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Carbocations, Carbanions, Free Radicals, Carbenes, and Nitrenes
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
Enol esters can also be prepared in the opposite type of exchange reaction, catalyzed by
mercuric acetate1806 or Pd(II) chloride,1807 for example,
RCOOH ỵ R0 COOCH
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
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.
Bosco, J.W.J.; Saikia, A.K. Chem. Commun. 2004, 1116.
See House, H.O.; Trost, B.M. J. Org. Chem. 1965, 30, 2502.
See Mondal, M.A.S.; van der Meer, R.; German, A.L.; Heikens, D. Tetrahedron 1974, 30, 4205.
Henry, P.M. J. Am. Chem. Soc. 1971, 93, 3853; Acc. Chem. Res. 1973, 6, 16.
Das, B.; Venkataiah, B. Synthesis 2000, 1671.
Chavan, S.P.; Kale, R.R.; Shivasankar, K.; Chandake, S.I.; Benjamin, S.B. Synthesis 2003, 2695.
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.
DeLuca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 5152.
Charette, A.B.; Chua, P. Synlett 1998, 163.
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
MeOH, 10% MgBr 2
C. Attack by OCOR at an Acyl Carbon
16-66 Acylation of Carboxylic Acids with Acyl Halides
RCOCl þ R0 COOÀ
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
P2 O 5
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.
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.
See Yamaguchi, J.-i.; Aoyagi, T.; Fujikura, R.; Suyama, T. Chem. Lett. 2001, 466.
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.
Orita, A.; Nagano, Y.; Hirano, J.; Otera, J. Synlett 2001, 637.
Serieys, A.; Botuha, C.; Chemla, F.; Ferreira, F.; Perez-Luna, A. Tetrahedron Lett. 2008, 49, 5322.
Srivastava, R.R.; Kabalka, G.W. Tetrahedron Lett. 1992, 33, 593.
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.
Plusquellec, D.; Roulleau, F.; Lefeuvre, M.; Brown, E. Tetrahedron 1988, 44, 2471; Wang, J.; Hu, Y.; Cui, W.
J. Chem. Res. (S) 1990, 84.
Hu, Y.; Wang, J.-X.; Li, S. Synth. Commun. 1997, 27, 243.
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
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.
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
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.
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.
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.
Kim, J.; Jang, D.O. Synth. Commun. 2001, 31, 395.
Villemin, D.; Labiad, B.; Loupy, A. Synth. Commun. 1993, 23, 419.
Rinderknecht, H.; Ma, V. Helv. Chim. Acta 1964, 47, 152. See also, Nangia, A.; Chandrasekaran, S. J. Chem.
Res. (S) 1984, 100.
Weiss, J.; Havelka, F.; Nefedov, B.K. Bull. Acad. Sci. USSR Div. Chem. Sci. 1978, 27, 193.
16-68 Preparation of Mixed OrganicInorganic Anhydrides
RCOị2 O ỵ HONO2
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
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.
See Satchell, D.P.N. Q. Rev. Chem. Soc. 1963, 17, 160, pp. 182–184.
See Scheithauer, S.; Mayer, R. Top. Sulfur Chem. 1979, 4, 1.
Ahmad, S.; Iqbal, J. Tetrahedron Lett. 1986, 27, 3791.
Hirabayashi, Y.; Mizuta, M.; Mazume, T. Bull. Chem. Soc. Jpn. 1965, 38, 320.
Nomura, R.; Miyazaki, S.; Nakano, T.; Matsuda, H. Chem. Ber. 1990, 123, 2081.
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.
Rao, Y.; Li, X.; Nagorny, P.; Hayashida, J.; Danishefsky, S.J. Tetrahedron Lett. 2009, 50, 6684.
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.
Gauthier, J.Y.; Bourdon, F.; Young, R.N. Tetrahedron Lett. 1986, 27, 15.
ADDITION TO CARBON–HETERO MULTIPLE BONDS
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
an amide.1850 Selenoamides [RC(À
ÀSe)NR0 2] have also been prepared from amides.
PhMe , 200 °C
D. Attack by Halogen
16-71 The Conversion of Carboxylic Acids to Halides
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
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.
Shapiro, G.; Marzi, M. J. Org. Chem. 1997, 62, 7096.
Roos, E.C.; Bernabe, P.; Hiemstra, H.; Speckamp, W.N.; Kaptein, B.; Boesten, W.H.J. J. Org. Chem. 1995,
El Kaim, L.; Grimaud, L.; Lee, A.; Perroux, Y.; Tiria, C. Org. Lett. 2004, 6, 381.
Bon, E.; Bigg, D.C.H.; Bertrand, G. J. Org. Chem. 1994, 59, 4035.
Sibi, M.P.; Hasegawa, H.; Ghorpade, S.R. Org. Lett. 2002, 4, 3343.
Ley, S.V.; Leach, A.G.; Storer, R.I. J. Chem. Soc. Perkin Trans. 1 2001, 358.
Mohammadpoor-Baltork, I.; Khodaei, M.M.; Nikoofar, K. Tetrahedron Lett. 2003, 44, 591.
Inamoto, K.; Shiraishi, M.; Hiroya, K.; Doi, T. Synthesis 2010, 3087.
Saravanan, V.; Mukherjee, C.; Das, S.; Chandrasekaran, S. Tetrahedron Lett. 2004, 45, 681.
You, H.-W.; Lee, K.-J. Synlett 2001, 105.
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
NBS , LiOAc
E. Attack by Nitrogen at an Acyl Carbon1855
16-72 Acylation of Amines by Acyl Halides
RCOX ỵ NH3
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.
See Challis, M.S.; Butler, A.R. in Patai, S. The Chemistry of the Amino Group, Wiley, NY, 1968, pp. 279–290.
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.
See Bhattacharyya, S.; Gooding, O.W.; Labadie, J. Tetrahedron Lett. 2003, 44, 6099.
Reddy, A.S.; Kumar, M.S.; Reddy, G.R. Tetrahedron Lett. 2000, 41, 6285.
Meshram, H.M.; Reddy, G.S.; Reddy, M.M.; Yadav, J.S. Tetrahedron Lett. 1998, 39, 4103.
Hajipour, A.R.; Mazloumi, Gh. Synth. Commun. 2002, 32, 23.
Cho, D.H.; Jang, D.O. Tetrahedron Lett. 2004, 45, 2285.
Shi, F.; Li, J.; Li, C.; Jia, X. Tetrahedron Lett. 2010, 51, 6049.
Ghosh, R.; Maiti, S.; Chakraborty, A. Tetrahedron Lett. 2004, 45, 6775.
Lee, W.S.; Park, K.H.; Yoon, Y.-J. Synth. Commun. 2000, 30, 4241.
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.
See Paulsen, H.; Stoye, D. in Zabicky, J. The Chemistry of Amides, Wiley, NY, 1970, pp. 515–600.
For an improved method, see Ando, W.; Tsumaki, H. Synth. Commun. 1983, 13, 1053.
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 C N R
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.
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
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.
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.
For a review of thiophosgene, see Sharma, S. Sulfur Rep. 1986, 5, 1.
Kurita, K.; Iwakura, Y. Org. Synth. VI, 715.
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,
See Yasuhara, T.; Nagaoka, Y.; Tomioka, K. J. Chem. Soc. Perkin Trans. 1 1999, 2233.
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.
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.
Lemoucheux, L.; Seitz, T.; Rouden, J.; Lasne, M.-C. Org. Lett. 2004, 6, 3703.
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
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.
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.
Anuradha, M.V.; Ravindranath, B. Tetrahedron 1997, 53, 1123.
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).
Tsubouchi, H.; Tsuji, K.; Ishikawa, H. Synlett 1994, 63.
Kacprzak, K. Synth. Commun. 2003, 33, 1499.
Le, Z.-G.; Chen, Z.-C.; Hu, Y.; Zheng, Q.-G. Synthesis 2004, 995.
Martin, B.; Sekljic, H.; Chassaing, C. Org. Lett. 2003, 5, 1851.
Eaton, J.T.; Rounds, W.D.; Urbanowicz, J.H.; Gribble, G.W. Tetrahedron Lett. 1988, 29, 6553.
Vlietstra, E.J.; Zwikker, J.W.; Nolte, R.J.M.; Drenth, W. Recl. Trav. Chim. Pays-Bas 1982, 101, 460.
Barrett, A.G.M.; Lana, J.C.A. J. Chem. Soc., Chem. Commun. 1978, 471.
Vauthey, I.; Valot, F.; Gozzi, C.; Fache, F.; Lemaire, M. Tetrahedron Lett. 2000, 41, 6347.
Singh, D.U.; Singh, P.R.; Samant, S.D. Tetahedron Lett. 2004, 45, 4805.
Martin, M.T.; Roschangar, F.; Eaddy, J.F. Tetrahedron Lett. 2003, 44, 5461.
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
RCOOH ỵ NH3
RCOO NH4 ỵ
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,
Arseniyadis, S.; Subhash, P.V.; Valleix, A.; Mathew, S.P.; Blackmond, D.G.; Wagner, A.; Mioskowski, C. J.
Am. Chem. Soc. 2005, 127, 6138.
See Gooen, L.J.; Ohlmann, D.M.; Lange, P.P. Synthesis 2009, 160.
See Beckwith, A.L.J. in Zabicky, J. The Chemistry of Amides, Wiley, NY, 1970, pp. 105–109.
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.
Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 2001, 1371.
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.
da C. Rodrigues, R.; Barros, I.M.A.; Lima, E.L.S. Tetrahedron Lett. 2005, 46, 5945.
Wodka, D.; Robbins, M.; Lan, P.; Martinez, R.L.; Athanasopoulos, J.; Makara, G.M. Tetrahedron Lett. 2006,
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.
De Luca, L.; Giacomelli, G.; Porcheddu, A.; Salaris, M. Synlett 2004, 2570.
Peng, Y.; Song, G. Org. Prep. Proceed. Int. 2002, 34, 95.
Hosseini-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71, 6652.
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.
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:
The anhydride has been isolated from the reaction mixture and then used to acylate an
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.
See Klausner, Y.S.; Bodansky, M. Synthesis 1972, 453.
It was first used this way by Sheehan, J.C.; Hess, G.P. J. Am. Chem. Soc. 1955, 77, 1067.
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.
Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2001, 42, 6667.
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.
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.
Shiina, I.; Suenaga, Y.; Nakano, M.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 2811.
For a list of reagents, with references, see Larock, R.C. Comprehensive Organic Transformations, 2nd ed.,
Wiley–VCH, NY, 1999, pp. 1941–1949.
Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196.
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.
Klosa, J. J. Prakt. Chem. 1963,  19, 45.
Wilson, J.D.; Weingarten, H. Can. J. Chem. 1970, 48, 983.
Cossy, J.; Pale-Grosdemange, C. Tetrahedron Lett. 1989, 30, 2771.
Thorsen, M.; Andersen, T.P.; Pedersen, U.; Yde, B.; Lawesson, S. Tetrahedron 1985, 41, 5633.
Jaszay, Z.M.; Petnehazy, I.; T€oke, L. Synth. Commun. 1998, 28, 2761.
Higuchi, T.; Miki, T.; Shah, A.C.; Herd, A.K. J. Am. Chem. Soc. 1963, 85, 3655.
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
or by treatment with trisalkylaminoboranes [B(NHR0 )3], with trisdialkylaminoboranes [B
RCOOH ỵ BNR2 0 ị3
or with bis(diorganoamino)magnesium reagents [(R2N)2Mg].1926 The reaction of thiocarboxylic acids and azides, in the presence of triphenylphosphine, gives the corresponding
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.
Pelter, A.; Levitt, T.E.; Nelson, P. Tetrahedron 1970, 26, 1539; Pelter, A.; Levitt, T.E. Tetrahedron 1970, 26,
Sanchez, R.; Vest, G.; Despres, L. Synth. Commun. 1989, 19, 2909.
Park, S.-D.; Oh, J.-H.; Lim, D. Tetrahedron Lett. 2002, 43, 6309.
Merrifield, R.B. J. Am. Chem. Soc. 1963, 85, 2149.
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.
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.