II
Ronald J. Baumgarten
Universitv of Illinois at Chicago Circle
Aliphatic Deaminations in Organic Synthesis
T h e attempt to synthesize an organic compou~ldis often like a complex puzzle involving the judicious choires of various procedures such as addit,ion, elimination and substitution, cyclization and ring opening, and building and degradation. Very oft,en, for example, the organic chemist is concerned with the conversion of one funct,ionality (RX) to another (RY). When X represents halogen, ester, nitrile, hydroxide, or carboxyl among other groups, the conversion to t,he new functionality, Y, generally can be accomplished with a variety of techniques (1, 2a). Occasionally, however, the organic chemist is confront,ed with a functional group which is relatively difficult, to displace in good yields. Until about ten years ago, t,he aliphatic primary amino group was considered t o be an example of such a challenging funct,ionality. During the past few years, however, varied new deamination procedures have been developed. The purpose of this article is to review some of these synt,hetic sequences. Degradations of secondary and t,ert,inryamines also will be considered briefly.
The third major rlass of deaminations involves those cases where the R group becomes reduced during the conversion of RNHI to RY. This type is called "reductive deamination" (Sa) ; an example (6) is shown in eqn. (4). As with "simple deamination," reductive deamination may be accomplished via a derivative of the amine [see also eqn. (70)].
In~discussingthe various deamination procedures of amines, analogies will be drawn, wherever possible, to the closest common relative of amines, the alcohols. Simple Deamination SNZ-Type Displacemenis
A general Sh.2 reaction can be represented: RX+YeRY+X-
General Types of Deomination
The general conversion of an aliphatic amine (RNH2) to RY ran be divided into three categories. In the first and most ronmlon conversion, there is no change in the oxidation state of R during the deamination procedure. In this article, such deaminations will be callrd "simple deaminatious." Eqn. (I), involving RNTT?
+ I-INO!
-r
ROH a
+ complex mixture of products
+ NI
Ihc familiar nitrous acid deamination, illustrates this l.ypc of transformation (Zb, 10, 17). The higher yielding proredures, ho~vever,involve multistep conversions wlicrehy the aniine is deaminated via various amino derivatives. Eqn. (2) (2b, 21-28) is an example of a procedure involving the replacement of both amino hydrogens by other functiorialit~iesbefore the carbonnitrogcn hond is cleaved.
I
R-N-C-R'
A
ROCR'
II
+ N2
(2)
The srxond type involves those rases whcre the R group bwonies oxidized during the transformation of RNH, to RY. This type is called "oxidative deaniinaIioll" (.7n). .In example (4) is: 398
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Journal o f Chemicol Educaiian
Whether the equil~briumwill be favorable and thus allow the reaction t o proreed to a practical degree often can be predicted from acid-base theory. Thus, other factors being equal, if the anion X- is a weaker base than Y-, the equilibrium constant will be greater than one, and RY may be isolated in good yields. For example, RBr
(1)
(5)
+ OH- 7 ROH + Br-
(6)
involves formation of a weak conjugate base B r r via its displacen~enton RBr by the strong base OH-. On the other hand, both the reverse reaction in eqn. (0) and the rcaction given in eqn. (7) are highly unfavorablc in rcspect to the displaremmt of OH- (1). ROH
+ C&COO-
' - ROOCCHs
+ OH-
(7)
But ROH niay he ronvenient,ly converted t o RY by the simple device of substituting a functionality (R') for the H of the hydroxylic OH, which will render the anion OR'- a base weak enough to permit a favorable concentration of RY at equilibrium. For example, the R' may be a simple ester group, or even better, the tosyl group, e q n (8). The weakly basic tosylate R03SCsHCHs-r
+ KI
RI
+ p-CHaCsHi301-Kt
(8)
anion can be readily displaced by most Y groups (Zc, 6a). The above arguinents riow can be applied to the analogous anlines. 'Thus, wc may write the following rea~t~ion:
RNH,
+ CH,COO-
' ROOCCH,
+ NHn-
(9)
The equilibrium in this case lies even further t o the left than the equilibrium in eqn. (7) (the K. for NH, is 10Waacompared to a K. of 10V4 for water) (2d, 7).' The question may now be raised as to whether amide derivatives analogous t o the ester derivatives of alcohols can be used for SN~-typedisplacements. For example, consider t,he reaction illustrated in eqn. 10. H
0
Rd-bRf
0
+ -Ol-CH,--
0 ROeCCHa
0
+R
'I L H (10)
The equilibrium here, however, is still unfavorable for deamination. These arnides, while much stronger acids than the rorresponding amines, are nonetheless very weak acids, which, therefore, form very strong conjugate bases. I n particular, the dissociation constants of amides of carboxylic acids are in the range of lo-" (2d,7-9). Sufonamides are considerably stronger as acids than the carboxylic amides, with, for example a pK. of 10.6 for p-aminobenzene sulfnnamide (10) and a pK. of 8.65 for N-phenyl henzenesulfonamide (11); but even such pK,'s are in the weak-acid range. Furthermore, amides preferentially undergo saponification in the presence of strong bases. Evaluation of the above considerations makes it easy to see why S~2-t,ype deamination of amines and amides is impractical. Before the SN2displacement scheme is disposed of, however, it might be profitable to look into a further possibility. Whereas amides are still weak or very weak acids, certain imides such as saccharin are moderately strong acids. Values of 2.5 X 10W2 and 3.87 X 10W3 have been reported for the dissociation constant of saccharin (12); thus, the scheme given in eqn. (11) may be feasible under the right conditions.
The major complication involved in this procedure, is the competing and evidently preferential attachment of bases at the carbonyl function of saccharin as indicated in eqn. (12) (1.3).
are currently being conducted here to test this hypothesis. I t might also he pointed out that while phthalimide [K. = 1.09 X lo-' (14)], succinimide [K. = 3.02 X lo-" (14)], and the sulfonamides are fairly weak acids, their conjugate bases are nonetheless weaker bases than the hydroxide ion. The N-alkyl derivatives of these compounds, therefore, may give products resulting from cleavage a t the carbon-nitrogen bond. I n addition, many of the N-aryl derivatives of substituted benzene sulfonamides are relatively strong acids with pK,'s of ca. 5-11.5 (11). Finally, the nitrogen derivatives of heterocyclic imides such as uracil (pK. = 9.45) (15) and harbituric acid (K. = 1.05 X lo-') (14) possess the advantage of being relatively resistant to attack at the carbonyl functionality. SNI-Type Displacements Whereas the SN2-type displacements of OH- by Y- in alcohols (ROH) is thermodynamically unfavorable, consider what happens to alcohols in the presence of a strong acid such as HBr. With hydrobromic acid, the hydroxyl functionality is protonated and the very weak acid, water, is displaced by the bromide ion as indicated in eqn. (13). The complex products, such ROH
+ HBr
-
Br-
+
when R O E = s Z0 or 3- hlcohol
R B ~ - +complex products (13) ( S Ndisplacement) ~ when ROH = a primary sloohol
-1
as olefins and compounds derived from rearrangements within the R group, arise from the relatively stable carbonium ion intermediates which form with secondary and tertiary alcohols in polar solvents. Such carbonium ion type displacements ( S N ~displacements) are rarely used for synthetic purposes due to the low yields of any particular product (Be).2 At first glance it would appear as if the SN~-type displacement procedure could be applied similarly to primary amines. Amines, however, give the stable alkyl ammonium salts in the presence of strong acids (t?J), as in eqn. (14). These salts show no significant RNHl
C-O(12)
The appropriate choice of anions, solvents, temperature, etc., may: however, permit the isolation of the product,^ given in eqn. ( l l ) , and various experiments
Hydrolytic denminations of a-amino acids occur in certain forms of life. For example t,he prodr~tiunof the higher alcohols, responsible for the flavors and less desirable side-eireets of w-ines and liq~~ors, acme by a simultaneous deearborylation and hydrolytic denminstioo process in yemt cells. Thus, l e i ~ i n e gives rise to iso-nmyl aleolml, vsline yields iso-bntyl illcohol, and tyrosol arises h m tyrosine (105).
+
RBr H?O (Sx2 displacement)
+ HCI
-
RNHltC1-
(14)
tendency toward the loss of ammonia under normal conditions. Thus, the direct SN1type mechanism cannot be applied to amines. The Nitrous Acid Denminution Reaction
While the treatment of amines with most acids results in stable salt formation, the treatment of a primary amine with nitrous acid (or other nitrosating agents such as nitrosyl chloride and dinitrogen tetroxide) results in a complex series of intermediates \vhich
* SNZ reactions also may and nsually do give more than one product, but often the desired product can be obtained in good yields by controlling the reaction conditions. Volume 43, Number 8, August 1966
/
399
eventually leads to a carbonium ion as indicated in eqn. (15). Deamination thus occurs, but as would be expected from the S N charact,er ~ of the mechanism, the
RNH*
+ R'COC1-
RNHCOR'
NzO, or NOCl or
HWOt
0 0 N=0
CHaCHCHrN=N-OH
H*
- H?O
CH3CH2CHrN=N+
CHCHCH20H
Hz0
+ N* + complex products
products are complex; the procedure, eqn. (16), is therefore of poor synthetic value (2b, 16, 17, 18a, 19a):
Nonetheless, until the past ten years or so, this was the only general simple deamination reaction for primary aliphatic amines available to the organic chemist. Today this historically important reaction is still studied for theoretical reasons. Some recent reviews of the reaction of primary amines with nitrous acid have appeared in the literature (16, 19a); the reaction will not be considered further here. Secondary amines cannot be deaminated with nitrous acid; instead they give the stable N-nitroso derivatives of the parent amine (2b). Tertiary amines also may react with nitrous acid; here a complex mixture of products forms which may include aldehydes, secondary amines, and Nnitroso secondary amines. The reaction of tertiary arnines with nitrosating agents also has been reviewed
(.m.
Indirect Simple Deominations
+olefins (from R ) b
+ R'COOH + N*
(17)
Thus an amide derivative of a primary amine is first formed. This amide is then nitrosated and the resulting nitrosoamide is pyrolyzed at temperatures ranging from ca. -40°C (for nitrosoamides of tertiary carbinamines) to 20-30' (for secondary carbinamine derivatives), t o 60-80' (for primary carbinamine derivatives). Esters result from this deamination reaction [eqn. (17a)l. The nitrosoamide procedure is largely the work of Huisgen and co-workers (21, 22), and White and co-workers (23-38). Several other investigators have report,ed examples of this reaction (29-3'6). Various aspects of the nitrosoamide procedure now will be considered in greater detail. I n respect to the yields of ester [eqn. (17a)I as compared to the yields of olefin [eqn. (17b)], nitrosoamides derived from primary carbinamines give ester yields of ca. 80% (23, 37) ; secondary carbinamine derivatives give ester yields of ca. 2565% (23, 27); and the tertiary carbinamine derivatives give less than 20% yields of ester (28). The reasons for these great variations in yield with the nature of the R group are elucidated by a consideration of the mechanisms operating in the systems [eyns. (18, 19)]. Thus, a carbonium ion is formed with For nitrosoamides of ?primary carbinamines: 0
-
alow
n v c e , i d n f-
("on-polar media)
1
N=O c
[R"CH?N=NOCR']
R'COOH
+ R"CHN2
I
the seroodary and tertiary carbinamine derivatives [eyn. (19)] which explains the high yield of the olefin
For nitrosoamides of secondary and terliwy carbinamines: The Pyvolysis of N-Nitrosoanaicles (Ester Formation). 0 Although no high-yielding direct methods exist for the displacement of carbon-nitrogen bonds of a primary [RN=NOCR'] R + - OCR' + K2 amine by a carbon-Y bond without changing the oxida4-0 (19) tion state of the R group, two major indirect procedures have been developed over the last d e ~ a d e . ~ The first of these methods is known as the nitrosoamide N1 + ROCR' olefins derived from R + R'COOH pyrolysis reaction and is represented in eqn. (17).
I
K
ii
I n addition the procedures developed for the degradation of tertiary amines may often be applied a s an indirect deamination procedure for primary amines. For example, the pyrolysis of q u a t e r n q ammonium hydroxides (Hofmann eliminstion) is frequently conducted to obtain olefins from primary amines [see eqn. (32)l.
400 / Journal o f Chemical Education
by-products. This is not surprising since the mechanism of decomposition of secondary and tertiary carbinamine derivatives is indirectly related t o the mechanism given for the nitrous acid decomposition of primary amines [eqn. 15)]. On the other hand, it can also be seen, in eqn. (18), that carbonium ions are not formed during the pyrolysis of the primary carbinamine
derivatives in non-polar solvents. Instead, diazoallcanes ( R N C H N 2 arise ) via the a-elimination of R'COOH from the unstable diazoester (R"CH,N=NOOCR'). Olefin formation and other complications occur minimally via this mechanism. The probable reason why primary rarbinamines prefer the diazoalkane route is that the formation of the primary carbonium ion which would result from the mechanism given in eqn. (19) would be highly unfavorable in non-polar media. I n fact, in one special case-the nitrosoamides derived from the esters of amino acids-the diazoalkane derivative is isolated as such in up to 70% yields [eqn. ( 2 0 ) ] (37). The elucidation of these mechanisms was
the triaeene method is similar to the product distribution obtained from the nitrosoamide pyrolysis procedure. This is not surprising in view of the similar mechanistic pathway which these two deamination procedures follow [eqns. ( l a ) ,(19), (23)].6
+ +
RX olefins derived from R ArNH9
+
[R+H2SJArl4
+ N2accomplished through the work of White and coworkers (85-87), Huisgen and co-workers (28, 21), and others (31, 58). In these papers are detailed explanations for many interesting subtleties in these mechanisms which will not be discussed here. One further consideration should be mentioned, however: the possibility of a free radical pathway analogous to the mechanism for the decomposition of aromatic N-nitrosoanlides. In actuality, all evidence seems to rule out any significant participation of aliphatic nitrosoamides by this route (85).* Finally, it should be pointed out that the analogous N-nitroamide derivatives behave similarly to the Nnitro~oamides[eqn., ( 2 1 ) ](39,87).6
PSO?
ROOCR'
+ NnO + olefins derived from It
-
+ ArN2+
HX
RX
r-
RNHP;=NAr-
1
L
R, b
+ Nn + ArNHr
+ N 2 + ArNHz
The triazene deamination procedure was developed by White and Scherrer (41). A few isolated triazene deaminations had been reported previously (41). In addition, Zahn, Wollemann, and Waschka had found that glycolic acid could be obtained directly from the treatment of glycine with an aromatic diazonium salt
(4a. The Reaction of Amides with Phosphorus Pentahalides (Alkyl Halide Formation). A deamination reaction which has received scant attention, hut which appears to hold some promise as a general deamination procedure, involves the treatment of benzoyl amides with phosphorus pentahalides, as in eqn. (24). 1,4-
(21)
The T~.iazene Deaminatim Procedure, (Ester and Alky1 Halide Forination). The second major procedure for the indirect simple deamination of primary amines involves the initial formation of triazene derivatives of primary anlines. The triazenes are prepared from the react,ion of primary amines with aromatic diazonium salts. Treatment of these triazenes with various acids (HX), gives the corresponding RX derivatives and olefins as the major deamination products [eqn. (22)l. RNHr
RX
(22)
+ N. + ArNHt
Dibromobutane was obtained in 70y0yield (based on the amide) by this method (43). The Reaction of Certain Ainides with 100% Nitric Acid (Nitrate E'stev Formation). The treatment of most amides with 100% nitric acid results in the corresponding N-nitroamide (4).A few amides ( N methyl acetamide, certain amides of amino acid esters) give, however, nitrate esters on treatment with 100% nitric acid:
olefins derived from R
When H X is a carboxylic acid, the yields of the corresponding esters range from 3&95%. The yields from the primary carbinamine derivatives are much higher than the yields from the secondary carbinamine derivatives, and, in general, the distribution of products from
N-Nitroso-N-aeyl-0-alkylhydroxyl &mines, however, have been found to decompose via homolytic as well as heterolytir pathways ($6). White and Elliger also have developed an S N type ~ conversion of aliphatic alcohols to aliphatic amines (40).
White and Raumgarten (45) have proposed a mechanism for this reaction:
"t has been found (unpublished work of Ronald J. Baumgarten) that the p-nitrobenztriazene derivative of the ethyl ester of glycine gives ethyl diazo-acetate in good yield. This reaction serves as further evidence for the similarity between the me& anisms of the nitrososmide and triazene deaminat~onreactions (see eqn. 20). Volume 43, Number 8, August 1966
/
401
R NO, I 1
R Hi
0-
I
ammonium hydroxides (Hofnlann elimination) (lob, 47b), eqn. (32). I n particular, the latter pyrolysis is perhaps the most comn~onlyused deamination procedure of all. The Hofn~annelimination is especially important for the analyses of alkaloids. The pyrolyses of tertiary amine oxides and the Hofmann elimination reactions have been reviewed (@c, lob, 47b, 47c).
HNOz
I
I
Olefin Formation
Since olefins are in the same oxidation state as alcohols and amines (6b), deaminations resulting in alkenes can be classified with the simple deaminations. There are many routes open for the convenion of the analogous alcohols to olefins. A direct procedure involves the acid catalyzed dehydration of alcohols (2g), as in eqn. (27). More often, however, indirect
elimination procedures are used. For example, various ester derivatives of alcohols may be treated with strong bases t o get alkenes (Bh), eqn. (28); appropriate 0 mxcm,oJR"
-
trans + o R - elimination
RICH=CHR'
+ ROH
Beta-amino acids (e.g., 8-alanine) and their esters pyrolyze fairly readily to give acrylates and ammonia, as in eqn. (33a) (43):
There is also an interesting in viuo simple aliphatic deamination of an cr-amino acid to an alkene. Histidine, with the aid of the enzyme histidase, eliminates ammonia t o give urocanic acid (50), eqn. (33b).
(28)
control of the reaction conditions can minimize the proportion of S N products ~ in these eliminations. Olefins may also he obtained from the pyrolysis of carboxylic or xanthate ester derivatives of the alcohols (Bh, 46a) : MisceNaneous Tertiary Amine ond Quaternary Ammonium Salt Carbon-Nitrogen Bond Cleavages
CHs(CH&CH=CHR
+ CHsCOOH
(29)
Deaminations to alkenes may be accomplished by methods similar to those used to obtain olefins from alcohols and their derivatives, and by procedures not open to the alcohols. The nitrous acid (16-lo), eqn. (16), the nitrosoamide (Bl-55), eqn. (17), and the triazenedeamination procedures (4l), eqn. (22) give olefinic by-products. These reactions are not recommended for general alkene syntheses. A deamination reaction which is analogous to the ester pyrolysis reaction is the amide pyrolysis reaction (46b), eqn. (30). This pyrolysis is rarely used as a general synthetic procedure. Acid catalyzed pyrolyses of amides, with t,he production of olefins, have also been observed (47a). For example, deaminocolchinol methyl ether (from N-acetylcolchinol methyl ether) and cyclohexene (from N-acetyl cyclohexylamine) have been obtained by Cook and co-workers by this acid catalyzed pyrolytic deamination (@).
The Von Braun reaction for the degradation of tertiary amines which involves the formation of an nlkyl bromide and the cyano derivative of a secondary amine after treatment of the tertiary amine with cyanogen bromide, eqn. (34), has been reviewed ( 5 1 ~ ) . RaN
+ BrCN
-
Br-
+ RJ$-CN
-
RBr
[R$]x-
2 dR'X
+ NRa
/
Journal of Chemical Education
(35)
(where X may be: halide, sulfide, hydrosulfide, mereaptide, thiosulfate, thiocyanak, biaulfite, sulfite, and p-toluenesulfinate)
; i
402
(34)
Several other degradation reactions of tertiary amines or quaternary ammonium salts, wherein various alkyl derivatives are produced, have been observed (51b, lgc, 52-64). Some representative exan~plesare given in eqns. (3540).
R'NRaOH-.
The most frequently used procedures for the production of alkenes from amines involve the pyrolyses of tertiary amine oxides (46c) eqn. (31), or quaternary
+ RzN-CN
--4
R'OH
+ NRr
(37)
The reaction shown in eqn. (37) is occasionally observed for those amines which cannot undergo the normal elimination reaction.
CH,
CH&OCHICH;PO(OC~&)B (38)
Oxidative Deamination
I n numerous aliphatic deamination processes, the
R group may he oxidied. During the oxidation process, R may go either to the next higher oxidation
-
Oxidations with Chemical Reagents (Aldehyde-Ketone Fo~mation). I n the laboratory, alcohols are usually oxidized to aldehydes and ketones with such reagents as chromic acid, permanganate, or acetone-aluminum isopropoxide (2h) :
The course of the reaction of amines with various oxidizing agents is largely a function of the nature of amines, oxidizing agents, and the other reaction conditions. For example, primary carbinamines may give aldehydes (57) or carhoxylic acids (58) with unbuffered permanganate, while with the same reagent, secondary carbinamines may give nitroso compounds (59), oximes (59), and imines (60, 61, 186). Tertiary carbinamines, on treatment with unbuffered permanganate, give nitroalkanes in good yield (61). Various other oxidizing agents convert amines to aldehydes or ketones, or derivatives of these carbonyl compounds. Thus, argentic picolinate has been observed (4, 62) to oxidize primary and secondary amines to the corresponding carbonyl compound in 30-71% yields [eqns. (45), (4G)l. Oximes can he obtained in
state (e.g., ketone or aldehyde formation) or to the second higher oxidation state (e.g., RCH2NH2 RC=N RCOOH).
5
argentio
One Stage Oxidative Deaminatian
RCH3NHCH2RA RCH=NCH&
Dehydrogenation Methods (Aldehyde and Ketone Formation). The catalytic dehydrogenation of alcohols to aldehydes or ketones is a well known reaction (2h) :
The analogous dehydrogenation of amines to the corresponding ketimines and aldimines has, on the other hand, been a largely neglected reaction. Nevertheless, the few examples reported indicate that the dehydrogenation procedure may be used to obtain aldimines and ketimines from the parent amines (55) :
Since imines are rapidly hydrolyzed to the corresponding ketones and aldehydes, the dehydrogenation reaction can be considered to he essentially an oxidative deamination. With secondary amines, which are really analogous to ethers, an oxidative degradation can he performed (56) : CH,
~ioolinste
RCHO
A10
+ RCHaNH.
(46)
up to 85y0 yields (63, 64), by the treatment of primary amines with hydrogen peroxide and certain catalysts [eqn. (47)l. Oxidizing agent,s such as mercuric oxide
(65), chromic oxide (66), potassium peroxydisulfate (67), t-butyl hydroperoxide (68), N-bromosuccinimide (69), henzoylperoxide (69), and quinones (69) have also been employed in oxidative deamination, but either the yields are low or the reaction is successful for only certain type amines. Another interesting oxidative deamination procedure involves the intermediate formation of N-chloramines. Inparticular, Bachmann, Cava, andDreidmg have found (70) that 1-butyl hypochlorite converts certain primary amines t o the corresponding ketone or aldehyde in 3948% yields via the Y-chloramine and inline intermediates [eqn. (48)).
5% Raoey Ni
[(CHd2CHCH2hH-]2NH
79.w
---
CH, I
CH3 I
Photochemical Oxidation (Aldehyde and Ketone 8'01.ii~ation). When solutions of hpzophenone in various alcohols are irradiated at 3400 A, henzophenone is photoreduced to benzipinacol and the alcohol (e.g., isopropyl alcohol) is oxidized (71, 72) t o a ketone (e.g., acetone) : Volume 43, Number 8, August 1966
/
403
Recently, Coheri and Baumgarten found (73) that primary and secondary amines behave in a similar manner on irradiation with benzophenone a t 3100 A:
The well-known oxidative decarboxylation of uamino acids is called the Strecker degradation. Ozone, hydrogen peroxide, silver oxide, persulfates, oxygen, ketones and aldehydes, peracids, N-bromosuccinimide, triphenyl carbinol derivatives and analogs, alloxan, and ninhydrin are some of the oxidizing agents which have heen employed in this reaction. The Strecker degradation has been reviewed (74). A modificat,ion of the Strecker reaction in which an excess of x-bromosuccinimide is the oxidizing agent has been investigated by Luck and co-workers (75). With A--bl.o~~iosuccinimide, t,he nitrile niay be obtained as well as the aldehyde after the amino acid decarboxylates (75) : NllS
RCH(NH*)COOH ---+ [ItCH(NH,)Rr] benzene
wa (CH,),C=NCH(CH& (92% yield)
RCHO
+
+
+ C02.
NHS
h"
benzpinacol
(50)
(51)
HC-NH2
I
COOH
A mechanism analogous t o the mechanism proposed for the photooxidation of alcohols can be written (73, 78) as ill eqn. (52) :
(55)
A few examples of the alternative simple oxidative deamination of a-amino acids are also known. I n uitro experiments by Snell and co-workers (76) and Metaler (77) indicate that a-keto acid and pyridoxalan;ine equilibrate with a starting mixture of pyridoxal, certain metallic ions, and a-amino acid, eqn. ( 5 6 ) . 4Nitro-salicylaldehyde-ropper complexes have been found t o react similarly with a-amino acids (78,79). R I
benzpinacol
+ NH&
CH,OH metdie
+
ion
HC OH
CH,
I
C=O
I
COOH
+
H,NCH,
-Q OH
(56)
CH?
Oxidative trarlsdeaminations with glyoxylic acid and a-amino acids such as alanine, aspartic acid, and glutamic acid, also have been observed (80) :
Oxidatiue Deaminalions of a-Amino Acids. Two major pathways are possible for the oxidative deamination of a-amino acids. The first and more commonly observed route in vit7.0 is an oxidat,ive decarhoxylatioo, eqn. (53). The second pathway frequently observed in vivo hut rarely observed in vitro, involves the oxidation of the amino group t o the imino function with subsequelit hydrolysis to t,he ar-keto acid (IQd), as in eqn. (54).
NITt
1
NH 101
0 H?O
RCIICOOH uRJCOOH uRJCOOH
+ NH, (54)
404
/ Journal of Chemical Education
An indirect method for the oxidative deamination of a-amino acids without the loss of carbon dioxide is illustrated by the pyrolysis of an K-nitroamide derivative of an a-amino acid ester (45) :
Biological Oxidative Deaminations. Oxidative deaminat,ions can be enzyniatically accomplished in uivo either dirertly or via transaminations. Biological transamination requires pyridoxal phosphate as the
enzymatic co-factor. The mechanism of the transaminations involves Schiff base intermediates which are hydrolyzed to the a-keto acids (81,893):
The dehydrogenation of secondary amines t o nitriles in the presence of ammonia also has been observed (84,861 : 350-
(C;H,)%NH-+ZCH&H&H,C=N
(63)
NHI: zino and ohmmiurn oxide
Conversion of Amines to Nitriles with Oxidizing Agents. Reagents such as bromine (84, 87), iodine pentafluoride (88), and lead tetraacetate (89) may convert appropriate primary carbinamines to nitriles. Lead tetraacetate appears to be the best of the reagents tried for this purpose [eqn. (64)l.
The relationship between in vitro and in uiuo transamination has been discussed by Fruton and Simmonds (82). Direct biological oxidative deamination requires a flavoprotein to dehydrogenate the cr-amino acid to an a-imino acid. The a-imino acid is then hydrolyzed t o the corresponding a-keto acid (81):
cooI
HaN+-cH AH*
coo-
--
L1 o + FAOH. + FAD + H1O L-glutamate dehydro- CHz + genase
I CH,
AH1
Reductive Deaminations (Type Ill)
NHa
The literature on biological oxidative and transdeaminations was reviewed through 1942 by Wieland (85). Two-Stage Reactions (Nitrile and Carboxylic Acid Formation)
A primary carbinamine (RCH2NH2) contains four removable hydrogens. When these four hydrogens are removed via dehydrogenation or chemical oxidizing agents, a two-stage oxidation to the nitrile is accomplished. Since nitriles are easily hydrolyzed to the corresponding carboxylic acid, the entire reaction sequence may be characterized as a two-stage oxidative deamination [eqn. (61)l. Oxidations of amines to RCH,NH,
+
Nitriles also may be obtained (75) from the oxidative decarboxylation of amino acids nith N-bromosuccinmide (see eqn. (55) 1. Other Two-Stage Oxidative Deaminations. Amines may give carboxylic acids, among other products, when treat,ed, with oxidizing agents like permanganate (68, 61). Analogous oxidations of primary alcohols are of course, well-known (2h). Finally, butylamine has been observed (90) t o give low yields of hutyramide in the presence of ammonium sulfide, ammonia, and hydrogen sulfide:
[O]
-
RC=N
H10
RCOOH
+ NHs
Until recently, the replacement of a primary aliphatic amino group by hydrogen was a virtually unknown process in organic chemistry. With the Nickon-Sins-Hill reaction (5) and the difluoramioe reaction (6), two good procedures are now available to the organic chemist for the conversion of aliphatic amines to hydrocarbons. In addition, a few cases have been reported in which N-substituted amines have been hydrogenated to alkanes. Hydrogenation and Metallic Reduction o f Amines
Some isolated examples of the catalytic and metallic reductions of certain alcohols (e.g., benzyl alcohols) have been observed (Sla, 91b, 02, 95, 51c), as in eqn. (66). In addition, red phosphorus reduces 4-fluorenolcarhoxylic acid to 4-fluorenecarboxylicacid (92).
(61)
carhoxylic acids also may be accomplished directly by the treatment of the appropriate amines with oxidizing agents such as perinanganate (61,58). Dehydrogenation. Reports of catalytic dehydrogenations of amines t o nitriles are not numerous. One example involves the dehydrogenation of benzyl amine to bensonitrile (84,85):
oxide high presure
*
G@
033)
Similarly, catalytic reductions of certain amines have been reported (51d, 19d, 94-06):
Volume 43, Number 8, August 1966
/
405
A few amines have been reduced with sodium methylate in methanol, zinc, lithium aluminum hydride, and sodium amalgam (51b, 19d). Examples of the hydrogenolysis of quaternary ammonium salts are well known [eqn. (68)l. This reduction is often referred to as the Emde reaction (61d , 19d, 97).
-
C~H~CH=CHCH&CH~)~X-
H,
Na.Hg
C6H5CH=CHCH,
+ (CH&N + NaX
(68)
Difluoromine Redudions
Bumgardner, Martin, and Freeman have found (5) that various amines react with difluoramine t o give hydrocarbons in up to 77% yield (eqns. (4), (69)l. The authors proposed the following two mechanisms for this reaction (5,98) :
Also, in the dehydrogenation of benzyl amine with nickel, toluene is produced (84, 85) along with hensonitrile [see eqn. (62)l. Finally, an interesting biochemical reaction has been found to occur in Clostridia, whereby glycine is reductively deaminated to acetic acid (104): SH
/
R
\
NF
+ R'NHI
IR'N-NF
9 i j I
i
b
I
?
R = alkyl RN=NH R' = H or alkyl I
I
1
R' R' \4 +N=NI- tt )N-Rl
/I
R
Path "a" involves the diimide intermediate (I) which also has been proposed as an intermediate in the WolffIiishner reduction (99, 100) and in the Nickon-SinzHill reaction below (5,98,201). Path "b" involves the "azamine" intermediate (11). Secondary amines probably react via this pathway (5,98) [see also eqns. (71) (72)l. The Nickon-Sinz Reaction
A reduction of amines involving the reaction of sulfonamide derivatives of primary amines with hydroxylamine-0-sulfonic acid in aqueous base or with chlorarnine has been developed by Nickon and SinaHill (3, 98) : RNHn
+ ArR02CI
-
RNHS02Ar
NH.
+ HzNCH3C0011+ ADP + Pi
-
This novel deamination has been postulated as a possible model in biological oxidative phosphorylations (104). Summary
Many new methods have been developed in recent years for the conversion of aliphatic primary amines to a variety of other functionalities. The nitrosoamide pyrolysis and the acidic decomposition of triazenes afford relatively high yield routes for the conversion of primary amines to esters or alkyl halides. Many oxidizing agents and a photochemical process are now available for the oxidation of primary and secondary amines to aldehydes and ketones. Similarly, carboxylic acids may be obtained by the hydrolysis of the nitriles obtained from the oxidation of primary amines with the appropriate reagents. For the conversion of amines to hydrocarbons, either the Nickon-Sinz-Hill or the difluoramine procedures may be employed. The aliphatic amino group need no longer be considered a "dead-end" functionality in organic synthesis. Acknowledgmenh
The author wishes to thank Professor Maurice 1'1. Bursey of Purdne University and Mr. Sidney F. Boseo of the University of Illinois for reading the manuscript and for suggesting changes. Literature Cited
Corrected yields of hydrocarbon are as high as 95%. The detailed mechanism of this reaction, which involves the diimide intermediate (I) bas been further elncidated by Cram and co-workers (95,101). Oxidative deamination to form a ketone or aldehyde is a minor side reaction for some amines (5). Miscellaneous Redudive Deaminations
Either dibenzyl amine or N-nitroso dibenzyl anline may be reductively deaminated (98, 108, 105) with the formation of an "azarnine" intermediate (11), as in eqns. (71) and (72): 406
/
Journol o f Chemical Education
(1) GOULD,E. S., "Mechanism and Structure in Organic Chemistry," Henry Holt and Co., New York, 1959, pp. 261, 346. (2) (a) ROBERTS, J. D., AND CASERIO, M. C., "Basic P~inciples of Organic Chemistry," W. A. Benjamin, Ine., New York, 1964, p. 681; (b) ibid., pp. 665-70; ( c ) ibid., p. 762; ((1) ibid., pp. 221, 680; (c) ibid., pp. 391, 392; (f)ibid., p. 664; (g) ibid., pp. 30608; (h) ibid., pp. 400n* "X.
(31 A,. AND SINE-HILL. A,. J . Am. Chem. Soc... 86.. . . (a) , . NICKON. 1152 (1964);'( b ) ibid., 82, 753 (1'960). (4) BACON, R. G. R., AND HANNI,W. J. W., Proc. Chcm. Soc., 2 -0.-5- 11OSO\~ - - - - ,. (5) BuMean~N~n, C. L.,MARTIN, K. J., A N D FREEMAN, J. P., J. Am. Chem. Soc., 85, 97 (1963). (6) (a) CRAM,D. J., AND HAMMOND, G. S., "Organic Chemistry," 2nd ed., McGraw-Hill Book Ca., Inc., New York, \
1964, p. 259; (b) ibid., p. 98. NOLLER,C. R., "Chemistry of Organic Compounds," 3rd ed., W. B. Samiders Co., Philadelphia, 1965. P. 989. l)., ,so P K H I . ~ . .I~) . ,, Iiuide to i)ualw,w,~ ~J.+VII,SON, iin,ukl?~t 0rcal.i~.\nul!ii.," 3rd rd., lJ~vitls
