Organic Reaction Schemes and General Reaction-Matrix Types, II Basic Types of Synthetic Transformations
J a n C. J. Bart and Enea Garagnani Montedison S. p. A., Istituto Ricerche “G. Donegani”, Via del Lavoro 4, Novara, Italy
(Z. Naturforsch. 32 b, 455-464 [1977]; received August 31, 1976)
Reaction-Matrices, Synthesis-Planning
Organic synthetic transformations are described in terms of a set of 43 distinct general reaction-matrix types, of which ten account for rearrangement reactions only. The schemes identified conform partially to the semi-empirical rules governing synthetic transformations, as previously defined by Ugi et a l . 30.
1. Introduction general schemes by considering basic types of Chemistry is concerned both with the understand synthetic transformations, such as: modification ing of the statical properties of chemical compounds of side chains (lengthening, shortening, branching), and their dynamical interconversions, i.e. reactions ring synthesis and ring reactions (cleavage, contrac (redistributions of electron-density). In recent years tion, expansion), introduction and modification of attempts have been made to treat some of the most functional groups (removal, inter con version), etc. important aspects of statical and dynamical Thus the fundamental reactions in organic chem chemistry more systematically. In this respect we istry, as acid-base reactions, electrophilic and mention combinatorial studies of chemical graphs1, nucleophilic substitution and addition reactions, computer-oriented representations and methods for eliminations and insertion reactions were considered. computer handling of chemical structure informa Molecular rearrangement reactions were already tion2, the introduction of logical structures in dealt with in a previous paper31. chemistry3, applications of artificial intelligence in mass spectrometry4, molecular structure elucida 2. Procedures tion5 and organic synthesis6. In particular the latter The reactions that will be discussed have one problem has attracted much attention, namely feature in common. Electrons are transferred in through the computational procedures of C o r e y pairs during the processes of bond formation and et al .7-14 and others15-19. Due to a satisfactory breakage, and thus only polar or heterolytic knowledge of many organic chemical phenomena, it reactions are considered. The reaction scheme takes is now possible, mechanistically speaking, to recog into account the behaviour of the participating nize broad classes of reactions. Recent work on atoms without, however, furnishing a picture of the synthesis-planning has shown the need for a participating species at the more crucial instants different kind of rationalization of organic reaction during the course of the reaction. Thus, in fact, it schemes, namely in terms of net structural changes. records the situation before the reacting species Procedures based on various algebraic models of approach each other and after the products have constitutional chemistry are under development20-30. emerged. We therefore also consider reactions which In the practical application of general reaction involve overall transfers of electrons in pairs, even matrices to synthesis planning25-31 the use of a though the reaction mechanism involves homolytic restricted optimum set of algebraic expressions of steps. A classification according to mechanism is structural changes is required. Our research efforts not necessary for the purpose of definition of an are therefore directed towards deriving such a set of optimum set of general R-matrices of overall organic reactions. Requests for reprints should be sent to Dr. J. C. J. When possible then, we shall adhere to current B a r t , Montedison Research Laboratories “G. Done gani”, Via del Lavoro 4, Novara, Italy. usage and base our primary classification of syn 456 J. C. J. Bart-E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types thetic reactions on the overall change that occurs. Ar-H + S 03 ^ ArSOsH (ft 21, 1) Obviously, complex multistep reactions give rise to Other reactions, such as the Friedel-Crafts more specific R-matrices, which eventually are linear alkylation or acylation of an aromatic ring in the combinations of more general R-matrices corres presence of such catalysts as AICI 3, BF3, SnCl4 or I 2, ponding to basic reactions. Whenever such evidence wThich occur with skeletal rearrangement, are ft 2 type: is available, the overall R-matrix is not further considered for inclusion in the optimum set. Rather, Me I PhH such more specific R-matrices are useful for classifi Me-C-CH2C1: A1C13------cation and codification of organic reactions for re I Me trieval purposes, as will be illustrated in a next Ph Me paper32. The general desirability of generating precursors Me-C - CH2 + HC1: A1C13 (R 2, 1) I (intermediates) of established chemical stability and Me the necessity of adherence to ensembles of molecules, In case of nucleophilic aromatic substitutions a make it desirable to express a process as: greater variety of reaction schemes occurs as in a (C6H 5)2CH-OH + HC1 -> (C6H 5)2CH-C1 + H 20 number of substitutions the introduced group does not take the place of the expelled group, but a as a R 1-reaction31, even though the carbon-to- hydrogen shift is involved, e.g. in substitutions oxygen bond is broken first: involving elimination (benzyne mechanism), as in case of replacement of halogen by an amino-group (C6H 5)2CH-OH + H+ ^ (C6H 5)2CH+ + H 20 by the action of metal amides on aromatic halides: The latter process, which may be considered as an electrophilic substitution by hydrogen for the benz- hydryl group on oxygen, is schematically represented as A—B+C^A—C+B (Rll) (fl8, 5)
This kind of subclassification will be introduced Table I. Synthetic transformations of the type only where mechanistic differences have bearings on A-B + C-D -> A-C + B-D. the product distribution. R 1 3. Results and Discussion 1 Electrophilic and nucleophilic substitution reactions. The results of the classification of the more 2 Esterification and ester saponification. fundamental types of organic reactions in terms of 3 Formation and hydrolysis of carboxylamides. 4 C l a i s e n condensation. !R-matrices or electron-flow schemes, are summa 5 D i e c k m a n n r e a c tio n . rized in Tables I and II. 6 Cleavage of /S-diketones. 7 Halogenation of ketones. In accordance with previous findings31, !R1 8 Aldol condensation and related reactions. appears to account for the majority of organic 9 Cyanohydrin formation. reactions. In particular, with the restrictions 10 P e r k i n r e a c t io n . indicated above, electrophilic substitutions (e.g. 11 M i c h a e l reaction. aromatic substitution reactions, including alkyla- 12 Benzoin condensation. 13 Addition reactions (of halogens, hydrogen tions, acylations, nitrations, sulfonations, halogena- halides, hypohalous acids; hydration). tions, diazonium coupling reactions, etc.) are often 14 Formation of azomethines, oximes, arylhydra- !R 1 type, e.g. zones, semicarbazones. CISOaH + CH 3C-NH-C 6H 5 ~> 15 Additions of olefins to give four-membered rings. II 16 Addition reactions of organolithium compounds. 0 17 Addition reactions of G r i g n a r d reagents. 29CH3C-NH-C 6H 4-SO 3H + HCl (R 1, 1) 18 Friedel-Crafts acylation (without decarbonyla- II tion). 0 19 Beta-elimination reactions. 2 0 Intramolecular (cis) eliminations ( C h t j g a e v and RC1:AICI3 + C6H 6 -> C o p e reactions). c 6h 5-r + H+ + AlCU- (ftl, 1) 2 1 Intramolecular displacement by oxygen in halo- although other schemes may arise, as in case of carboxylic acids. sulfonation: 2 2 Tautomerizations. J. C. J. Bart-E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types 457
Table II. General reaction-matrix types of synthetic Table II (continued). transformations. R22 A-B-C * A-C + B: R2 A-B + C-D + E-F > A-C + D-E + B-F 1. CO2, CO, SO2 and N = N heterolysis 1. Friedel-C rafts alkylation (with skeletal (decarboxylation, etc.). rearrangement). 2. Internal nucleophilic substitutions without 2. 1,4 Additions to conjugated polyolefins. allylic rearrangement (Si^i). 3. 1,4 Tele-eliminations. 3. a-Elimination reactions of alkyl halides and 4. Telesubstitutions. related compounds. 5. D i e l s -A l d e r reactions. R23 A-B A + B: 6. Neighbouring-group partecipation in electrophilic addition reactions. 1. Nucleophilic aliphatic substitutions (SnI)- 2. Dissociation reactions. 7. G r o b ’s fragmentation of /3-halocinnamic 3. Pyrolysis of diazoalkanes or ketenes. acids. R24 A + B: A-B R3 A-B + C-D A + B-C + D: 1. Electron pair transfers ( L e w i s acid-base 1. Metal hydride addition. system ). 2 . H o e s c h reaction (form ation of im inochloride). 2. Formation of amino oxides, sulfoxides, sulfones. R7 A-B + C-D-E A-D-B + C-E 3. Addition of dichlorocarbenes. 1. Insertion reactions (e.g. Baeyer-V illiger oxidation of ketones). R25 A + B-C + D: * A-B + C-D 2. Neighbouring group partecipation in E 1-type 1. H o e s c h reaction. elimination reactions. 3. Epoxidation ( cis addition to C = C bond). R 2 6 A-B + C-D + E-F A + B-C + D-E + F: 1. Heterolytic addition of hydrogen to R8 A-B + C-D + E: » A-C + D-E + B: conjugated olefinic carbonyl compounds. 1. Addition of 1,3 dipoles to give five-membered R i t t e r reaction (first step). rings. R 27 + B -C + D -E + F -G -> 2. E2 type olefin elimination reactions. A-G + C-D + E-F 3. Sn 2' reactions in allylic systems. 4. Copulation reactions. 1,4 Tele-eliminations. Staedel-Rügheim er pyrazine synthesis 5 . Benzyne formation. (last step). 6. S a n d m e y e r reaction. R 28 A-: B + C-D + E-F + G: R9 A-B + C-D-E A-E + B-C -f D: A- F + B-D + E-G + C: 1. Internal nucleophilic substitutions with allylic 1. Nucleophilic 1,4 eliminations. rearrangement (Sn O- A- B -C + D = E + F -G -> 2. Tele-eliminations. R 29 A - A- E-F + B = D + C-G RIO A-B-C + D = E * A-D-C + B = E 1. Formation of ethoxybutenyne from a butynal 1. Telereactions. acetale. 2. £ t a r d r e a c tio n . 2. Conversion of acid anilide to imido chloride (Sonn-M üller m ethod). R 11 A-B + C -> A-C + B R 30 a -:B + C-D + E-F + G-H + I: 1. Electrophilic aliphatic substitutions. A- I + B-D + C-F + E-G + H: 2. Polymerization reactions (acid-catalyzed). 1. R e i s s e r t reaction (1st step). R 12 A: + B-C A-C + B: 2. Cyanation of aromatic carbocycles ( R i c h t e r 1. Nucleophilic aliphatic substitutions (Sn 2). reaction). 2. Polymerization reactions (base-catalyzed). R31 A=B + C-D + E-F -► C-A-E + D-B-F 3. Solvation. 1. Bischler indole synthesis (intermediate step). R 17 A-B + C-D + E-F + G-H - > 2. Clemmensen reduction. A-D + B-H + C-E + F-G 3. F e r r a r i o reaction. 1. Nucleophilic 1,6 eliminations. R32 A: + B: A=B 2. Tetramerization of acetylene. 1. Reaction of triphenyl-phosphine with chlorocarbene. R21 A-C + B: A-B-C R33 A + :B-C -> A-B + C: 1. Aromatic sulfonation. 2. Rearrangement of degradation products of 1. Carboxylation of carbocations. diazo-ketones. 2. Reaction of trialkylboranes with carbon 3. Insertion reaction of methylene. monoxide. 4. Cyclic addition to an olefinic double bond. R34 A = B -► A: + B: 5 . Diaminomethylation of activated carbon 1. Thermolysis reactions. atoms. 6. Reimer-Tiemann reaction. R 35 A = B + C: -> A = C + B: 7. K o l b e r e a c tio n . 1. Condensation of 1,3-propylenetrithio- 8. Formation of G r i g n a r d reagents. carbonate with trimethylphosphite. 458 J. C. J. Bart-E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types
Table II (continued). XH
base R36 A=B + C: + D: A=C + :B-D or Ar Ar (Hl, 1) : A-B + C: -> A = C + B: 1. Interaction of halocarbenes with diaryldiazo- m ethanes. YH Independently of the mechanistic paths, the R37 A=B + C: + D-E -► D-A-E + :B-C overall esterifications,^ ester and amide hydrolyses 1. N ierenstein procedure of halomethylation proceed according to H 1. In the C la is e n condensa of acylhalides (2nd step). 2. Aminomethylation of diazoalkanes. tion (Hi), which is related to the saponification, the 3. Amidomethylation (formation of N-chloro- attacking reagent is a carbanion, obtained by methylamides from N-chloramides). removal of a slightly acidic hydrogen from a ketone, 4. Dialkoxymethylation of diazoalkanes. a nitrile or an ester, followed by 5. Dialky lthiomethylat ion of diazoalkanes. R 6. Immoniomethylation of aromatic compounds. -C- h : + C-OR' -C-C-C-R -f -OR' R38 A-A-B + C-D + :E-F + G-H > II I II II I II A-C + D-E-H + B-G + F: 0 0 0 0 1. Hydroalkoxycarbonylation of conjugated Subprocesses are thus of the type H23 and 1112 olefins. (c/.^Table II). 2. Hydroalkoxycarbonylation of 1-alkynes. Hi-typereactions are also the electrophilic addi R39 A-B-C + D-E + F-G + H: -> tions to olefinic compounds, such as the additions of A-F + C-H + D : + E-B-G strong acids (hydrogen halides) and non-acid electro- 1. Carbamoylation of enamines. philes (halogens) to mono-olefinic compounds. In 2. Aminomethylenation of aromatic compounds. stead, similar additions to conjugated polyolefinic R40 A-B-C + D-E + F-G + H-I compounds conform to R2 and other schemes, as A-G + C-D + E-F + H-B-I demonstrated by A r e n s 33. The acid-initiated poly 1. Formation of 6-chloromethyleno testo merization of olefinic compounds by self-additions sterone. is better described by H 11. 2. Sem m ler-W olff reaction (overall). Most nucleophilic additions of bases of weak acids to carbonyl and olefinic compounds (overall R41 A-B-C + D-E-F -> B = E + A-F + C-D reactions) are fid: examples are the cyanohydrin 1. Hydrolysis of dihalomethylated compounds. formation 2. Aminomethylenation. 3. Hydrolysis of diaminomethylketones to HCN + R2C = 0 R 2C(CN) • OH (H 1,9), a-ketoaldehydes. the aldol addition 4. Diaminomethylenation of activated methylene groups. (CH3)2C = 0 + CH3-CO-CH 3 ^ 5 . Amino-alkoxymethylenation of activated (CH3)2C(OH) • CH2 • CO • CH3 (H 1, 8) methylene groups. and related reactions (Schmidt, Claisen, Knoeve- 6. Baeyer-Drewson indigo synthesis (last step). n a g e l , and P e r k in ) . Also the additions of H-N to 7. H o f m a n n isonitrile synthesis (reaction of C=0, such as the reversible formation of azo- primary amine with dichlorocarbene). methines, oximes, arylhydrazones and semicarba- R42 A=B + C = D -> A=C + B = D zones follow the general pattern of aldol condensa 1. Barbier-W ieland degradation (oxidation tions : step). /OH 2 . H o o k e r reaction (oxidation step). NH2X + RR'C = 0 RR'-Cx (Hi, 14) 3. M i e s c h e r degradation (oxidation step). NHX 4 . N e f reaction (oxidation step). where X = H , Aik, Ar, OH, NHAr or N H • CO • NH2. 5 . W i t t i g reaction (overall). 6. K endall-M attox reaction (second step). The same holds for the overall H -0 additions to the carbonyl-group to form carbonyl-hydrates and al- R43 A: + B-C-D A-C: + B-D coholates, or the base-catalysed addition of a pseudo- 1. Decomposition of a diazoaminosulfinate acidic ketone, ester, nitrile, or nitro-compound to the (Dutt-W orm all reaction). a, /^-double bond of a conjugated unsaturated ketone, ester or nitrile ( M ic h a e l reaction). Also the additions of metal-alkyls and G r ig n a r d An interesting example of an intramolecular R 1- reagents to carbonyl and conjugated olefinic type nucleophilic aromatic substitution is the carbonyl compounds are !Rl-type: S m ile s rearrangement, in which, under basic :C=C-C=0 + RX :C=C-C-0 (Rl, 17) conditions, an electronegative bridge -X - separates I I I I from aromatic carbon, and is replaced by the R M conjugated-basic atom Y of some acidic centre YH Further, the formal reaction schemes for /?-elimina- situated beyond the bridge in the original molecule: tion, either E l or E2, conform to Hi, e.g. J. C. J. Bart-E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types 459
ArCH=N-Cl ArfeN + HCl (ftl, 19) CICHafeN + HC1 C1CH2C+=NH + Cl- (ß3, 2) R 2CH-O-NO2 -> R 2C = 0 + HNO2 (ftl, 19) This holds equally well for several (unimolecular) The next scheme, ft 7, accounts for numerous pyrolytic eliminations, e.g. those involving carboxy- insertion reactions, of which the following cases may lic esters be mentioned: Peroxyacids attack ketones in a manner which is formally analogous to attack by diazomethane or by hydrazoic acid. Diazomethane -C-C-O-C-R — ► :C =Cc + HO-C-R (ft 1,20) interposes a -CH 2- group between the -C- group I I II II H O 0 O or xanthates (C h u g a e v reaction) or trialkylamine and an a-carbon, whereas hydrazoic acid interposes oxides (C o p e reaction). an -N H - group in this position. Peroxy-acids insert From general considerations of interrelations of an -0 - linkage, thus converting the ketone R-C-R' unsaturated aliphatic compounds (eliminations, ad ditions, substitutions and isomerizations)33, it may Ü) to the esters R-C-OR' and/or R'-C-OR (B a e y e r - easily be seen that ft 1 accounts for all possible II II eliminations in C2 and C3 atomic systems (cf. ref.33, O 0 Fig. 2) and for 21 different a, /^-eliminations among ViLLiGER oxidation): the 14 linear C4 patterns; another 5 possible elimination reactions in the latter systems conform R-C-R' + AcOOH to the ft 2 matrix and are the so-called a,d or 1,4 & eliminations (ref.33, Fig. 3). (A systematic procedure for evaluation of all possible eliminations in the RCOR'/R'COR + AcOH (Ä7, 1) II II general case of linear systems has recently been 0 0 described by A rens33). Similarly, III describes the a, a or 1 , 1 substitution reactions and ft 2 the a,y or Other R7 reaction types are El-type eliminations, 1,3-substitutions. Isomerizations may be described as analogously31-33. As addition reactions are the PI13C-CH2CI -> Ph2C=CHPh + HC1 (ft 7, 2) reverse of eliminations, the conclusions reached above for the latter hold analogously for the former. and the aforementioned cis addition to C=C bonds More complex tele-reactions are classified according (epoxidation): to other schemes, e.g. !R8 , ft 9, I I 10, !R 17, f t 27-29. 0 R Ra The extension of the ftl-scheme, the R 2-matrix, OH apart from accounting for part of the earlier X != (X + Rs' mentioned telereactions, e.g. Ra^ XR 4 0 /R /R R i \ /R3 CH3C=C-Ct_OR/ CH2=C=C=C\ + R'OH ;c-a + r 5- c ^ o h (ft 7, 3) R R (ft2, 3) / ^ r 2 0 r 4 describes such synthetically important reactions as A scheme of considerable synthetic interest is the F r ie d e l -C r a f t s alkylation and D i e l s -A l d e r represented by the ft 8 matrix and a.o. accounts reactions (other cis-additions involving cyclization, for the additions of 1,3-dipoles to give five-mem- such as epoxidation, conform to other schemes, bered rings, as illustrated by the following examples: e.g. R7). Interestingly enough, it appears that the a) Addition of diazoalkanes: R ic e -program for synthesis planning 34 deals mainly with ft 2 -type reactions in (five- or) six-atomic Me Me ensembles of molecules. We finally notice that not + v.- \ / H,C=N=N + C=C - (Ä8, 1) all 1,4 additions (ft 2, 2) are ft 2 type, as follows 2 ' I \ from the following acid-catalyzed 1,4 hydration: Me02C C02Me MoO,C CO,Me
(l I) + H —OH---- - (ftl, 13) b) Additions of azides to olefinic compounds to OH OH form triazolines: Still other additions, e.g. the heterolytic addition of hydrogen to carbonyl compounds
PhN=N= (ft 8, 1) M-H + -C=0 -> M+ + H -C-0- (S3, 1) conform to scheme ft3. The latter also accounts for reactions such as that of chloroacetonitrile and HC1 c) (Cyclic) additions of nitrile oxides. to form an iminochloride (cf. H o e sc h reaction): d) Cyclic additions of nitrones: 460 J. C. J. Bart-E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types
P h I Y- + RX YR + X- (Sn2) (ft 12, 1) N Y: + RX YR++ X- (S n 2) (ft 12, 1 ) Ph-CH=N -0 +CH7=CHPh- P h ' (ß 8, 1) R 3S+ + Y - YR + R2S (Sn2) (ft 12, 1) I
N
(R21,5) cich 2 c=*nh (ft 25, 1)
C1CH2-C=NH2 Cl Instead, the reverse reaction, ft 22, stands for The heterolytic addition of hydrogen to conjugat processes such as decarboxylation and decarbonyla- ed olefinic carbonyl compounds is a representative tion as well as aliphatic substitution reactions (Siä of ft 26: mechanism) without rearrangement (cf. ft 9 for Sn^ M-CRa-CRa-H + :C =0 type), as in case of chlorosulfites: R-CH=CHCHa-0-S-Cl -> M+ + CR2=C R 2 + H- c - o - (ft26, 1 ) II 0 The next three reaction schemes, ft27-ft29, were R-CH=CHCH 2C1 + S 0 2 (ft 22, 2) already cited above in connection to the telere Other extrusion reactions conform to other schemes, actions35. Examples are: e.g. G r o b ’s fragmentation reactions, eliminations in which a group of atoms, potentially having some Br-CH 2CH=CHCH 2OCH3 — ► stability as a cation, takes the place of the ß- CH2=CH-CH=,CH 2 + CHsOMgBr (ft 27, 1) hydrogen atom in ordinary elimination, so that a CH3 substantial portion of the molecule may become split off: OH- + H-O-CH — CH2-C H = 0 /O CH3 h - o - c o - c h 2- c ( -> HaO + 0 = C H + CH2= C H -0 - (ft 28, 1 ) OH /OH KOH CH3C=CCH(OC2H 5)2 — ► CH2=C( + 0=C0 (ft2 , 7) x OH HC=C-CH=CHOC 2H 5 + C2H 5OH 36 (ft 29, 1) Other cases are the pyrolytic ft 1 eliminations (If we consider reaction schemes as an isomerization (C h u g a e v and C o p e reactions). of ensembles of molecules, ft 28 should be more Of considerable interest are also the fundamental properly classified as ft 17.) heterolytic bond breaking and formation processes The first step of the R e is s e r t reaction is typical ft 23 and ft 24. The former has already been cited of ft 30: above in connection to Sn I type nucleophilic sub HCl stitution reactions; it also accounts for dissociation H processes as C»N NH C f )4 2 Ni(CO Ni + 4 CO (4* ft 23, ) COPh and the formation of carbenes, e.g. (ft 3 0 , 1) R R 'C --C =0+: RR C: + :C = 0 : (ft 23, 3) Instead, an intermediate step in the B is c h l e r The reverse process, ft 24, is typical of electron- indole synthesis may be described by ft 31: pair transfers on L e w is acid-base systems, e.g. H RC1 + AlCls RC1: AlCls (ft 24, 1 ), 0-C-C-N-0 + NHa-0 -> the formation of amine oxides, sulfoxides, sulfo- nes from addition of an oxygen atom at the N or S 0 H H atoms of amines or sulfides: 0 -N -C = C H -N - 0 + HaO (ft3 1 , 1) R-S-R + 0| -> R-S+-R (R24, 2) 1 L I H 0 H iA i- The same holds for the overall scheme of the and the addition of dichlorocarbenes: C l e m m e n s e n reduction: - C = 0 + 2 H -H - * 'CHa + H -O -H (ft 31 , 2) RNH2 + :CC12 -> RNH 2 • CC12 (ft 24, 3) as the process does not appear to proceed through The other electron-flow processes which were the corresponding carbinol. encountered appear as rather isolated minor cases. Several other reaction matrices were found among We briefly mention these results, ft 25, the reverse the synthetic transformations described by ref.37. of R3, describes the H o e sc h reaction of a stable We record here typical examples of these reaction intermediate iminochloride with resorcinol: schemes. 462 J. C. J. Bart—E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types
The reaction of carbenes with triphenylphosphine H proceeds by R32 to yield alkylenetriphenylphos- phoranes, e.g. -C-i--N=N: + H-X -> II " (C6H5)3P: + : C H -C 1 0 (C6H5)3P = C H - C 1 (Ü32, 1 ) H (C6H5)3P: + :C(SC2H5)2 -C-dj-X + :N=N: (R 5) II I (C6H5)3P = C(SC2H5)2 (ft32, 1) 0 H The next scheme, R33, accounts for the carboxy- just as the other^ entries under heading R37 lation of a nonactivated tertiary carbon atom: (Table II), except (R37, 6 ). The hydroalkoxycarbonylation of conjugated R 3C+ + CO r 3c^c=o (H33, 1) olefins and 1-alkynes is a !R38 reaction, which is an extension of !R15: as well as for the reaction of carbon monoxide with a trialkylborane: CH2=C H -C H 2C1 + HC=CH + CO ..9ff»oya CH2=C H -C H 2-CH=CH-COOCH 3 (ft 38,2) R3B + CO -> R 3B -C = 0 (ft 33, 2) An example of R39 is the carbamoylation of An example of !R34 is the thermolysis of enamines l^'^^'-tetraphenyl^^'-dehydrobiimidazolidine f| I + 0 —N=C=0 ------+ H CI OR 39, 1) CH-CO-NH-0 I (ft 34, 1) 0 -C H ? Cl C H ,~ I The next reaction scheme, II40, is documented by the formation of a 6 -chloromethyleno derivative A reaction which accounts for !R 35 is the conden of testosterone: sation of 1,3-propylenetrithiocarbonate with tri- methylphosphite to yield l,3-dithian-2-ylidenetri- (!R40, 1 ) methoxyphosphorane: CH-CI
<^~~^=s+p(och 3)3 — p(och3)3+s (!R35, 1) As examples of R41 we report the aminomethyl- enation of activated methylene groups with S-al- kylisothioformamides: The reaction of halocarbenes with diaryldiazo- methanes may be considered alternatively as :CH2 + R-S-CH=NR' -► :C—CH-NHR' + RSH (fUl,2), 0 2C = N 2 + :CC12 0 2C=CC12 + N2 (ft36, 1) the hydrolysis of diaminomethylketones to a-keto- or as aldehydes:
0 2C-N=N: + :CC12 ~>02C=CC12 + N2 (ft36', 1 ) and may therefore be described by two distinct Q - t . o R-C0-CH0 (1141,3) reaction schemes, 1136 and !R36'. Also the second step in the N ie r e n s t e in proce dure of halomethylation of acylhalides may be described by two reaction matrices, as follows: or the diaminomethylenation of activated methy lene groups: H CN -C-i=N=N: + H-X / II CH2 + RS-C-N(CH3)2 -> 0 H CN NCH3 NC N(CH3)2 -C-i-X + :N=N: (ft37, 1) il I 0 H /C=C^ + RSH (ffc41,4)
or NC NH-CH 3 J. C. J. Bart-E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types 463
Another reaction type which deserves mentioning concerns a metathesis of four doubly bonded atoms (S. 42). Apart from oxidation processes, which formally may be considered to involve O 2 instead of oxidants as Cr (>3 and KMn0 4 , the scheme describes the overall W it t ig reaction and other such concerted reactions. Other more
(CßHs^P = CR 1 R 2 -j- R 3COR4 —*■ isolated cases are the G i b b s phthalic anhydride and RiRaC = CR 3R 4 + (C6H5)3PO (ft 42, 5) the v o n R ic h t e r reactions41. and the formation of a conjugated ketone from a phenyl-hydrazone or semicarbazone (K e n d a l l - 4. Conclusions M a t t o x reaction): This paper extends the set of general reaction- matrix types which may be of use to generate C H-jCOCOOH NNHR synthetic routes for any organic structure. The CH3CCO O H RHNN conceptual base for utilizing this information has (R 4 2 , 6) been developed first by U gi et al. 25~30. Combination With regard to the oxidation^ reactions just with the results of a previous study concerning mentioned, these are sometimes ft 1 0 -type, as in rearrangement reactions thus reveals that some case of the oxidation of alkyl-groups in aromatic 43 basic types of general reaction-matrices may be compounds to aldehydes by means of chromyl distinguished, of which ten account for organic chloride (E t a r d reaction), formally rearrangement reactions only. Out of the remaining 33 ft-matrices, almost twenty schemes do not C6H 5CH3 >0= Q - > CeHsCHO + H 20 (ft 10, 2 ) conform to a set of semi-empirical rules describing evidentiating the relation between the two schemes. The last reaction type identified, f t 43 , is the the main features of organic chemistry30'42. The inverse of ft 5 and describes the decomposition of general reaction-matrices listed have value for the a diazoaminosulphinate: synthetic chemist not only because they offer new Ar-N= N-NHSO2R -> insights and demonstrate that organic chemistry is actually contained in a restricted set of algebraic Ar-N=N=N: + H02SR (ft 4 3 , 1) equations but may also lead to new efforts, and Notice that the description of the azide in the + reexamination of various synthetic transformations. alternative mesomeric form, Ar-Ne-N =N :, leads The results of the present work indicate that to a reaction type which is the reverse of f t 37. account should be taken of the qualitatively ob During our studies we have occasionally en served and logically expressed differences in countered reactions which are not easily described characteristics of organo-chemical reactions for the by means of the restricted set of ft-matrices purpose of synthesis-planning, reaction data-retrie- developed here and in a previous paper 31 and which val and related projects. Obviously, the fundamen constitutes an empirical basis for U g i ’s mathemati tal principles offered here and in previous papers cal model of organic chemistry30. Typical reactions are only a starting point for more extensive studies. which cannot easily be handled concern: a) higher More specifically, and in line with other studies on order eliminations and additions, e.g. 1 ,6 elimina the microstructure of chemical data bases43, it is tions 33; b) higher order substitutions and isomeriza- suggested that a detailed quantitative analysis of tions, e.g. 1,5-substitutions33; c) the more complex the incidence distribution of the reaction schemes tele-w reactions (n ^ 8 )-notable examples are the may add further useful information for the practical rearrangements of “retro” into “normal” conjugated applications in mind. These aspects will be dealt carotenoids38-40; d) oligomerization reactions, e.g. with in a next paper.
1 A. B a l a b a n (ed.), “Chemical Applications of 4 A. M. D uefield, A. Y. Robertson, C. D j e r a s s i , Graph Theorv”, Academic Press, New York, N. Y. B . G. B u c h a n a n , G. L. Sutherland, E. A. 1975. Feigenbaum, and J. Lederberg, J. Amer. Chem. 2 M. F . L y n c h , J. M. H a r r i s o n , W . G. T o w n , and Soc. 91, 2977 [1969]. J. E. A s h , “Computer Handling of Chemical 5 L. M. M asinter, N . S. Sridharan, J. L e d e r b e r g , Structure Information”, Macdonald, London 1971. and D . H. S m it h , J. Amer. Chem. Soc. 96, 7702 3 I. Ugi, D. M arquarding, H. KLlusacek, G. G okel, [1974]. and P. G illespie, Angew. Chem. 82, 741 [1970]. 6 A. J. T h a k k a r , Topics Curr. Chem. 39, 3 [1973]. 464 J. C. J. Bart-E. Garagnani • Organic Reaction Schemes and General Reaction-Matrix Types
7 E . J. C o b e y and W . T. W i p k e , Science 166, 178 sentation and Manipulation of Chemical Informa [1969]. tion ” (Eds. W . T. W i p k e , S. R. H e l l e r , R . J. 8 E. J . C o r e y , Quart. Rev. 25, 455 [1971]. F e l d m a n n , and E . H y d e ), p. 129, J. Wiley & Sons, 9 E. J. C o r e y , W . T. W i p k e , R. D. C r a m e r , and New York, N. Y. 1974. W . J. H o w e , J. Amer. Chem. Soc. 94, 421 [1972]. 26 I. U g i and P. D . G i l l e s p i e , Angew. Chem. 83, 980 10 E. J. C o r e y , W . T. W i p k e , R. D. C r a m e r , and [1971]. W . J. H o w e , J. Amer. Chem. Soc. 94, 431 [1972]. 27 I. U g i and P. D . G i l l e s p i e , Angew. Chem. 83, 982 11 E. J. C o r e y , R . D. C r a m e r , and W. J. H o w e , [1971], J. Amer. Chem. Soc. 94, 440 [1972]. 28 I. U g i , P. D. G i l l e s p i e , and C. G i l l e s p i e , Trans. 12 E. J . C o r e y and W. L. Jorgensen, J. Amer. Chem. N. Y. Acad. Sei. 34, 416 [1972]. Soc. 98, 189 [1976]. 29 J. D u g u n d j i and I. U g i , Topics Curr. Chem. 39, 19 13 E. J.C o r e y and W . L. Jorgensen, J.Amer. Chem. [1973]. Soc. 98, 203 [1976]. 30 J. B l a i r , J. G a s t e i g e r , C. G i l l e s p i e , P. D. 14 E. J. Corey, H. W. Orf, and D. A. P e n s a k , G i l l e s p i e , and I. U g i , Tetrahedron 30, 1845 [1974], J. Amer. Chem. Soc. 98, 210 [1976]. 31 J. C. J.B a r t and E . G a r a g n a n i , Z. Naturforsch. 15 M. Bersohn, Bull. Chem. Soc. Japan 45, 1897 31b, 1646 [1976]. [1972]. 32 E. G a r a g n a n i and J. C. J.B a r t , unpublished 16 G. G. S m it h , Ph. D. Thesis, University of Pittsburgh results. 1973. 33 J. F.A r e n s , Rec. Trav. Chim. Pays-Bas 94, 3 [1975]. 17 H. G elernter, N. S. Sridharan, A. J . H a r t , and 34 R. V. S t e v e n s a n d T. F. B r o w n s c o m b e , u n S . C. Y e n , Topics Curr. Chem. 41, 113 [1973], published results. 18 W. T. W i p k e , in “Proceedings of the NATO/CNA 35 J. F. A r e n s , Bull. Soc. Chim. Fr. 1968, 3037. ASI Conference on Computer Representation and 36 P. L. V i g u i e r , Ann. Chim. 8, 481 [1913]. Manipulation of Chemical Information” (Eds. W. T. 37 J. M a t h i e u and J. Wte i l l -R a y n a l , “Form ation W i p k e , S. R. H e l l e r , R. J. F e l d m a n n , and of C-C Bonds”, Vol. 1, Introduction of a Functional E. H y d e ) , p. 147, J. Wiley & Sons, New York, Carbon Atom, G. Thieme, Stuttgart 1973. N. Y. 1974. 38 L. W a l l c a v e and L. Z e c h m e i s t e r , J. Amer. Chem. 19 P. E. B l o w e r and H . W. W hitlock, J. Amer. Soc. 75, 4495 [1953]. Chem. Soc. 98, 1499 [1976]. 39 R . E n t s c h e l and P. K a r r e r , Helv. Chim. Acta 40, 20 J. B. H endrickson, J. Amer. Chem. Soc. 93, 6847 1809 [1957]. [1971], 40 E . M. S h a n t z , J. D . C a w l e y , and N . D. E m b r e e , 21 J. B. H endrickson, J. Amer. Chem. Soc. 93, 6854 J. Amer. Chem. Soc. 65, 901 [1963]. [1971]. 41 “The Merck Index of Chemicals and Drugs”, 11th 22 J. B. H endrickson, J. Amer. Chem. Soc. 97, 5763 ed., pp. 1137-1231, Merck & Co., Rahway, N .J. [1975]. 1968. 23 J. B. H endrickson, J. Amer. Chem. Soc. 97, 5784 42 E. P e s c a t o r i , unpublished results. [1975]. 43 M. F . L y n c h , in “Proceedings of the NATO/CNA 24 J. B. Hendrickson, Topics Curr. Chem. 62, 49 ASI Conference on Computer Representation and [1976], Manipulation of Chemical Information”, (eds. 25 J. B l a i r , J. G asteiger, C. G illespie, P. D. W. T. W i p k e , S. R . H e l l e r , R. J. F e l d m a n n , and G illespie, and I. U g i , in “Proceedings of the E. H y d e ), p. 31, J. Wiley & Sons, New York, N. Y. NATO/CNA ASI Conference on Computer Repre 1974.