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Carbocations, Carbanions, Free Radicals, Carbenes, and Nitrenes

Carbocations, Carbanions, Free Radicals, Carbenes, and Nitrenes

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1208



ADDITION TO CARBON–HETERO MULTIPLE BONDS



With enol esters (e.g., 108), reaction with an alcohol gives an ester and the enol of a ketone,

which readily tautomerizes to the ketone as shown. Hence, enol esters are good acylating

agents for alcohols.1802 This transformation has been accomplished in ionic liquid media,1803

and there is a PdCl2/CuCl2 mediated version.1804 Isopropenyl acetate can also be used to

convert other ketones to the corresponding enol acetates in an exchange reaction:1805

CH2

H3C



CHR'2



+



OAc



R



CR'2



H+



R



O



CH3



+

H3C



OAc



O



Enol esters can also be prepared in the opposite type of exchange reaction, catalyzed by

mercuric acetate1806 or Pd(II) chloride,1807 for example,

HgðOAcÞ2

H2 SO4





RCOOH ỵ R0 COOCH



CH2



I



J



0



RCOOCH



CH2 ỵ R COOH



A closely related reaction is equilibration of a dicarboxylic acid and its diester to

produce monoesters: The reaction of a carboxylic acid with ethyl acetate, in the presence of

NaHSO4 SiO2, was shown to give the corresponding ethyl ester.1808 Iodine catalyzes the

transesterification of b-keto esters.1809

OS II, 5, 122, 360; III, 123, 146, 165, 231, 281, 581, 605; IV, 10, 549, 630, 977; V, 155,

545, 863; VI, 278; VII, 4, 164, 411; VIII, 155, 201, 235, 263, 350, 444, 528. See also, OS

VII, 87; VIII, 71.

16-65 Alcoholysis of Amides

Alkoxy-de-amidation

O

R1



O



R2—OH



NR2



R1



OR2



Alcoholysis of amides is possible,1810 although it is usually difficult. It has been most

common with the imidazolide type of amides (e.g., 100). For other amides, an activating agent

is usually necessary before the alcohol will replace the NR2 unit. N, N-Dimethylformamide,

however, reacted with primary alcohols in the presence of 2,4,6-trichloro-1,3,5-pyrazine

(cyanuric acid) to give the corresponding formate ester.1811 Treatment of an amide with

triflic anhydride (CF3SO2OSO2CF3) in the presence of pyridine, and then with an excess

of alcohol, leads to the ester,1812 as does treatment with Me2NCH(OMe)2 followed by

Ilankumaran, P.; Verkade, J.G. J. Org. Chem. 1999, 64, 9063.

Grasa, G.A.; Kissling, R.M.; Nolan, S.P. Org. Lett. 2002, 4, 3583.

1804

Bosco, J.W.J.; Saikia, A.K. Chem. Commun. 2004, 1116.

1805

See House, H.O.; Trost, B.M. J. Org. Chem. 1965, 30, 2502.

1806

See Mondal, M.A.S.; van der Meer, R.; German, A.L.; Heikens, D. Tetrahedron 1974, 30, 4205.

1807

Henry, P.M. J. Am. Chem. Soc. 1971, 93, 3853; Acc. Chem. Res. 1973, 6, 16.

1808

Das, B.; Venkataiah, B. Synthesis 2000, 1671.

1809

Chavan, S.P.; Kale, R.R.; Shivasankar, K.; Chandake, S.I.; Benjamin, S.B. Synthesis 2003, 2695.

1810

For example, see Czarnik, A.W. Tetrahedron Lett. 1984, 25, 4875. For a list of references, see Larock, R.C.

Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp. 197–1978.

1811

DeLuca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 5152.

1812

Charette, A.B.; Chua, P. Synlett 1998, 163.

1802

1803



REACTIONS



1209



the alcohol.1813 Trimethyloxonium tetrafluoroborate converted primary amides to

methyl esters.1814 The reaction of acetanilide derivatives with sodium nitrite in the

presence of acetic anhydride–acetic acid leads to phenolic acetates.1815 Acyl hydrazides

(RCONHNH2) were converted to esters by reaction with alcohols and various

reagents,1816 and methoxyamides (RCONHOMe) were converted to esters with

TiCl4/ROH.1817 The reaction of an oxazolidinone amide (109) with methanol and

10% MgBr2 gave the corresponding methyl ester.1818

O



O



O



MeOH, 10% MgBr 2



N



Ph



O



Ph



OMe



109



C. Attack by OCOR at an Acyl Carbon

16-66 Acylation of Carboxylic Acids with Acyl Halides

Acyloxy-de-halogenation

RCOCl þ R0 COOÀ



I



RCOOCOR0



Unsymmetrical, as well as symmetrical, anhydrides are often prepared by the treatment of

an acyl halide with a carboxylic acid salt. If a metallic salt is used, Naỵ, Kỵ, or Agỵ are the most

common cations, but more often pyridine or another tertiary amine is added to the free acid.

The resulting salt is subsequently treated with the acyl halide. Zinc–DMF has been used to

mediate the synthesis of symmetrical anhydrides from acid chlorides.1819 Cobalt(II) chloride

(CoCl2) has been used as a catalyst.1820 Mixed formic anhydrides are prepared from sodium

formate and an aryl halide, by use of a solid-phase copolymer of pyridine-1-oxide.1821

Symmetrical anhydrides can be prepared by reaction of the acyl halide with aq NaOH or

NaHCO3 under phase-transfer conditions,1822 or with sodium bicarbonate with ultrasound.1823

OS III, 28, 422, 488; IV, 285; VI, 8, 910; VIII, 132. See also, OS VI, 418.

16-67 Acylation of Carboxylic Acids with Carboxylic Acids

Acyloxy-de-hydroxylation

P2 O 5



2RCOOH



J



I



RCOị2 O ỵ H2 O



Anelli, P.L.; Brocchetta, M.; Palano, D.; Visigalli, M. Tetrahedron Lett. 1997, 38, 2367.

Kiessling, A.J.; McClure, C.K. Synth. Commun. 1997, 27, 923.

1815

Glatzhofer, D.T.; Roy, R.R.; Cossey, K.N. Org. Lett. 2002, 4, 2349. See Naik, R.; Pasha, M.A. Synth.

Commun. 2005, 35, 2823.

1816

See Yamaguchi, J.-i.; Aoyagi, T.; Fujikura, R.; Suyama, T. Chem. Lett. 2001, 466.

1817

Fisher, L.E.; Caroon, J.M.; Stabler, S.R.; Lundberg, S.; Zaidi, S.; Sorensen, C.M.; Sparacino, M.L.;

Muchowski, J.M. Can. J. Chem. 1994, 72, 142.

1818

Orita, A.; Nagano, Y.; Hirano, J.; Otera, J. Synlett 2001, 637.

1819

Serieys, A.; Botuha, C.; Chemla, F.; Ferreira, F.; Perez-Luna, A. Tetrahedron Lett. 2008, 49, 5322.

1820

Srivastava, R.R.; Kabalka, G.W. Tetrahedron Lett. 1992, 33, 593.

1821

Fife, W.K.; Zhang, Z. J. Org. Chem. 1986, 51, 3744. For a review of acetic formic anhydride see Strazzolini,

P.; Giumanini, A.G.; Cauci, S. Tetrahedron 1990, 46 1081.

1822

Plusquellec, D.; Roulleau, F.; Lefeuvre, M.; Brown, E. Tetrahedron 1988, 44, 2471; Wang, J.; Hu, Y.; Cui, W.

J. Chem. Res. (S) 1990, 84.

1823

Hu, Y.; Wang, J.-X.; Li, S. Synth. Commun. 1997, 27, 243.

1813

1814



1210



ADDITION TO CARBON–HETERO MULTIPLE BONDS



Anhydrides can be formed from two molecules of an ordinary carboxylic acid only if a

dehydrating agent is present so that the equilibrium can be driven to the right. Common

dehydrating agents1824 are acetic anhydride, trifluoroacetic anhydride, dicyclohexylcarbodiimide,1825 and P2O5. Triphenylphosphine/CCl3CN with triethylamine has also been

used with benzoic acid derivatives.1826 The method is very poor for the formation of mixed

anhydrides, which in any case generally undergo disproportionation to the two simple

anhydrides when they are heated. However, simple heating of dicarboxylic acids does give

cyclic anhydrides, provided that the ring formed contains five, six, or seven members, for

example:

CH3 O



CH3

COOH



Δ



COOH



H2O



+



O

O



Malonic acid and its derivatives, which would give four-membered cyclic anhydrides, do

not give this reaction when heated, but undergo decarboxylation (12-40) instead.

Carboxylic acids exchange with amides and esters; these methods are sometimes used to

prepare anhydrides if the equilibrium can be shifted. Enolic esters are especially good for

this purpose, because the equilibrium is shifted by formation of the ketone.

O



O

R



+



R1



OH



CH2

O



O



CH3



R



O



O



+

R1



O



H3C



CH3



The combination of KF with 2-acetoxypropene under microwave conditions was effective.1827 Carboxylic acids also exchange with anhydrides; indeed, this is how acetic

anhydride acts as a dehydrating agent in this reaction.

Anhydrides can be formed from certain carboxylic acid salts (e.g., by treatment of

trimethylammonium carboxylates with phosgene):1828





2RCOO N HEt3



COCl2



I







RCOOCOR ỵ 2 N HEt3



Cl ỵ CO2



or of thallium(I) carboxylates with thionyl chloride,1710 or of sodium carboxylates with

CCl4 and a catalyst (e.g., CuCl or FeCl2).1829

OS I, 91, 410; II, 194, 368, 560; III, 164, 449; IV, 242, 630, 790; V, 8, 822; IX, 151.

Also see, OS VI, 757; VII, 506.



1824



For lists of other dehydrating agents with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed., Wiley–VCH, NY, 1999, pp. 1930–1932; Ogliaruso, M.A.; Wolfe, J.F. in Patai, S. The Chemistry

of Acid Derivatives, pt.1, Wiley, NY, 1979, pp. 437–438.

1825

See Rammler, D.H.; Khorana, H.G. J. Am. Chem. Soc. 1963, 85, 1997. See also, Hata, T.; Tajima, K.;

Mukaiyama, T. Bull. Chem. Soc. Jpn. 1968, 41, 2746.

1826

Kim, J.; Jang, D.O. Synth. Commun. 2001, 31, 395.

1827

Villemin, D.; Labiad, B.; Loupy, A. Synth. Commun. 1993, 23, 419.

1828

Rinderknecht, H.; Ma, V. Helv. Chim. Acta 1964, 47, 152. See also, Nangia, A.; Chandrasekaran, S. J. Chem.

Res. (S) 1984, 100.

1829

Weiss, J.; Havelka, F.; Nefedov, B.K. Bull. Acad. Sci. USSR Div. Chem. Sci. 1978, 27, 193.



REACTIONS



1211



16-68 Preparation of Mixed OrganicInorganic Anhydrides

Nitrooxy-de-acyloxy-substitution

RCOị2 O ỵ HONO2



I



RCOONO2



Mixed organicinorganic anhydrides are seldom isolated, although they are often

intermediates when acylation is carried out with acid derivatives catalyzed by inorganic

acids. Sulfuric, perchloric, phosphoric, and other acids form similar anhydrides, most of

which are unstable or not easily obtained because the equilibrium lies in the wrong

direction. These intermediates are formed from amides, carboxylic acids, and esters, as

well as anhydrides. Organic anhydrides of phosphoric acid are more stable than most others

and, for example, RCOOPO(OH)2 can be prepared in the form of its salts.1830 Mixed

anhydrides of carboxylic and sulfonic acids (RCOOSO2R0 ) are obtained in high yields by

treatment of sulfonic acids with acyl halides or (less preferred) anhydrides.1831

OS I, 495; VI, 207; VII, 81.

16-69 Attack by SH or SR at an Acyl Carbon1832



Mercapto-de-halogenation

O



O

+



R



H2S

R



Cl



SH



Alkylthio-de-halogenation

O



O

+



R



Cl



R'SH

R



SR'



Thiol acids and thiol esters1833 can be prepared in this manner, which is analogous to

Reaction 16-57 and 16-64. Anhydrides1834 and aryl esters (RCOOAr)1835 are also used as

substrates, but the reagents in these cases are usually HSÀ and RSÀ. Thiol esters can also be

prepared by treatment of carboxylic acids with P4S10ÀÀPh3SbO,1836 or with a thiol (RSH)

and either polyphosphate ester or phenyl dichlorophosphate (PhOPOCl2).1837 Carboxylic acids

are converted to thioacids with Lawesson’s reagent (structure 18 in Reaction 16-11).1838 Esters

RCOOR0 can be converted to thiol esters (RCOSR2) by treatment with trimethylsilyl sulfides

(Me3SiSR2) and AlCl3.1839

Alcohols, when treated with a thiol acid and zinc iodide, give thiol esters (R0 COSR)1840

OS III, 116, 599; IV, 924, 928; VII, 81; VIII, 71.

Avison, A.W.D. J. Chem. Soc. 1955, 732.

Karger, M.H.; Mazur, Y. J. Org. Chem. 1971, 36, 528.

1832

See Satchell, D.P.N. Q. Rev. Chem. Soc. 1963, 17, 160, pp. 182–184.

1833

See Scheithauer, S.; Mayer, R. Top. Sulfur Chem. 1979, 4, 1.

1834

Ahmad, S.; Iqbal, J. Tetrahedron Lett. 1986, 27, 3791.

1835

Hirabayashi, Y.; Mizuta, M.; Mazume, T. Bull. Chem. Soc. Jpn. 1965, 38, 320.

1836

Nomura, R.; Miyazaki, S.; Nakano, T.; Matsuda, H. Chem. Ber. 1990, 123, 2081.

1837

Imamoto, T.; Kodera, M.; Yokoyama, M. Synthesis 1982, 134. See also, Dellaria, Jr., F.F.; Nordeen, C.; Swett,

L.R. Synth. Commun. 1986, 16, 1043.

1838

Rao, Y.; Li, X.; Nagorny, P.; Hayashida, J.; Danishefsky, S.J. Tetrahedron Lett. 2009, 50, 6684.

1839

Mukaiyama, T.; Takeda, T.; Atsumi, K. Chem. Lett. 1974, 187. See also, Hatch, R.P.; Weinreb, S.M. J. Org.

Chem. 1977, 42, 3960; Cohen, T.; Gapinski, R.E. Tetrahedron Lett. 1978, 4319.

1840

Gauthier, J.Y.; Bourdon, F.; Young, R.N. Tetrahedron Lett. 1986, 27, 15.

1830

1831



1212



ADDITION TO CARBON–HETERO MULTIPLE BONDS



16-70 Transamidation

Alkylamino-de-amidation

O

NR1R2



R



O



R3R4NH



+



R



NR3R4



R1R2NH



+



It is sometimes necessary to replace one amide group with another, particularly when

the group attached to nitrogen functions as a protecting group1841N-Benzyl amides can be

converted to the corresponding N-allyl amide with allylamine and Ti catalysts.1842

Reaction of N-Boc 2-phenylethylamine with Ti(OiPr)4 and benzyl alcohol, for example,

gives the N-Cbz derivative.1843N-Carbamoyl amines were converted to N-acetyl amines

with acetic anhydride, Bu3SnH, and a Pd catalyst1844 Triethylaluminum converts methyl

carbamates (ArNHCO2Me) to the corresponding propanamide.1845

A related process reacts acetamide with amines and aluminum chloride to give the

N-acetyl amine.1846 Another related process converted imides to O-benzyloxy amides by

the Sm catalyzed reaction with O-benzylhydroxylamine.1847

Thioamides can be prepared from amide by reaction with an appropriate sulfur reagent. The

reaction of N,N-dimethylacetamide under microwave irradiation, with the polymer-bound

¼ polymeric backbone) gave 111.1848 Reaction of the thioamide with

reagent 110 (where

Bi(NO3)3 5 H2O regenerates the amide.1849 Other methods are known to convert a thioamide to

1851

an amide.1850 Selenoamides [RC(À

ÀSe)NR0 2] have also been prepared from amides.

S



O

R



NMe2



+



N



P



OEt

N H



S



PhMe , 200 °C

microwave h␯



110



R



NMe2

111



D. Attack by Halogen

16-71 The Conversion of Carboxylic Acids to Halides

Halo-de-oxido,oxo-tersubstitution

RCOOH



I



RÀX



In certain cases, carboxyl groups can be replaced by halide. Acrylic acid derivatives

ÀCHCOOH), for example, react with 3 molar equivalents of Oxone in the presence

(ArCHÀ

ÀCHBr).1852 Diphosphorus tetraiodide/

of NaBr to give a vinyl bromide (ArCHÀ

tetraethylammonium bromide (TEAB) readily converts conjugated acids to vinyl

See Knipe, A.C. J. Chem. Soc. Perkin Trans. 2 1973, 589.

Eldred, S.E.; Stone, D.A.; Gellman, S.H.; Stahl, S.S. J. Am. Chem. Soc. 2003, 125, 3422.

1843

Shapiro, G.; Marzi, M. J. Org. Chem. 1997, 62, 7096.

1844

Roos, E.C.; Bernabe, P.; Hiemstra, H.; Speckamp, W.N.; Kaptein, B.; Boesten, W.H.J. J. Org. Chem. 1995,

60, 1733.

1845

El Kaim, L.; Grimaud, L.; Lee, A.; Perroux, Y.; Tiria, C. Org. Lett. 2004, 6, 381.

1846

Bon, E.; Bigg, D.C.H.; Bertrand, G. J. Org. Chem. 1994, 59, 4035.

1847

Sibi, M.P.; Hasegawa, H.; Ghorpade, S.R. Org. Lett. 2002, 4, 3343.

1848

Ley, S.V.; Leach, A.G.; Storer, R.I. J. Chem. Soc. Perkin Trans. 1 2001, 358.

1849

Mohammadpoor-Baltork, I.; Khodaei, M.M.; Nikoofar, K. Tetrahedron Lett. 2003, 44, 591.

1850

Inamoto, K.; Shiraishi, M.; Hiroya, K.; Doi, T. Synthesis 2010, 3087.

1851

Saravanan, V.; Mukherjee, C.; Das, S.; Chandrasekaran, S. Tetrahedron Lett. 2004, 45, 681.

1852

You, H.-W.; Lee, K.-J. Synlett 2001, 105.

1841

1842



REACTIONS



1213



bromides.1853 In other cases, conjugated acids, (e.g., 112), have been converted to the bromide

by reaction with (NBS, Reaction 14-3) and LiOAc.1854

O

O



O

COOH



NBS , LiOAc



O



MeCN



Br



112



E. Attack by Nitrogen at an Acyl Carbon1855

16-72 Acylation of Amines by Acyl Halides

Amino-de-halogenation

RCOX ỵ NH3



I



RCONH2 ỵ HX



The treatment of acyl halides with ammonia or amines is a very general reaction for

the preparation of amides.1856 The reaction is exothermic and must be carefully

controlled, usually by cooling or dilution. Ammonia gives unsubstituted amides,

primary amines give N-substituted amides,1857 and secondary amines give N,Ndisubstituted amides. Arylamines can be similarly acylated. Hydroxamic acids have

been prepared by this route.1858 In some cases, aq alkali is added to combine with the

liberated HCl. This is called the Schotten–Baumann procedure, as in Reaction 16-61.

Activated Zn can be used to increase the rate of amide formation when hindered amines

and/or acid chlorides are used.1859 A solvent-free reaction was reported using DABCO

and methanol.1860 Metal-mediated reactions using In,1861 Sm,1862 or a BiOCl mediated

reaction1863 have been reported. A variation of this basic reaction uses DMF with acyl

halides to give N,N-dimethylamides.1864 Formic acid and iodine react with amines to

give the formamide.1865

Hydrazine and hydroxylamine also react with acyl halides to give, respectively,

hydrazides (RCONHNH2)1866 and hydroxamic acids (RCONHOH).1867 When phosgene

is the acyl halide, both aliphatic and aromatic primary amines give chloroformamides

Telvekar, V.N.; Chettiar, S.N. Tetrahedron Lett. 2007, 48, 4529.

Cho, C.-G.; Park, J.-S.; Jung, I.-H.; Lee, H. Tetrahedron Lett. 2001, 42, 1065.

1855

See Challis, M.S.; Butler, A.R. in Patai, S. The Chemistry of the Amino Group, Wiley, NY, 1968, pp. 279–290.

1856

See Beckwith, A.L.J. in Zabicky, J.The Chemistry of Amides, Wiley, NY, 1970, pp. 73–185; Jedrzejczak,

M.; Motie, R.E.; Satchell, D.P.N. J. Chem. Soc. Perkin Trans. 2 1993, 599.

1857

See Bhattacharyya, S.; Gooding, O.W.; Labadie, J. Tetrahedron Lett. 2003, 44, 6099.

1858

Reddy, A.S.; Kumar, M.S.; Reddy, G.R. Tetrahedron Lett. 2000, 41, 6285.

1859

Meshram, H.M.; Reddy, G.S.; Reddy, M.M.; Yadav, J.S. Tetrahedron Lett. 1998, 39, 4103.

1860

Hajipour, A.R.; Mazloumi, Gh. Synth. Commun. 2002, 32, 23.

1861

Cho, D.H.; Jang, D.O. Tetrahedron Lett. 2004, 45, 2285.

1862

Shi, F.; Li, J.; Li, C.; Jia, X. Tetrahedron Lett. 2010, 51, 6049.

1863

Ghosh, R.; Maiti, S.; Chakraborty, A. Tetrahedron Lett. 2004, 45, 6775.

1864

Lee, W.S.; Park, K.H.; Yoon, Y.-J. Synth. Commun. 2000, 30, 4241.

1865

Kim, J.-G.; Jang, D.O. Synlett 2010, 2093. For other formylation reactions, see Shekhar, A.C.; Kumar, A.R.;

Sathaiah, G.; Paul, V.L.; Sridhar, M.; Rao, P.S. Tetrahedron Lett. 2009, 50, 7099; Brahmachari, G.; Laskar, S.

Tetrahedron Lett. 2010, 51, 2319; Rahman, M.; Kundu, D.; Hajra, A.; Majee, A. Tetrahedron Lett. 2010, 51,

2896; Deutsch, J.; Eckelt, R.; K€ockritz, A.; Martin, A. Tetrahedron 2009, 65, 10365.

1866

See Paulsen, H.; Stoye, D. in Zabicky, J. The Chemistry of Amides, Wiley, NY, 1970, pp. 515–600.

1867

For an improved method, see Ando, W.; Tsumaki, H. Synth. Commun. 1983, 13, 1053.

1853

1854



1214



ADDITION TO CARBON–HETERO MULTIPLE BONDS



(ClCONHR) that lose HCl to give isocyanates (RNCO).1868 This is one of the most

common methods for the preparation of isocyanates.1869 Similar

O

Cl



O



+ RNH2



Cl



Cl



–HCl



O C N R



NHR



treatment with thiophosgene1870 gives isothiocyanates. A safer substitute for phosgene in

this reaction is trichloromethyl chloroformate (CCl3OCOCl).1871 When chloroformates

(ROCOCl) are treated with primary amines, carbamates (ROCONHR0 ) are obtained.1872

An example of this reaction is the use of benzyl chloroformate to protect the amino group

of amino acids and peptides.

O

PhO



O



+



O



RNH2

PhO



Cl



O



NHR

113



The PhCH2OCO group in 113 has been called the carbobenzoxy group,1873 and is often

abbreviated Cbz or Z, but it is really a benzyl carbamate. Another important group

similarly used is Boc, which is a tert-butyl carbamate. In this case, the chloride

(Me3COCOCl) is unstable, so the anhydride [(Me3COCO)2O] is used instead, in an

example of Reaction 16-73. Amino groups in general are often protected by conversion to

amides.1874 The reactions proceed by the tetrahedral mechanism.1875

An interesting variation of this transformation reacts carbamoyl chlorides with organocuprates to give the corresponding amide.1876

OS I, 99, 165; II, 76, 208, 278, 328, 453; III, 167, 375, 415, 488, 490, 613; IV, 339, 411,

521, 620, 780; V, 201, 336; VI, 382, 715; VII, 56, 287, 307; VIII, 16, 339; IX, 559; 81,

254. See also, OS VII, 302.

16-73 Acylation of Amines by Anhydrides

Amino-de-acyloxy-substitution

O

R

1868



O



O

O



+

R'



NH3

R



+



R'COOH



NH3



Richter, R.; Ulrich, H. pp. 619–818, and Drobnica, L.; Kristian, P.; Augustın, J. pp. 1003–1221, in Patai,

S. The Chemistry of Cyanates and Their Thio Derivatives, pt. 2, Wiley, NY, 1977.

1869

See Ozaki, S. Chem. Rev. 1972, 72, 457, see pp. 457–460. For a review of the industrial preparation of

isocyanates by this reaction, see Twitchett, H.J. Chem. Soc. Rev. 1974, 3, 209.

1870

For a review of thiophosgene, see Sharma, S. Sulfur Rep. 1986, 5, 1.

1871

Kurita, K.; Iwakura, Y. Org. Synth. VI, 715.

1872

Heydari, A.; Shiroodi, R.K.; Hamadi, H.; Esfandyari, M.; Pourayoubi, M. Tetrahedron Lett. 2007, 48, 5865;

Upadhyaya, D.J.; Barge, A.; Stefania, R.; Cravotto, G. Tetrahedron Lett. 2007, 48, 8318; Shrikhande, J.J.;

Gawande, M.B.; Jayaram, R.V. Tetrahedron Lett. 2008, 49, 4799. See Vilaivan, T. Tetrahedron Lett. 2006, 47,

6739.

1873

See Yasuhara, T.; Nagaoka, Y.; Tomioka, K. J. Chem. Soc. Perkin Trans. 1 1999, 2233.

1874

Greene, T.W. Protective Groups in Organic Synthesis Wiley, NY, 1980, pp 222–248, 324–326; Wuts, P.G.M.;

Greene, T.W. Protective Groups in Organic Synthesis, 2nd ed., Wiley, NY, 1991, pp 327–330; Wuts, P.G.M.;

Greene, T.W. Protective Groups in Organic Synthesis, 3rd ed., Wiley, NY, 1999, pp 518–525; 737–739.

1875

Kivinen, A. in Patai, S. The Chemistry of Acyl Halides, Wiley, NY, 1972; Bender, M.L.; Jones, M.J. J. Org.

Chem. 1962, 27, 3771. See also, Song, B.D.; Jencks, W.P. J. Am. Chem. Soc. 1989, 111, 8479.

1876

Lemoucheux, L.; Seitz, T.; Rouden, J.; Lasne, M.-C. Org. Lett. 2004, 6, 3703.



REACTIONS



1215



This reaction, similar in scope and mechanism1877 to Reaction 16-72, can be carried out

with ammonia or primary or secondary amines.1878 Note that there is a report where a

tertiary amine (an N-alkylpyrrolidine) reacted with acetic anhydride at 120  C, in the

presence of a BF3 etherate catalyst, to give N-acetylpyrrolidine (an acylative dealkylation).1879 Amino acids can be N-acylated using acetic anhydride and ultrasound.1880

However, ammonia and primary amines can also give imides, in which two acyl groups are

attached to the nitrogen. The conversion of cyclic anhydrides to cyclic imides is generally

facile,1881 although elevated temperatures are occasionally required to generate the

imide.1882 Microwave irradiation of formamide and a cyclic anhydride generates the

cyclic imide.1883 Cyclic imides have also been formed in ionic liquids.1884 Cyclic imides

were also formed by microwave irradiation of a polymer-bound phthalate after initial

reaction with an amine.1885

O



O

O

O



O

NH2

OH



+ NH3

O



N-H

O



The second step for imide formation, which is much slower than the first, is the attack of the

amide nitrogen on the carboxylic carbon. Unsubstituted and N-substituted amides have

been used instead of ammonia. Since the other product of this reaction is RCOOH, this is a

way of “hydrolyzing” such amides in the absence of water.1886

Even though formic anhydride is not a stable compound (see Reaction 11-17), amines

can be formylated with the mixed anhydride of acetic and formic acids (HCOOCOMe)1887

or with a mixture of formic acid and acetic anhydride. Acetamides are not formed with

these reagents. Secondary amines can be acylated in the presence of a primary amine by

conversion to their salts and addition of 18-crown-6.1888 The crown ether complexes the

primary ammonium salt, preventing its acylation, while the secondary ammonium salts,

which do not fit easily into the cavity, are free to be acylated. Dimethyl carbonate can be

used to prepare methyl carbamates in a related procedure.1889N-Acetylsulfonamides were

prepared from acetic anhydride and a primary sulfonamide, catalyzed by Montmorillonite

K10–FeO1890 or sulfuric acid.1891

For a discussion of the mechanism, see Kluger, R.; Hunt, J.C. J. Am. Chem. Soc. 1989, 111, 3325.

See Beckwith, A.L.J. in Zabicky, J. The Chemistry of Amides, Wiley, NY, 1970, pp. 86–96. See also, Naik, S.;

Bhattacharjya, G.; Talukdar, B.; Patel, B.K. Eur. J. Org. Chem. 2004, 1254.

1879

Dave, P.R.; Kumar, K.A.; Duddu, R.; Axenrod, T.; Dai, R.; Das, K.K.; Guan, X.-P.; Sun, J.; Trivedi, N.J.;

Gilardi, R.D. J. Org. Chem. 2000, 65, 1207.

1880

Anuradha, M.V.; Ravindranath, B. Tetrahedron 1997, 53, 1123.

1881

See Wheeler, O.H.; Rosado, O. in Zabicky, J. The Chemistry of Amides, Wiley, NY, 1970, pp. 335–381;

Hargreaves, M.K.; Pritchard, J.G.; Dave, H.R. Chem. Rev. 1970, 70, 439 (cyclic imides).

1882

Tsubouchi, H.; Tsuji, K.; Ishikawa, H. Synlett 1994, 63.

1883

Kacprzak, K. Synth. Commun. 2003, 33, 1499.

1884

Le, Z.-G.; Chen, Z.-C.; Hu, Y.; Zheng, Q.-G. Synthesis 2004, 995.

1885

Martin, B.; Sekljic, H.; Chassaing, C. Org. Lett. 2003, 5, 1851.

1886

Eaton, J.T.; Rounds, W.D.; Urbanowicz, J.H.; Gribble, G.W. Tetrahedron Lett. 1988, 29, 6553.

1887

Vlietstra, E.J.; Zwikker, J.W.; Nolte, R.J.M.; Drenth, W. Recl. Trav. Chim. Pays-Bas 1982, 101, 460.

1888

Barrett, A.G.M.; Lana, J.C.A. J. Chem. Soc., Chem. Commun. 1978, 471.

1889

Vauthey, I.; Valot, F.; Gozzi, C.; Fache, F.; Lemaire, M. Tetrahedron Lett. 2000, 41, 6347.

1890

Singh, D.U.; Singh, P.R.; Samant, S.D. Tetahedron Lett. 2004, 45, 4805.

1891

Martin, M.T.; Roschangar, F.; Eaddy, J.F. Tetrahedron Lett. 2003, 44, 5461.

1877

1878



1216



ADDITION TO CARBON–HETERO MULTIPLE BONDS



There are acylating reagents other than anhydrides of course. The reaction with acyl

halides is discussed in Reaction 16-72. There are a few specialized reagents. Kinetic

resolution of racemic amines was accomplished using (1S,2S)-N-acetyl-1,2- bis(trifluoromethanesulfonamido)cyclohexane.1892

OS I, 457; II, 11; III, 151, 456, 661, 813; IV, 5, 42, 106, 657; V, 27, 373, 650, 944, 973;

VI, 1; VII, 4, 70; VIII, 132; 76, 123.

16-74 Acylation of Amines by Carboxylic Acids

Amino-de-hydroxylation

RCOOH ỵ NH3



I



RCOO NH4 ỵ



pyrolysis



RCONH2



I



When carboxylic acids are treated with ammonia or amines, salts are obtained. The salts of

ammonia or primary or secondary amines can be pyrolyzed to give amides,1893 but the method

is less convenient than Reaction 16-72, 16-73, and 16-75 and is seldom of preparative value.1894

Heating in the presence of a base (e.g., hexamethyldisilazide) makes the amide-forming

process more efficient.1895 Boronic acids catalyze the direct conversion of carboxylic acid and

amine to amides.1896 Polymer-bound reagents have also been used.1897 Triphenylphosphine/trichloroisocyanuric acid converts acids and amides to the amide.1898 The Burgess reagent

(Et3NỵSO2NCO2Me; see Reaction 17-29) activates carboxylic acids for amide formation.1899 The reaction of a carboxylic acid and imidazole under microwave irradiation gives the

amide.1900 Microwave irradiation of a secondary amine, formic acid, 2-chloro-4,6-dimethoxy

[1,3,5]triazine, and a catalytic amount of DMAP leads to the formamide.1901 Ammonium

bicarbonate and formamide converts acids to amides with microwave irradiation.1902 Formamides are produced from formic acid and anion nitriles in the presence of ZnO.1903

Lactams are readily produced from g- or d-amino acids,1904 for example,

H3C



COOH

NH2



1892



H3C



N

H



O



Arseniyadis, S.; Subhash, P.V.; Valleix, A.; Mathew, S.P.; Blackmond, D.G.; Wagner, A.; Mioskowski, C. J.

Am. Chem. Soc. 2005, 127, 6138.

1893

See Gooen, L.J.; Ohlmann, D.M.; Lange, P.P. Synthesis 2009, 160.

1894

See Beckwith, A.L.J. in Zabicky, J. The Chemistry of Amides, Wiley, NY, 1970, pp. 105–109.

1895

Chou, W.-C.; Chou, M.-C.; Lu, Y.-Y.; Chen, S.-F. Tetrahedron Lett. 1999, 40, 3419. Also see White, J.M.;

Tunoori, A.R.; Turunen, B.J.; Georg, G.I J. Org. Chem. 2004, 69, 2573.

1896

Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 2001, 1371.

1897

Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579; Chichilla, R.; Dodsworth, D.J.; Najera, C.;

Soriano, J.M. Tetrahedron Lett. 2003, 44, 463.

1898

da C. Rodrigues, R.; Barros, I.M.A.; Lima, E.L.S. Tetrahedron Lett. 2005, 46, 5945.

1899

Wodka, D.; Robbins, M.; Lan, P.; Martinez, R.L.; Athanasopoulos, J.; Makara, G.M. Tetrahedron Lett. 2006,

47, 1825.

1900

Khalafi-Nezhad, A.; Mokhtari, B.; Rad, M.N.S. Tetrahedron Lett. 2003, 44, 7325; Perreux, L.; Loupy, A.;

Volatron, F. Tetrahedron 2002, 58, 2155. See also, Bose, A.K.; Ganguly, S.N.; Manhas, M.S.; Guha, A.; PomboVillars, E. Tetrahedron Lett. 2006, 47, 4605.

1901

De Luca, L.; Giacomelli, G.; Porcheddu, A.; Salaris, M. Synlett 2004, 2570.

1902

Peng, Y.; Song, G. Org. Prep. Proceed. Int. 2002, 34, 95.

1903

Hosseini-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71, 6652.

1904

See Blade-Font, A. Tetrahedron Lett. 1980, 21, 2443. Also see Wei, Z.-Y.; Knaus, E.E. Tetrahedron Lett.

1993, 34, 4439 for a variation of this reaction.



REACTIONS



1217



This lactonization process can be promoted by enzymes (e.g., pancreatic porcine

lipase).1905 Reduction of v-azide carboxylic acids leads to macrocyclic lactams.1906

Although treatment of carboxylic acids with amines does not directly give amides, the

reaction can be made to proceed in good yield at room temperature or slightly above by the

use of coupling agents,1907 the most important of which is dicyclohexylcarbodiimide. This

reagent is very convenient and is used1908 a great deal in peptide synthesis.1909 A polymersupported carbodiimide has been used.1910 The mechanism is probably the same as in

Reaction 16-63 up to the formation of 114. This intermediate is then attacked by another

molecule of RCOOÀ to give the anhydride (RCO)2O, which is the actual species that reacts

with the amine:

R



O



N



O

C6H11 +

O HN

R

O

C6H11

114



tetrahedral

mechanism

two steps



R



O

O



R



+



Dicyclohexylurea



O



The anhydride has been isolated from the reaction mixture and then used to acylate an

amine.1911

The synthetically important Weinreb amides [RCON(Me)OMe, see Reaction 16-82]

can be prepared from the carboxylic acid and MeO(Me)NH HCl in the presence of

tributylphosphine and 2-pyridine-N-oxide disulfide.1912 Di(2-pyridyl)carbonate has been

used in a related reaction that generates amides directly.1913 Other promoting agents1914 are

ArB(OH)2 reagents,1915N,N’-carbonyldiimidazole (115, in Reaction 16-63),1916

POCl3,1917 TiCl4,1918 molecular sieves,1919Lawesson’s reagent (Reaction 16-11),1920

and (MeO)2POCl.1921 Certain dicarboxylic acids form amides simply on treatment

with primary aromatic amines. In these cases, the cyclic anhydride is an intermediate

and is the species actually attacked by the amine.1922 Carboxylic acids can also be

Gutman, A.L.; Meyer, E.; Yue, X.; Abell, C. Tetrahedron Lett. 1992, 33, 3943.

Bosch, I.; Romea, P.; Urpı, F.; Vilarrasa, J. Tetrahedron Lett. 1993, 34, 4671. See Bai, D.; Shi, Y. Tetrahedron

Lett. 1992, 33, 943 for the preparation of lactam units in p-cyclophanes.

1907

See Klausner, Y.S.; Bodansky, M. Synthesis 1972, 453.

1908

It was first used this way by Sheehan, J.C.; Hess, G.P. J. Am. Chem. Soc. 1955, 77, 1067.

1909

See Gross, E.; Meienhofer, J. The Peptides, 3 Vols., Academic Press, NY, 1979–1981. See Bodanszky, M.;

Bodanszky, A. The Practice of Peptide Synthesis, Springer, NY, 1984.

1910

Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2001, 42, 6667.

1911

See Rebek, J.; Feitler, D. J. Am. Chem. Soc. 1974, 96, 1606. Also see Rebek, J.; Feitler, D. J. Am. Chem. Soc.

1973, 95, 4052.

1912

Banwell, M.; Smith, J. Synth. Commun. 2001, 31, 2011. For another procedure, see Kim, M.; Lee, H.; Han,

K.-J.; Kay, K.-Y. Synth. Commun. 2003, 33, 4013.

1913

Shiina, I.; Suenaga, Y.; Nakano, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 2811.

1914

For a list of reagents, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed.,

Wiley–VCH, NY, 1999, pp. 1941–1949.

1915

Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196.

1916

See Vaidyanathan, R.; Kalthod, V.G.; Ngo, D.; Manley, J.M.; Lapekas, S.P. J. Org. Chem. 2004, 69, 2565.

Also see Grzyb, J.A.; Batey, R.A. Tetrahedron Lett. 2003, 44, 7485.

1917

Klosa, J. J. Prakt. Chem. 1963, [4] 19, 45.

1918

Wilson, J.D.; Weingarten, H. Can. J. Chem. 1970, 48, 983.

1919

Cossy, J.; Pale-Grosdemange, C. Tetrahedron Lett. 1989, 30, 2771.

1920

Thorsen, M.; Andersen, T.P.; Pedersen, U.; Yde, B.; Lawesson, S. Tetrahedron 1985, 41, 5633.

1921

Jaszay, Z.M.; Petnehazy, I.; T€oke, L. Synth. Commun. 1998, 28, 2761.

1922

Higuchi, T.; Miki, T.; Shah, A.C.; Herd, A.K. J. Am. Chem. Soc. 1963, 85, 3655.

1905

1906



1218



ADDITION TO CARBON–HETERO MULTIPLE BONDS



converted to amides by heating with amides of carboxylic acids (exchange),1923 sulfonic

acids, or phosphoric acids, for example,1924

O

N



N



N



RCOOH

N



+



Ph2PONH2



RCONH2



+



Ph2POOH



115



or by treatment with trisalkylaminoboranes [B(NHR0 )3], with trisdialkylaminoboranes [B

(NR2)3],1925

RCOOH ỵ BNR2 0 ị3



I



RCONR2 0



or with bis(diorganoamino)magnesium reagents [(R2N)2Mg].1926 The reaction of thiocarboxylic acids and azides, in the presence of triphenylphosphine, gives the corresponding

amide.1927

An important technique, discovered by R.B. Merrifield1928 and since used for the

synthesis of many peptides,1929 is called solid-phase synthesis or polymer-supported

synthesis.1930 The reactions used are the same as in ordinary synthesis, but one of the

reactants is anchored onto a solid polymer. For example, if it is desired to couple two amino

acids (to form a dipeptide), the polymer selected might be polystyrene with CH2Cl side

chains. One of the amino acids, protected by (Boc), would then be coupled to the side

chains. It is not necessary that all the side chains be converted, but a random selection will

be converted. The Boc group is then removed by hydrolysis with trifluoroacetic acid in

CH2Cl2 and the second amino acid is coupled to the first, using DCC or some other

coupling agent. The second Boc group is removed, resulting in a dipeptide that is still

anchored to the polymer. If this dipeptide is the desired product, it can be cleaved from the



For example, see Schindbauer, H. Monatsh. Chem. 1968, 99, 1799.

Zhmurova, I.N.; Voitsekhovskaya, I.Yu.; Kirsanov, A.V. J. Gen. Chem. USSR 1959, 29, 2052. See also, Liu,

H.; Chan, W.H.; Lee, S.P. Synth. Commun. 1979, 9, 31.

1925

Pelter, A.; Levitt, T.E.; Nelson, P. Tetrahedron 1970, 26, 1539; Pelter, A.; Levitt, T.E. Tetrahedron 1970, 26,

1545, 1899.

1926

Sanchez, R.; Vest, G.; Despres, L. Synth. Commun. 1989, 19, 2909.

1927

Park, S.-D.; Oh, J.-H.; Lim, D. Tetrahedron Lett. 2002, 43, 6309.

1928

Merrifield, R.B. J. Am. Chem. Soc. 1963, 85, 2149.

1929

Birr, C. Aspects of the Merrifield Peptide Synthesis, Springer, NY, 1978. For reviews, see Bayer, E. Angew.

Chem. Int. Ed. 1991, 30, 113; Kaiser, E.T. Acc. Chem. Res. 1989, 22, 47; Jacquier, R. Bull. Soc. Chim. Fr. 1989,

220; Barany, G.; Kneib-Cordonier, N.; Mullen, D.G. Int. J. Pept. Protein Res. 1987, 30, 705; Andreev, S.M.;

Samoilova, N.A.; Davidovich, Yu.A.; Rogozhin, S.V. Russ. Chem. Rev. 1987, 56, 366; Gross, E.; Meienhofer, J.

The Peptides, Vol. 2, Academic Press, NY, 1980, the articles by Barany, G.; Merrifield, R.B. pp. 1–184; Fridkin, M.

pp. 333–363; Erickson, B.W.; Merrifield, R.B. in Neurath, H.; Hill, R.L.; Boeder, C.-L. The Proteins, 3rd ed., Vol.

2, Academic Press, NY, 1976, pp. 255–527. For R. B. Merrifield’s Nobel Prize lecture, see Merrifield, R.B. Angew.

Chem. Int. Ed. 1985, 24, 799.

1930

Laszlo, P. Preparative Organic Chemistry Using Supported Reagents, Academic Press, NY, 1987; Mathur,

N.K.; Narang, C.K.; Williams, R.E. Polymers as Aids in Organic Chemistry, Academic Press, NY 1980; Hodge,

P.; Sherrington, D.C. Polymer-Supported Reactions in Organic Synthesis, Wiley, NY, 1980. For reviews, see

Pillai, V.N.R.; Mutter, M. Top. Curr. Chem. 1982, 106, 119; Akelah, A.; Sherrington, D.C. Chem. Rev. 1981, 81,

557; Akelah, A. Synthesis 1981, 413; Rebek, J. Tetrahedron 1979, 35, 723; McKillop, A.; Young, D.W. Synthesis

1979, 401, 481; Crowley, J.I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135; Patchornik, A.; Kraus, M.A. Pure Appl.

Chem. 1975, 43, 503.

1923

1924



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