POTASSIUM AMIDE 1
Potassium Amide Aryne Formation. Potassium amide in liquid ammonia has
been used extensively in the generation and trapping of benzynes
via dehydrohalogenation of phenyl halides.7 One of the definitive
KNH2
experiments providing evidence for the existence of benzyne
involved the treatment of [1-14C]chlorobenzene with potassium
[17242-52-3] H2KN (MW 55.13)
amide in liquid ammonia to provide equal amounts of [1-14C]-
InChI = 1/K.H2N/h;1H2/q+1;-1/rH2KN/c1-2/h2H2
aniline and [2-14C]aniline (eq 1).8 The potassium
InChIKey = FEMRXDWBWXQOGV-WQAKZGBJAR
amide ammonia system has since been used for the prepa-
ration of various substituted anilines.9
(strong base and nucleophile; used for the generation and trapping
of arynes; has been used extensively to study the reactivity of
Cl
heterocyclic systems)
" KNH2, NH3
" NH3
43%
Solubility: 1.7 M in liquid ammonia;1 1.3 × 10-4 M in THF.2
Preparative Methods: a solution of potassium amide in liquid
NH2
"
"
ammonia is prepared by adding pieces of Potassium to liquid
+ (1)
Ammonia in an ordinary three-necked flask equipped with a
NH2
mechanical stirrer.3 A piece of potassium is added to liquid
ammonia and after the appearance of a blue color, a few crystals
of iron(III) nitrate hydrate are added as catalyst. The remaining
Potassium amide has also been utilized extensively for the
pieces of potassium are added at a rate which maintains active
generation and trapping of various six-membered hetarynes in-
hydrogen evolution. Discharge of the deep blue color indicates
cluding those generated from halogenated pyridines, diazines, iso-
complete conversion to potassium amide. External cooling is
quinolines, naphthyridines, and certain multicyclic systems.10 Of
not required since the evaporation of ammonia will provide
the various hetarynes, the evidence supporting the existence of
ć%
ample cooling.4 If the reaction must be maintained at -78 C
3,4-pyridyne is recognized as the most convincing. Treatment of
then a dry ice acetone condenser is necessary, otherwise an air
either 3- or 4-chloropyridine with potassium amide in liquid am-
condenser is sufficient. The resulting opaque mixture contains
monia provides a constant ratio of the isomeric amine products
potassium amide which is mostly in solution. A more elabo-
(eq 2).11
rate two-flask assembly for the generation and transfer of a
potassium amide solution has also been described.5
Cl NH2
Handling, Storage, and Precautions: potassium amide is flamm-
1/3
able and ignites on contact with moisture. Excess material is
N N
destroyed by careful treatment with ethanol or isopropanol.
or +
KNH2, NH3
In the preparation of potassium amide the following precau-
Cl NH2 (2)
70%
tions should be noted. Potassium is a silvery gray metal but it
N
can form an explosive peroxide coating. If it acquires an or-
2/3
ange or red color or an appreciable oxide coating it should be
N N
considered extremely hazardous. Extreme caution should be
exercised in any attempt to isolate potassium amide as it is sus-
pected to be shock sensitive following partial oxidation. An
Although mixtures of amines are usually formed in potassium
explosion has been reported during the isolation of dry potas-
amide-induced aryne formations, in some cases selectivity for one
sium amide.6 Reactions should be performed in a fume hood to
isomer can be achieved. For example, it was found that treatment
prevent exposure to ammonia. Hydrogen is evolved during the
of a tricyclic bromobenzo[f]quinoline with potassium amide in
generation of potassium amide. No ignition source should be
liquid ammonia provided only one product via its postulated het-
present.
aryne intermediate (eq 3).12 Steric interference by the angular ring
is presumed to block formation of the other isomer.
Introduction. Potassium amide is both a strong base and a
Br
strong nucleophile and thus it has been used most effectively in
reactions which exploit both of these properties, such as the gen- KNH2, NH3
N N
eration and trapping of arynes, the amination of aromatic systems,
and the rearrangement of various heterocyclic systems. Examples
of these types of transformations are described below. The reagent
has also been used simply as a strong base to induce deprotona-
(3)
tion or elimination reactions, provided there are no competing NH2
H2N
nucleophilic reaction pathways available. This is currently a less
important feature of the reagent given the ready availability of
N N
strong, nonnucleophilic bases, but a few examples are described
at the end of this section.
Avoid Skin Contact with All Reagents
2 POTASSIUM AMIDE
Even in the presence of potassium amide, an intramolecular to succeed, the nucleophilic addition of the amide ion must be very
nucleophile can often compete effectively with amide ion to trap fast relative to the formation of the benzyne. This phenanthridine
an aryne intermediate, resulting in ring closure. For example, 2- synthesis tolerates a variety of substituents in the aniline ring, with
phenylbenzothiazole has been prepared in 90% yield utilizing the exception of hydroxy and nitro groups which are thought to
this strategy (eq 4).13 Intramolecular cyclization onto potassium slow the amide addition to the azomethine group significantly.18
amide-generated benzyne derivatives has been achieved with car-
bon, nitrogen, oxygen, and sulfur nucleophiles.14 The strategy has Rearrangement of Heterocyclic Systems. The generation
also been successfully used with certain hetarynes, particularly 5- of pyridyne utilizing potassium amide prompted the investiga-
substituted 3,4-pyridynes (eq 5).15 In some cases, however, when tion of the reaction of potassium amide with other heterocyclic
potassium amide is used as the aryne-generating base, competitive azine systems in a search for other hetarynes. However, the halo-
amination can occur to a significant extent (eq 6). genated precursors to hetarynes are often more reactive toward
nonaryne reactions and in some cases alternative mechanisms for
H
amination are involved. Although it was initially believed that 4-
N Ph
N
KNH2, NH3
bromo-6-phenylpyrimidine reacted with potassium amide via a
(4)
Ph
S 90%
6-substituted 4,5-didehydro intermediate, extensive examinations
S
Br
of the reaction of potassium amide with halopyrimidines led to
the elucidation of another mechanism for nucleophilic substitu-
Br
CN
tion which proceeds through a ring opened intermediate (eq 8).19
CN
KNH2, NH3
This mechanism is referred to as SN(ANRORC) for addition of the
N Me
nucleophile, ring opening, and ring closure. The evidence accu-
N N
N
Me
mulated to support its existence has been reviewed.20 In particular,
labeling studies have been used to demonstrate that the amide an-
N Me (5)
ion nitrogen becomes incorporated into the ring system (eq 9).
N
This mechanism has been shown to be operative (to a greater or
69%
lesser extent) in the reaction of potassium amide with a variety
of halogen-substituted heterocyclic systems in addition to pyrim-
Br
idines, including quinazolines, triazines, and purines. A review
CO2Et NH2
of the extensive literature in the area, categorized by ring type, is
KNH2, NH3
available.21
N N N
Me
N CO2Et
Ph Ph
Me
KNH2, NH3
H N N
O

N
H
N Br N Br
(6)
H2N
N
N
Me
Ph Ph
Ph
15%
N N (8)
N
Potassium amide-generated arynes can also be trapped intra- NH
N N NH2
H2NBr
molecularly by a sufficiently nucleophilic phenyl ring. For exam-
ple, appendage of a negatively charged atom to an aromatic ring
can confer sufficient nucleophilicity to the ortho and para po-
Ph Ph
sitions for this type of reaction.16 An example of this strategy is
KNH2, NH3
*N
shown in the synthesis of phenanthridines from haloanils (eq 7).17 *N
*
In this case, potassium amide is used not only to generate the req- N NH2
N Br
*
uisite benzyne but also to activate the system to ring closure via
Ph
Ph
addition of amide ion to the azomethine linkage. For the reaction
*N
*N
(9)
N Br
N O
H
Cl
KNH2, NH3
N N
Under the conditions of potassium amide in liquid ammonia,
NH2 many other examples of skeletal rearrangements of heterocyclic
systems are known.22 For example, ring contractions have been
documented, such as that of 2-chloropyrazine to 2-cyanoimidazole
(eq 10).23 In this system, as in many cases, multiple rearrangement
(7) pathways lead to multiple products. The details of these potassium
N
amide-induced heterocyclic ring transformation studies are avail-
>90%
able in a monograph.22a
A list of General Abbreviations appears on the front Endpapers
POTASSIUM AMIDE 3
N Cl ArOH + NaOH + (EtO)2POCl
KNH2, NH3
80 90%
 65 °C
KNH2, K in NH3
N
ArOPO(OEt)2 ArNH2 (13)
56 78%
N NH2
N N
+ + (10)
CN
N N
N
H H
Anion Generation. Potassium amide is a strong base which
13 15% 13 15% 35%
can be used in simple deprotonation reactions for the generation
of various anions. In enolate chemistry, potassium amide in liquid
ammonia has been used to generate the dianions of ²-diketones
A particularly useful transformation is the rearrangement of
and ²-ketoaldehydes.30 These species can then be regioselectively
2-substituted 4-halopyrimidines into s-triazines via a ring-opened
alkylated at the Å‚-position. In unsymmetrical ²-diketones the sec-
intermediate (eq 11).24 This reaction allows for the preparation
ond deprotonation occurs at the less substituted Å‚-position (eq 14).
of unsymmetrically substituted s-triazines which are difficult to
The scope of this reaction, including a tabular survey of known ex-
obtain by other methods. Competing formation of the 4-amino-
amples, has been carefully reviewed.30 Potassium amide in liquid
pyrimidine is minimized by utilizing the chloro derivatives
ammonia has also been used for the preparation of 1,3-dinitro-2-
(X = Cl).
keto derivatives from the reaction of cycloalkanones with alkyl
nitrates.31
X
X O O OK OK
1. PhCH2Cl
KNH2, NH3
N KNH2, NH3 2. H3O+
N

H
58%
R1 N
R1 N
NH2
O O
(14)
N NH
N N
(11)
Ph
R1 N
R1 N
H
R1 = alkyl, aryl <40%
Deprotonation of benzyl ethers by potassium amide in liquid
R1 = R2 N 80 90%
2
ammonia has been used to effect the Wittig rearrangement.32 In
a preparation of phenanthrene, use of potassium amide accom-
plished the rearrangement to the carbinol in 90% yield after 1 h,
whereas Phenyllithium required 1 week (eq 15).33
Direct Amination of Aromatic Rings. Potassium amide can
be used to induce a direct nucleophilic substitution of amide an-
ion for hydrogen in certain azines.25 Potassium amide in liquid
ammonia adds readily to pyrazine, pyrimidine, and pyridazine to
KNH2

O
give anionic Ã-adducts which can be oxidized by Potassium Per-
NH3
O O
manganate to give the corresponding aminoaza heterocycle in
1 h 90%
good yield (eq 12).26 More highly electron deficient systems, like
pteridines and nitroaza aromatics, are able to add ammonia itself
to give neutral Ã-adducts which are also oxidized by KMnO4 to
heteroarylamines.27 This modified Chichibabin reaction has been
reviewed elsewhere.28
OH
MeCOCl, reflux
(15)
85%
NH2
H NH2
KNH2, NH3 KMnO4

(12)
N N
N 91%
N N
N
Examples of large-scale preparations utilizing potassium amide
in liquid ammonia for the benzylic deprotonation of lutidine and
diphenylacetonitrile have been published.3,34 Allylic deprotona-
tion of 2-chloromethyl-1-butene with potassium amide in THF
Potassium amide can also displace a suitably situated halide
ć%
at 65 C has been used in an effective preparation of vinylcyclo-
on a heteroaromatic ring to provide the aromatic amine, but this
propane (eq 16).35
reaction is often accompanied by other products from competing
rearrangement pathways (eq 10). Simple phenols can be converted
KNH2, THF
to the corresponding aniline in a two-step process involving treat-
Et
65 °C
(16)
ment of the aryl diethyl phosphate ester with potassium amide and
ca. 60%
Cl
potassium metal in liquid ammonia (eq 13).29
Avoid Skin Contact with All Reagents
4 POTASSIUM AMIDE
Elimination Reactions. Potassium amide in liquid ammo- 14. Hoffmann, R. W., Dehydrobenzene and Cycloalkynes; Academic: New
York, 1967; pp 150.
nia can be used as a base to induce elimination reactions.36 For
example, this reagent has been used in a preparation of dimethoxy- 15. Ahmed, I.; Cheeseman, G. W. H.; Jaques, B., Tetrahedron 1979, 35,
1145.
cyclopropene via an intramolecular alkylation followed by elimi-
16. Kessar, S. V., Acc. Chem. Res. 1978, 11, 283.
nation (eq 17).37 Potassium amide-induced elimination followed
17. Kessar, S. V.; Gopal, R.; Singh, M., Tetrahedron 1973, 29, 167.
by an additional deprotonation has also been used to generate
18. Kessar, S. V.; Pal, D.; Singh, M., Tetrahedron 1973, 29, 177.
8,8-dimethylcyclooctatrienyl anion (eq 18).38
19. de Valk, J.; van der Plas, H. C., Recl. Trav. Chim. Pays-Bas 1971, 90,
1239.
MeO OMe
MeO OMe
KNH2, NH3
20. van der Plas, H. C., Acc. Chem. Res. 1978, 11, 462.
Br Cl (17)
40 50%
21. van der Plas, H. C., Tetrahedron 1985, 41, 237.
22. (a)For examples see: van der Plas, H. C. Ring Transformations of
Heterocycles; Academic: New York, 1973; 2. (b) Rykowski, A.; van
Cl
der Plas, H. C., J. Org. Chem. 1987, 52, 71. (c) Nagel, A.; van der Plas,
KNH2
+  (18)
H. C.; Geurtsen, G.; van der, A., J. Heterocycl. Chem. 1979, 16, 305.
NH3
Cl
23. Lont, P. J.; van der Plas, H. C.; Koudijs, A., Recl. Trav. Chim. Pays-Bas
1971, 90, 207.
24. van der Plas, H. C. Ring Transformations of Heterocycles; Academic:
Related Reagents. Lithium Amide; Lithium Diisopropyl- New York, 1973; Vol. 2, p 135.
amide; Potassium 3-Aminopropylamide; Potassium Hexamethyl- 25. The general area of nucleophilic substitution (including KNH2) of
disilazide; Potassium Diisopropylamide; Sodium Amide. hydrogen in azines has been reviewed: Chupakhin, O. N.; Charushin,
V. N.; van der Plas, H. C., Tetrahedron 1988, 44, 1.
26. Hara, H.; van der Plas, H. C., J. Heterocycl. Chem. 1982, 19, 1285.
27. (a) Hara, H.; van der Plas, H. C., J. Heterocycl. Chem. 1982, 19, 1527.
(b) Wozniak, M.; van der Plas, H. C.; van Veldhuizen, B., J. Heterocycl.
1. Biehl, E. R.; Stewart, W.; Marks, A.; Reeves, P. C., J. Org. Chem. 1979,
Chem. 1983, 20, 9.
44, 3674.
28. van der Plas, H. C.; Wozniak, M., Croat. Chem. Acta 1986, 59, 33.
2. Buncel, E.; Menon, B., J. Organomet. Chem. 1977, 141, 1.
29. Rossi, R. A.; Bunnett, J. F., J. Org. Chem. 1972, 37, 3570.
3. Hauser, C. R.; Dunnavant, W. R., Org. Synth., Coll. Vol. 1963, 4, 962.
30. Harris, T. M.; Harris, C. M., Org. React. 1969, 17, 155.
4. Fieser & Fieser 1967, 1, 907.
31. Feuer, H.; Hall, A. M.; Golden, S.; Reitz, R. L., J. Org. Chem. 1968, 33,
5. Bunnett, J. F.; Hrutfiord, B. F.; Williamson, S. M., Org. Synth., Coll. Vol.
3622.
1973, 5, 12.
32. Hauser, C. R.; Kantor, S. W., J. Am. Chem. Soc. 1951, 73, 1437.
6. Sanders, D. R., Chem. Eng. News 1986, 64 (21), 2.
33. Weinheimer, A. J.; Kantor, S. W.; Hauser, C. R., J. Org. Chem. 1953, 18,
7. Hoffmann, R. W., Dehydrobenzene and Cycloalkynes; Academic: New
801.
York, 1967; Chapter 1 and references therein.
34. Kofron, W. G.; Baclawski, L. M., Org. Synth., Coll. Vol. 1988, 6, 611.
8. Roberts, J. D.; Simmons, H. E., Jr.; Carlsmith, L. A.; Vaughan, C. W., J.
35. Arora, S.; Binger, P.; Köster, R., Synthesis 1973, 146.
Am. Chem. Soc. 1953, 75, 3290.
36. Hauser, C. R.; Skell, P. S.; Bright, R. D.; Renfrow, W. B., J. Am. Chem.
9. Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic: New
Soc. 1947, 69, 589.
York, 1967; pp 115.
37. Baucom, K. B.; Butler, G. B., J. Org. Chem. 1972, 37, 1730.
10. Reinecke, M. G., Tetrahedron 1982, 38, 427.
38. Staley, S. W.; Pearl, N. J., J. Am. Chem. Soc. 1973, 95, 2731.
11. Pieterse, M. J.; den Hertog, H. J., Recl. Trav. Chim. Pays-Bas 1961, 80,
1376.
12. Reinecke, M. G., Tetrahedron 1982, 38, 485. Katherine S. Takaki
13. Hrutford, B. F.; Bunnett, J. F., J. Am. Chem. Soc. 1958, 80, 2021. Bristol-Myers Squibb Company Wallingford, CT, USA
A list of General Abbreviations appears on the front Endpapers