was used as a solvent and the product mixtu~c-vas fractionallydastilled. 7. A. J. Speaialeand L. R. Smith, Org. Sm., Coll. Vol. V, p 204 (1973). 8. The reactions of phenyllithi)rm and phenylmegneslumbromide with triphenyleilylieocyanateand triphenyle~yl tsotbtocyanstewere studied by Gilman and coworkers; see Ii.Gilmen, B. Eofferth,end EL W. Melvin, J. Amer. m. Sot., 72, 3045,cl950). The trtiethylsilyl. compoundax are more readfly avatiable than the triphenylsflylrompounds and trWthylsilano1 ti more easily separablethan trtphenylsilanolfrom &e products. 9. Other Grignard reacttonswhich result in one-carbonhomologationeafford esters, alcohols, acids, and titrttea. Soma representativereferencesare F. C. Whitmore and D. J. Loder, Org. Syn u p. 282 ($943);J. liouben,Chew Ber.\z, 2087 (l903);A. Schaap, L. Brand& and 3. F. Areas, Xecl. Trav. Chim. Pays-Bee,84. 1200 (1965); Ii.Gilman and Ri Ii.Kirby, Org. Svn Coll. Vol. r, p.361 (1941);V. Grignard and Ch. Courtot, u. sot. chim., nemoZres~'i28(1915).