3114 J. Org. Chem., Vol. 42, No. 19, 1977
`Oldenziel, van Leusen, and van Leusen
`3114 J. Org. Chern., Vol. 42, No. 19,1977
`Oldenziel, van Leusen, and van Leusen
`A General One-Step Synthesis of Nitriles from Ketones Using
`A General One-Step Synthesis of Nitriles from Ketones Using
`Tosylmethyl Isocyanide. Introduction of a One-Carbon Unit’
`Tosylmethyl Isocyanide. Introduction of a One-Carbon Unitl
`
`Otto H. Oldenziel, Daan van Leusen, and Albert M. van Leusen*
`Otto H. Oldenziel, Daan van Leusen, and Albert M. van Leusen*
`Depa,ptment of Organic Chemistry, T h e University, Zernikelaan, Groningen, The Netherlands
`Department of Organic Chemistry, The University, Zernikelaan, Groningen, The Netherlands
`Received February 7,1977
`Received February 7, 1977
`
`Ketones are converted efficiently, in one step, to nitriles (R2CO - R2CHC=N) at temperatures between 0 and
`
`Ketones are converted efficiently, in one step, to nitriles (R2CO -+ R2CHC==N) at temperatures between 0 and
`45 O C by the use of TosMIC (tosylmethyl isocyanide) and base. This conversion is effectively a reductive cyanation,
`45°C by the use of TosMIC (tosylmethyl isocyanide) and base. This conversion is effectively a reductive cyanation,
`unlike the classical cyanohydrin reaction. The reaction is shown to be generally applicable.
`unlike the classical cyanohydrin reaction. The reaction is shown to be generally applicable.
`
`Tosylmethyl isocyanide (TosMIC, 1) is a synthon with
`Tosylmethyl isocyanide (TosMIC, 1) is a synthon with
`diverse and steadily expanding applications. Thus far em-
`diverse and steadily expanding applications. Thus far em(cid:173)
`phasis in the chemistry of TosMIC has centered mainly on
`phasis in the chemistry of TosMIC has centered mainly on
`heterocyclic synthesis. The preceding paper in this series deals
`heterocyclic synthesis. The preceding paper in this series deals
`with the synthesis of imidazoles from TosMIC and aldimi-
`with the synthesis of imidazoles from TosMIC and aldimi(cid:173)
`nes,2a and summarizes other azole (and azoline) syntheses.2
`nes,2a and summarizes other azole (and azoline) syntheses.2
`The present paper will show, however, that the application
`The present paper will show, however, that the application
`of TosMIC by no means is restricted to the domain of het-
`of TosMIC by no means is restricted to the domain of het(cid:173)
`erocyclic synthesis only.
`erocyclic synthesis only.
`We here wish to concentrate on the use of TosMIC in an
`We here wish to conclmtrate on the use of TosMIC in an
`efficient, direct conversion of ketones to nitriles3
`efficient, direct conversion of ketones to nitriles:3
`
`(1)
`
`cause it allows the ketone - nitrile conversion to be carried
`
`T ~ ~ C H ~ N = C
`1
`
`I-BuOK
`
`T ~ ~ C H N = C
`TosCHN=C
`3
`
`4
`
`R2’
`
`H *;c
`To s
`
`Results and Discussion
`Results and Discussion
`The synthesis of nitriles according to eq 1 is applicable to
`The synthesis of nitriles according to eq 1 is applicable to
`a wide variety of different ketones (Table I). The substrates
`a wide variety of different ketones (Table I). The substrates
`range from simple aliphatic and aromatic ketones to sterically
`range from simple aliphatic and aromatic ketones to sterically
`hindered ones, including camphor and P,p-dimethyl-a-te-
`hindered ones, including camphor and /1,/1-dimethyl-a-te(cid:173)
`tralone (to give 2c and 2g, respectively). Also, the cyanation
`tralone (to give 2c and 2g, respectively). Also, the cyanation
`can be realized with 3- and 17-steroidal ketones (2h-k). So far
`can be realized with 3- and 17 -steroidal ketones (2h-k). So far
`only the severely hindered carbonyl of di-tert -butyl ketone
`only the severely hindered carbonyl of di-tert-butyl ketone
`has resisted reaction, whereas tert-butyl methyl ketone (pi-
`has resisted reaction, whereas tert-butyl methyl ketone (pi(cid:173)
`nacolone) and diisopropyl ketone are convertible (2q and
`nacolone) and diisopropyl ketone are convertible (2q and
`2P).
`2p).
`Reaction Conditions. The conditions of reaction 1 were
`Reaction Conditions. The conditions of reaction 1 were
`adapted to differences in reactivity of the ketones concerned.
`adapted to differences in reactivity of the ketones concerned.
`Typically, for ketones of normal reactivity t-BuOK was added
`Typically, for ketones of normal reactivity t -BuOK was added
`2
`at 0 “C to a solution of a ketone and 1.0-1.5 equiv of TosMIC
`at 0 °C to a solution of a ketone and 1.0-1.5 equiv of TosMIC
`in 1,2-dimethoxyethane (containing a little t-BuOH or EtOH).
`TosMIC adds one carbon unit to a ketone, as in the classical
`in 1,2-dimethoxyethane (containing a little t -BuOH or EtOH).
`TosMIC adds one carbon unit to a ketone, as in the classical
`The reaction went to completion in 1-2 h at room temperature
`cyanohydrin r e a ~ t i o n , ~ but without the simultaneous forma-
`The reaction went to completion in 1-2 h at room temperature
`cyanohydrin reaction,4 but without the simultaneous forma(cid:173)
`(2a,b,d,e,i-k,m-o). Under these mild conditions, however,
`tion of an a-hydroxy group. In this sense the reaction of
`(2a,b,d,e,i-k,m-o). Under these mild conditions, however,
`tion of an a-hydroxy group. In this sense the reaction of
`TosMIC is a “reductive cyanation”. Reaction 1 is unique be-
`camphor and diisopropyl ketone gave only trace amounts of
`TosMIC is a "reductive eyanation". Reaction 1 is unique be(cid:173)
`camphor and diisopropyl ketone gave only trace amounts of
`nitrile (2c,p), and tert-butyl methyl ketone gave no more than
`nitrile (2c,p), and tert-butyl methyl ketone gave no more than
`cause it allows the ketone -+ nitrile conversion to be carried
`36% of 2-cyano-3,3-dimethylbutane (2q).
`out in a single operation.5~6
`out in a single operation.5•6
`36% of 2-cyano-3,3-dimethylbutane (2q).
`The best way to convert camphor to 2-cyanocamphane (2c)
`Obviously, the nitriles can be exploited further, for instance,
`The best way to convert camphor to 2-cyanocamphane (2c)
`Obviously, the nitriles can be exploited further, for instance,
`was with 3 equiv of TosMIC in dimethyl sulfoxide (containing
`by conversion to carboxylic acids or derivatives thereof.6,’ A
`was with 3 equiv of TosMIC in dimethyl sulfoxide (containing
`by conversion to carboxylic acids or derivatives thereof.6,7 A
`some MeOH) at a slightly elevated temperature (45 “C). Thus,
`reaction of TosMIC with aldehydes and ketones leading in two
`some MeOH) at a slightly elevated temperature (45°C). Thus,
`reaction of TosMIC with aldehydes and ketones leading in two
`steps via N-( 1-tosyl-1-alkeny1)formamides to carboxylic acids
`80% of 2c was obtained after 70 h. In hexamethylphosphoric
`80% of 2c was obtained after 70 h. In hexamethylphosphoric
`steps via N-(I-tosyl-l-alkenyl)formamides to carboxylic acids
`triamide (HMPT) the same reaction went faster (17 h), but
`has been reported independently by Schollkopf et a1.P and
`triamide (HMPT) the same reaction went faster (17 h), but
`has been reported independently by Schollkopf et al.,8a and
`the product was less pure. Comparable reaction conditions
`this reaction has later been shown to proceed through nitriles
`the product was less pure. Comparable reaction conditions
`this reaction has later been shown to proceed through nitriles
`were used with success for other sterically hindered ketones
`(as in eq 1).8b
`(as in eq 1).8b
`were used with success for other sterically hindered ketones
`Dehydration of aldoximes also leads to nitriles, however,
`(nitriles 2g,p,q). Benzophenone and a-tetralone,’O which did
`Dehydration of aldoximes also leads to nitriles, however,
`(nitriles 2g,p,q). Benzophenone and a-tetralone,lO which did
`with the same number of carbon atoms as in the starting al-
`not react in DME, were also converted to the corresponding
`not react in DME, were also converted to the corresponding
`with the same number of carbon atoms as in the starting al(cid:173)
`
`d e h y d e ~ , ~ and therefore is a process quite different from re-
`nitriles (21,f) in MezSO and HMPT, respectively.
`nitriles (21,f) in Me2S0 and HMPT, respectively.
`dehydes,9 and therefore is a process quite different from re(cid:173)
`action 1.
`Reaction Scheme. A rationale for reaction 1 is given in
`Reaction Scheme. A rationale for reaction 1 is given in
`action 1.
`Scheme I. Proposed Mechanism for Conversion of Ketones to Nitriles with TosMIC According to Equation 1
`Scheme 1. Proposed Mechanism for Conversion of Ketones to Nitriles with TosMIC According to Equation 1
`R’
`\c=o
`
`- ;%-- - 7
`
`7
`
`R2+-O
`H~.)_
`6
`6
`
`5
`
`TOS
`Tos
`
`N
`
`0-
`I)
`"
`R'
`~
`'C=C=N-C-H
`I
`R2/ IJ
`1
`OR 10
`OR 10
`
`-HCOOR
`-HCOOR
`
`---.!!.
`
`___c
`
`,-
`
`R'
`/C-C:::N
`
`R2
`
`12
`12
`
`j H'
`pr
`o-
`C H - C C d AR
`I)
`,
`-- /c,
`,N-C-H
`R’,
`N-C-H
`R
`RO-
`'CH-C-::::-~ I
`~
`LTos
`~Tos OR
`R2’
`R2/
`R2, c-c .-?,+“ -
`-- 12 . TosH . co
`-- R
`--
`
`-11
`-Tos
`
`16
`16
`
`H , /
`R'
`
`R2
`
`C:::N
`2
`
`8
`a
`
`+O
`0
`'
`7
`R,_ h~C,
`c- c:%" Ii H
`,~-::::-O
`2/
`/5,::-
`*O
`19
`C,H,’
`C7H7
`0 19
`
`12
`
`TosH
`
`C O
`
`P‘
`
`10s
`
`N
`
`R'
`R!f:/
`TOS! ~H
`I ”
`7
`7
`j H'
`R’
`R'
`R2--+--0
`R 2 - L 0
`H~)-H
`13
`13
`
`Tos
`Tos
`
`N
`
`Tos
`
`14
`14
`
`17
`17
`
`- +o
`7O
`171 \c=c
`,N-C
`N_C
`R'
`\
`,
`'c=c/
`'H
` H
`To s
`\
`/
`/
`F12
`Tos
`f12
`8
`a
`U H'
`/ ' H -
`--
`h O
`’ ‘10s
`",I
`/NH-C/'
`c=c
`‘H
`'C=C
`,
`R2
`R 2
`,
`I?’ \ , N = C
`I~'
`c=c
`/N=C
`c=c
`\Tos
`1~2/
`'Tos
`172’
`
`-Tos -
`-10s-
`
`
`-
`
`H'
`
`,
`
`R 1 \
`R'
`
`h O
`Y
`C=C=N-C
`‘H
`R2/
`R2/
`'H
`9
`9
`
`-TosH
`
`~ f -TosH
`/O
`-::::-0
`R'
`R’ \ ,N-C/
`'CH_c;'lN-C, H
`CH-C/
`‘H
`/
`\
`
`To s
`'Tos
`R2/
`R 2
`15
`15
`
`R’
`R'
`
`:t~H
`
`N
`N
`
`18
`1a
`
`E t 0
`EtO
`
`NPC02230720
`
`NOVARTIS EXHIBIT 2124
`Par v Novartis, IPR 2016-00084
`Page 1 of 5
`
`

`
`Synthesis of Nitriles from Ketones
`Synthesis of Nitriles from Ketones
`
`1.3
`1.3
`1.3
`1.3
`
`1.3
`1.3
`1.3
`1.3
`
`3
`3
`3
`3
`1.1
`1.1
`
`1.1
`1.1
`
`1.0
`1.0
`
`3
`3
`
`3
`3
`
`1.3
`1.3
`
`1.3
`1.3
`
`497-38-1
`497-38-1
`
`464-49-3
`464-49-3
`
`502-42-1
`502-42-1
`
`108-94-1
`108-94-1
`
`529-34-0
`529-34-0
`
`1624-62-0
`1624-62-0
`
`897-06-3
`897-06-3
`
`566-88-1
`566-88-1
`
`1.5
`1.5
`17
`17
`
`17
`17
`2.5
`2.5
`
`70
`70
`17
`17
`1.5
`1.5
`
`1.5
`1.5
`
`1.5
`1.5
`
`21
`21
`
`40
`40
`
`17
`17
`
`2
`2
`
`35
`35
`20
`20
`
`20
`20
`20
`20
`
`45
`45
`45
`45
`20
`20
`
`20
`20
`
`20
`20
`
`20
`20
`
`45
`45
`
`20
`20
`
`Lit. data
`Lit. data
`
`-180
`-180
`
`166-17524
`166-17524
`
`48-51
`48-51
`(endo)
`(endo)
`
`5125
`5125
`
`135-148
`135-148
`
`26
`26
`
`93
`93
`84
`84
`
`73
`73
`62
`62
`
`80
`80
`73
`73
`<5
`<5
`
`85-86
`85-86
`(10 mm)33
`(10 mm)33
`67 (10 mm)33
`67 (10 mm)33
`
`80
`80
`
`80
`80
`
`85-86
`85-86
`(10 mm)
`(IOmm)
`62-67
`62-67
`(12 mm)
`(12mm)
`47 Chromatg 109-111
`47 Chromat g
`109-111
`(1.5 mm)34
`(1.5 mm)34
`
`76
`76
`
`h
`h
`
`69
`69
`
`205-207
`205-207
`
`207-2106b
`207-2106b
`
`20
`20
`
`47
`47
`
`159-164
`159-164
`
`k
`k
`
`J. Org. Chem., Vol. 42, No. 19,1977 3115
`J. Org. Chem., Vol. 42, No. 19,1977 3115
`Table I. Nitriles Synthesized from Ketones and Tosylmethyl Isocyanide (TosMIC) According to Equation 1
`Table I. Nitriles Synthesized from Ketones and Tosylmethyl Isocyanide (TosMIC) According to Equation 1
`Registry TosMIC, Base (equiv) Time, Temp,C Isolated Bp or
`Substrateo and
`Substrate a and
`Registry TosMIC, Base (equiv) Time, Temp,e Isolated Bp or
`product
`no.
`equiv
`and solventb
`h
`"C
`yield,% mp, "C
`yield, % mp,oC
`and solvent b
`product
`no.
`equiv
`h
`°C
`Adamantanone*
`700-58-3
`Adamantanone*
`700-58-3
`2-Cyanoadamantane (%a)
`t-BuOK (2.4),
`2-Cyanoadamantane (2a)
`t-BuOK (2.4),
`DME
`DME
`2-Cyanoadamantane (2a)
`t-BuOK (3.5),
`2-Cyanoadamantane (2a)
`t-BuOK (3.5),
`MezSO
`Me2S0
`2-Norbornanone*
`2-Norbornanone*
`2-Cyanonorbornane (2b)
`t-BuOK (3.5),
`2-Cyanonorbornane (2b)d
`t-BuOK (3.5),
`MezSO
`Me2S0
`2-Cyanonorbornane (2b) e
`EtONa (1.3),
`2-Cyanonorbornane (2b)e
`EtONa (1.3),
`DME
`DME
`(+)-Camphor*
`(+ )-Camphor*
`2-Cyanocamphane (2c)f
`t-BuOK (7),
`2-Cyanocamphane (2c)f
`t-BuOK (7),
`Me2SO
`Me2SO
`2-Cyanocamphane (2c)
`t-BuOK (7),
`2-Cyanocamphane (2c)
`t-BuOK (7),
`H M P T
`HMPT
`t-BuOK (2),
`2-Cyanocamphane (2c)
`2-Cyanocamphane (2c)
`t-BuOK (2),
`DME
`DME
`C ycloheptanone
`Cycloheptanone
`Cyanocycloheptane (2d)
`t-BuOK (2),
`Cyanocycloheptane (2d)
`t-BuOK (2),
`DME
`DME
`Cyclohexanone
`Cyclohexanone
`Cyanocyclohexane (%e)
`t-BuOK (2),
`Cyanocyclohexane (2e)
`t-BuOK (2),
`DME
`DME
`a-Tetralone
`a-Tetralone
`l-Cyano-1,2,3,4-tetrahydronaph-
`t-BuOK (5),
`l-Cyano-l,2,3,4-tetrahydronaph-
`t-BuOK (5),
`thalene (2f)
`H M P T
`thalene (2f)
`HMPT
`P,P-Dimethyl-a-tetralone*
`2977-45-9
`{3,{3-Dimethyl-a-tetralone*
`2977-45-9
`l-Cyano-2,2-dimethyl-1,2,3,4-tet-
`t-BuOK (7),
`l-Cyano-2,2-dimethyl-l,2,3,4-tet-
`t-BuOK (7),
`rahydronaphthalene (2g)
`H M P T
`rahydronaphthalene (2g)
`HMPT
`Estrone 3-methyl ether
`Estrone 3-methyl ether
`17P-Cyano-1,3,5( 10)-estratrien-
`t-BuOK (3.5),
`17{3-Cyano-l,3,5(10)-estratrien-
`t-BuOK (3.5),
`3-01 methyl ether (2h)
`MezSO
`3-01 methyl ether (2h)
`Me2S0
`Androsta-l,4-diene-3,17-dione*
`Androsta-l,4-diene-3,17 -dione*
`EtONa (1.2),
`17-Cyanoandrosta. 1,4-dien-3-
`EtONa (1.2),
`17 -Cyanoandrosta .. l,4-dien-3-
`one (2i)'
`DME
`one (2i)i
`DME
`5a-Cholestan-3-one
`5a-Cholestan-3-one
`3-Cyano-5a-cholestane (2j)~'
`t-BuOK (2.5),
`3-Cyano-5a-cholestane (2j)i
`t-BuOK (2.5),
`DME
`DME
`5P-Cholestan-3-one
`5{3-Cholestan-3-one
`3-Cyano-5P-cholestane (2k)'
`t-BuOK (3),
`3-Cyano-5{3-cholestane (2k) I
`t-BuOK (3),
`DME
`DME
`Benzophenone*
`Benzophenone*
`Diphenylacetonitrile (21)
`t-BuOK (3.5),
`Diphenylacetonitrile (21)
`t-BuOK (3.5),
`MezSO
`Me2S0
`Acetophenone
`Acetophenone
`2-Phenylpropionitrile (2m)
`t-BuOK (2),
`2-Phenylpropionitrile (2m)
`t-BuOK (2),
`DME
`DME
`p -Bromoacetophenone*
`p -Bromoacetophenone*
`2-p -Bromophenylpropionitrile
`t-BuOK (2),
`2- p -Bromophenylpropionitrile
`t-BuOK (2),
`( 2 4
`DME
`(2n)
`DME
`Di-n-propyl ketone
`Di-n-propyl ketone
`4-Cyanoheptane (20)
`t-BuOK (2.5),
`4-Cyanoheptane (20)
`t-BuOK (2.5),
`DME
`DME
`Diisopropyl ketone
`Diisopropyl ketone
`3-Cyano-2,4-dimethylpentane (2p)
`t-BuOK (7),
`3-Cyano-2,4-dimethylpentane (2p)
`t-BuOK (7),
`H M P T
`HMPT
`3-Cyano-2,4-dimethylpentane (2p)
`t-BuOK (2),
`3-Cyano-2,4-dimethylpentane (2p)
`t-BuOK (2),
`DME
`DME
`tert -Butyl methyl ketonep
`tert-Butyl methyl ketone P
`2-Cyano-3,3-dimethylbutane (2q)
`t-BuOK (3.5),
`2-Cyano-3,3-dimethylbutane (2q)
`t-BuOK (3.5),
`Me2SO
`Me2S0
`2-Cyano-3,3-dimethylbutane (2q)
`t-BuOK (2),
`2-Cyano-3,3-dimethylbutane (2q)
`t-BuOK (2),
`DME
`DME
`815-24-0
`Di-tert- butyl ketone
`Di-tert- butyl ketone
`815-24-0
`3-Cyano-2,2,4,4-tetramethyl- 62796-07-0
`67-78
`t-BuOK (7),
`3-Cyano-2,2,4,4-tetramethyl-
`67-78
`62796-07-0
`t-BuOK (7),
`pentane
`H M P T
`(10 mm)40
`(10 mm)40
`pentane
`HMPT
`Substrates are marked with an asterisk when further details are given in the Experimental Section. Alcohol (1-2 equiv) was
`a Substrates are marked with an asterisk when further details are given in the Experimental Section. b Alcohol (1-2 equiv) was
`added in all cases (see text and Experimental Section). All reactions were started around 0 "C, and usually after 15 min continued
`added in all cases (see text and Experimental Section). e All reactions were started around 0 °C, and usually after 15 min continued
`at the temperature indicated. Endo-exo = 4:3. e Endo-exo = 1:l. f Endo-exo = 4:l or 1:4. g Hydrolyzed (NaOH, 30% Hz02) to amide,
`at the temperature indicated. d End<Hlxo = 4:3. e End<Hlxo = 1:1. f End<Hlxo = 4:1 or 1:4. g Hydrolyzed (NaOH, 30% H20 2) to amide,
`mp 163-165 "C (lit.34 165-167 "C). See Experimental Section. i a:@ = 1:l (see Table 11, Experimental Section). 1a:P = 0.7 (Table
`mp 163-165 °C (lit.34 165-167 °C). h See Experimental Section. i a:{3 = 1:1 (see Table II, Experimental Section). ia:{3 = 0.7 (Table
`11). Lit.35 3a-C=N, mp 166-168 "C; 3j3-C=N, m p 142-144 "C. la:@ = 0.9 (Table 11). m Short-path distilled, bath temperature
`11). k Lit.35 3a-C==N, mp 166-168 °C; 3{3-C==N, mp 142-144 °C. la:{3 = 0.9 (Table II). m Short-path distilled, bath temperature
`64 "C (12 mm). As rn, 65 "C (13 mm). 65% of ketone recovered. p Pinacolone.
`64°C (12 mm). n As m, 65°C (13 mm). 065% of ketone recovered. P Pinacolone.
`
`74-78
`74-78
`(2 mm)
`(2mm)
`112-116
`112-116
`(1 mm)
`(Imm)
`74 m
`74 m
`
`601-53-6
`601-53-6
`
`119-61 -9
`119-61-9
`
`98-86-2
`98-86-2
`
`99-90-1
`99-90-1
`
`123-19-3
`123-19-3
`
`565-80-0
`565-80-0
`
`75-97-8
`75-97-8
`
`1.3
`1.3
`
`1.5
`1.5
`
`1.3
`1.3
`
`1.0
`1.0
`
`1.0
`1.0
`
`1.2
`1.2
`
`3
`3
`1.0
`1.0
`
`1.3
`1.3
`1.0
`1.0
`
`3
`3
`
`5
`5
`
`5
`5
`
`17
`17
`
`1.5
`1.5
`
`1.5
`1.5
`
`1.5
`1.5
`
`70
`70
`1.5
`1.5
`
`17
`17
`1.5
`1.5
`
`170
`170
`
`20
`20
`
`20
`20
`
`20
`20
`
`20
`20
`
`20
`20
`
`20
`20
`
`45
`45
`20
`20
`
`20
`20
`20
`20
`
`45
`45
`
`68
`68
`
`79
`79
`
`65
`65
`(5
`<5
`
`70
`70
`36
`36
`
`0
`0
`
`85
`85
`
`53
`53
`
`114-121
`114-121
`
`57-72
`57-72
`
`36
`36
`
`69
`69
`
`67-71
`67-71
`
`7430
`7430
`
`100 (8 mm)37
`100 (8 mm)37
`
`183-18433
`183-18433
`
`n2lD
`n21D
`1.4177n
`1.4177 n
`
`170-171
`n23D 1.4158
`n 23D 1.4158
`
`fS
`} 151-152 r
`nAEmmj
`nZ5D 1.4092 }
`
`40-42
`40-42
`(15mm)
`n 25D
`1.4099
`1.4099
`
`151-152
`
`39
`
`n 25D 1.4092
`
`NPC02230721
`
`NOVARTIS EXHIBIT 2124
`Par v Novartis, IPR 2016-00084
`Page 2 of 5
`
`

`
`3116 J. Org. Chem., 'Vol. 42, No. 19, 1977
`3116 J. Org. Chem., Vol. 42, No. 19, 1977
`
`Scheme I. An important aspect of the proposed mechanism
`Scheme I. An important aspect of the proposed mechanism
`is the ring opening of 7 to 8; beyond that stage the mechanism
`is the ring opening of 7 to 8; beyond that stage the mechanism
`is more speculative. The following observations are consistent
`is more speculative. The following observations are consistent
`with Scheme I: (1) A I4C label in the methylene group of 1
`with Scheme I: (1) A 14C label in the methylene group of 1
`appears integrally in the nitrile 2a (cf. eq 2). (2) In addition
`appears integrally in the nitrile 2a (cf. eq 2). (2) In addition
`to 2a, ethyl formate (1 1) has been detected qualitatively (RO-
`to 2a, ethyl formate (11) has been detected qualitatively (RO(cid:173)
`= EtO-1, which accouiits for the fate of the isocyano carbon
`= EtO-), which accounts for the fate of the isocyano carbon
`of 1. (3) The reaction can be interrupted at the stage of 7 as
`of 1. (3) The reaction can be interrupted at the stage of 7 as
`well as 8 to give 13 or 14. (4) Under the conditions of reaction
`well as 8 to give 13 or 1<l. (4) Under the conditions of reaction
`1 both 13 and 14 can be converted to 2, and further also 13 to
`14 (R' - R2 = pentamethylene). (5) Rapid H-D exchange is
`1 both 13 and 14 can be converted to 2, and further also 13 to
`14 (RI - R2 = pentamethylene). (5) Rapid H-D exchange is
`observed in 13 (R' = Et2 = Me) at C(4) only (with K2C03 in
`observed in 13 (RI = H2 = Me) at C(4) only (with K2C03 in
`CD3OD-DME). For further details concerning these argu-
`CD30D-DME). For further details concerning these argu(cid:173)
`ments and the (as yet unsolved) question of a one-step or
`ments and the (as yet unsolved) question of a one-step or
`two-step cycloaddition of 3 to 6, we refer to previous dis-
`two-step cycloaddition of 3 to 6, we refer to previous dis(cid:173)
`
`c u s s i o n ~ ~ ~ , ~ , ~ , ~ and the Experimental Section of the present
`cussions2a.3.8.11 and the Experimental Section of the present
`paper.
`paper.
`An alternative mechanism involving a base-catalyzed
`An alternative mechanism involving a base-catalyzed
`condensation of 1 and a ketone to give 17 (Scheme I), followed
`condensation of 1 and a. ketone to give 17 (Scheme 1), followed
`by addition of water to 14 and eventually formation of 2 (and
`by addition of water to 14 and eventually formation of 2 (and
`131, is highly unlikely. Compounds 17 have not been detected,
`13), is highly unlikely. Compounds 17 have not been detected,
`even though they are expected not to be hydrated to 14 under
`even though they are expected not to be hydrated to 14 under
`the conditions of the reaction.l*
`the conditions of the rl~action.12
`In the second part of Scheme I attack of a nucleophile at the
`In the second part of Scheme I attack of a nucleophile at the
`carbonyl of 9 or 15 is assumed.3a38b The postulated interme-
`carbonyl of 9 or 15 is assumed. 3a.8b The postulated interme(cid:173)
`diates 9 and 15 both possess a second carbon center that might
`diates 9 and 15 both possess a second carbon center that might
`well be more electrophilic than the carbonyl. (This may be true
`well be more electrophilic than the carbonyl. (This may be true
`of 15; also, nucleophilic
`in particular for the N==C-Tos
`in particular for the N==C-Tos groupI3 of 15; also, nucleophilic
`reactions of ketenimines are well known14.) However, initial
`reactions of ketenimines are well knownI4.) However, initial
`nucleophilic attack at these other centers does not necessarily
`nucleophilic attack at these other centers does not necessarily
`preclude the formation of 2. In addition to the nucleophiles
`preclude the formation of 2. In addition to the nucleophiles
`RO- (R = Me, Et, or t-Bu) reacting with 9 or 15, TosMIC
`RO- (R = Me, Et, or t-Bu) reacting with 9 or 15, TosMIC
`anion (3) may act as such in some cases.15
`anion (3) may act as such in some cases. 15
`Occasionally, reaction 1, when carried out in MezSO or
`Occasionally, reaction 1, when carried out in Me2S0 or
`HMPT, was accompanied by evolution of gas. For the reaction
`HMPT, was accompanied by evolution of gas. For the reaction
`of 1 with adamantanone in HMPT the gas was shown spec-
`of 1 with adamantanone in HMPT the gas was shown spec(cid:173)
`troscopically (MS and IR) to be carbon monoxide. This re-
`troscopically (MS and IR) to be carbon monoxide. This re(cid:173)
`action gave 73% of 2 - l i d C ~ N and 44% of CO (determined
`action gave 73% of 2-AdC=N and 44% of CO (determined
`gravimetrically and volumetrically after CuO oxidation to
`gravimetrically and volumetrically after CuO oxidation to
`Con). Carbon monoxide might be formed by decomposition
`CO2). Carbon monoxide might be formed by decomposition
`of the hypothetical mixed anhydride p-CH3C&S(O)OCHO
`of the hypothetical mixed anhydride p-CH3C6H4S(O)OCHO
`(or the isomeric TosCI-IO), which could result from nucleo-
`(or the isomeric TosCHO), which could result from nucleo(cid:173)
`philic action of Tos-, possibly through 19. Alternatively, CO
`philic action of Tos-, possibly through 19. Alternatively, CO
`could arise from decomposition of tert-butyl formate (1 1, R
`could arise from decomposition of tert-butyl formate (11, R
`= t-Bu) in the medium used here.16 These assumptions at
`= t-Bu) in the medium used here.1 6 These assumptions at
`least account for the fact that the CO was not radiolabeled
`least account for the fact that the CO was not radiolabeled
`when the reaction was performed with Tos14CH2N=C (eq
`when the reaction was performed with TOSI4CH2N=C (eq
`2).
`2).
`
`( 2)
`
`2 8
`1
`Competing Reactions. 4-Tosyl-2-oxazolines (13, and 7,
`Competing Reactions. 4-Tosyl-2-oxazolines (13, and 7,
`Scheme I) play a crucial role in the reaction of TosMIC with
`Scheme I) playa crucial role in the reaction of TosMIC with
`ketones (and aldehydes).17 Compounds 13 can be converted
`ketones (and aldehydes).17 Compounds 13 can be converted
`not only to nitriles 2 but also to tosylalkenylformamides 14
`not only to nitriles 2 but also to tosylalkenylformamides 14
`as discussed above. With EtONa or EtOTl in EtOH (or
`as discussed above. With EtONa or EtOTl in EtOH (or
`EtOH-DME) 13 will give 4-ethoxy-2-oxazolines18 18, which
`EtOH-DME) 13 will give 4-ethoxy-2-oxazolinesI8 18, which
`are convenient precursors for the synthesis of a-hydroxy al-
`are convenient precursors for the synthesis of a-hydroxy al(cid:173)
`
`d e h y d e ~ . ~ ~ By a proper choice of the conditions of the reaction
`dehydes. 19 By a proper choice of the conditions of the reaction
`of TosMIC with ketones either of the products 2,13,14, or 18
`of TosMIC with ketones either of the products 2, 13, 14, or 18
`can be obtained exclusively; therefore special attention should
`can be obtained exclusively; therefore special attention should
`be given to these conditions.
`be given to these conditions.
`The tosyloxazolines 13 are obtained in protic solvents using
`The tosyloxazolines 13 are obtained in protic solvents using
`weak bases (e.g., KzCO:~ in MeOH,2bs20 or NaCN in EtOH8a).
`weak bases (e.g., K2COS in MeOH,2b.20 or NaCN in EtOH8a).
`In an aprotic medium (t-BuOK in THF) at -10 "C the reac-
`In an aprotic medium (t-BuOK in THF) at -10 °C the reac(cid:173)
`tion goes one step further to give 8 (14),8 but at temperatures
`tion goes one step further to give 8 (14),8 but at temperatures
`of 20-45 OC the reaction slowly continues to go all the way to
`of 20-45 ° C the reaction slowly continues to go all the way to
`nitriles 2. This last process is speeded up considerably by
`nitriles 2. This last process is speeded up considerably by
`addition of 1-2 equiv of an alcohol (t-BuOH or better MeOH
`addition of 1-2 equiv of an alcohol (t-BuOH or better MeOH
`
`Oldenziel, van Leusen, and van Leusen
`Oldenziel, van Leusen, and van Leusen
`
`the reaction step 9 -. 12 (or 15 - 2).
`t,$
`
`1 0 s
`
`+
`
`ather p r o d u c t s
`other products
`
`( 3 1
`( 3)
`
`or EtOH) to the aprotic solvent (DME).21 However, the ad-
`or EtOH) to the aprotic solvent (DME).2I However, the ad(cid:173)
`dition of more alcohol should be avoided, otherwise 4-alk-
`dition of more alcohol should be avoided, otherwise 4-alk(cid:173)
`oxy-2-oxazolines (18) will be formed as well. The role of the
`. oxy-2-oxazolines (18) will be formed as well. The role of the
`added alcohols is explained (in part) by their contribution to
`added alcohols is explained (in part) by their contribution to
`the reaction step 9 -- 12 (or 15 -- 2).
`TO\I[)
`
`1
`
`-
`
`' 2 ' H I
`
`
`2o
`I
`~
`20
`cu2roS
`CH 2Tos
`TosMIC itself is known to undergo a base-catalyzed cy-
`TosMIC itself is known to undergo a hase-catalyzed cy(cid:173)
`clodimerization to give inter alia imidazole 20 (eq 3).2a This
`clodimerization to give inter alia imidazole 20 (eq 3).2a This
`explains the low yields of nitriles 2 obtained previously with
`explains the low yields of nitriles 2 obtained previously with
`the less reactive (usually sterically hindered) ketones (Table
`the less reactive (usually sterically hindered) ketones (Table
`I, e.g., 2c,p,q, reactions in DME). The cyclodimerization of
`I, e.g., 2c,p,q, reactions in DME). The cyclodimerization of
`TosMIC, visualized as a reaction of TosMIC anion (3) with
`TosMIC, visualized as a reaction of TosMIC anion (3) with
`
`TOSMIC,~~ can be suppressed effectively by working in MezSO
`TosMIC,2a can be suppressed effectively by working in Me2S0
`(or HMPT) with 2 equiv of t-BuOK with respect to TosMIC.
`(or HMPT) with 2 equiv of t-BuOK with respect to TosMIC.
`Thus, TosMIC will be transformed completely into its anion
`Thus, TosMIC will be transformed completely into its anion
`3.22 These conditions then allow reaction 1 to be carried out
`3.22 These conditions then allow reaction 1 to be carried out
`at 45 OC for prolonged periods to achieve a high yield con-
`at 45°C for prolonged periods to achieve a high yield con(cid:173)
`version of the less reactive ketones without appreciable loss
`version of the less reactive ketones without appreciable loss
`of TosMIC.
`of TosMIC.
`Stereochemistry. The endo-exo ratio of 2-cyanonorbor-
`Stereochemistry, The endo-exo ratio of 2-cyanonorbor(cid:173)
`nane (2b) is nearly 1:l (by GLC and NMR). This ratio may
`nane (2b) is nearly 1:1 (by GLC and NMR). This ratio may
`well reflect thermodynamic control through 12 (Scheme I),
`well reflect thermodynamic control through 12 (Scheme 1),
`but most certainly is not the result of indiscriminatory attack
`but most certainly is not the result of indiscriminatory attack
`of TosMIC anion (3) on norbornanone from both the exo and
`of TosMIC anion (3) on norbornanone from both the exo and
`endo side. In fact, we have established previously that the
`endo side. In fact, we have established previously that the
`large TosMIC anion attacks norbornanone only from the exo
`large TosMIC anion attacks norbornanone only from the exo
`side, as expected, to give 13b (4). This was concluded from the
`side, as expected, to give 13b (4). This was concluded from the
`stereochemistry of the derivative 18b and its subsequent hy-
`stereochemistry of the derivative 18b and its subsequent hy(cid:173)
`drolysis to 2-end0 -hydroxynorbornane-2-exo-carboxaldehyde
`drolysis to 2-endo-hydroxynorbornane-2-exo-carboxaldehyde
`(2 1) exclusively. l 8 ~ 9
`(21) exclusively.18,19
`x
`
`tlJ::j
`
`J:jCHO
`OH
`
`JyC=N
`
`(4 )
`
`21
`21
`
`2c
`13b i.701
`13b x= TOS
`2c
`18b X;EID
`1ab X= EtC
`Camphor with its hindered exo side required accordingly
`Camphor with its hindered exo side required accordingly
`a rather long reaction time to provide 80% of 2-cyanocam-
`a rather long reaction time to provide 80% of 2-cyanocam(cid:173)
`phane (2c, a mixture of unassigned endo and exo isomers, ratio
`phane (2c, a mixture of unassigned endo and exo isomers, ratio
`of 4:l). Likewise, mixtures of a- and P-cyanosteroids were
`of 4:1). Likewise, mixtures of a- and iJ-cyanosteroids were
`obtained for 2i-k, although from estrone 3-methyl ether only
`obtained for 2i-k, although from estrone 3-methyl ether only
`the 17P-cyano compound (2h) was found (after crystalliza-
`the 17iJ-cyano compound (2h) was found (after crystalliza(cid:173)
`tion6b). The ratio of the epimers 2i-k was determined by lH
`tion6b). The ratio of the epimers 2i-k was determined by IH
`NMR (Table 11, in Experimental Section).
`NMR (Table II, in Experimental Section).
`Experimental Section
`Experimental Section
`General remarks are as in ref 2a. Carbon-14 radioactivity was
`General remarks are as in ref 2a. Carbon-14 radioactivity was
`measured with a Nuclear Chicago Unilux I11 Scintillation Counter.
`measured with a Nuclear Chicago Unilux III Scintillation Counter,
`Starting Materials. Commercially available ketones were used
`Starting Materials. Commercially available ketones were used
`as such. Estrone 3-methyl ether and 5a-cholestan-3-one were pur-
`as such. Estrone 3-methyl ether and 5a-cholestan-3-one were pur(cid:173)
`chased from Steraloids Inc., Pawling, N.Y. Samples of androsta-
`chased from Steraloids Inc" Pawling, N.Y. Samples of androsta-
`1,4-dien-3-one and 58-cholestan-3-one were donated by Gist-Brocades
`1,4-dien-3-one and 5{3-cholestan-3-one were donated by Gist-Brocades
`N.V., Delft, Holland. TosMIC (1) was prepared as described in ref 2a
`N.V., Delft, Holland. TosMIC (1) was prepared as described in ref 2a
`or purchased from Ofichem, Gieten, Holland. 14C-Labeled formal-
`or purchased from Ofichem, Gieten, Holland, 14C-Labeled formal(cid:173)
`dehyde was obtained from NEN Chemicals, Frankfurt, Germany.
`dehyde was obtained from NEN Chemicals, Frankfurt, Germany.
`Synthesis of Nitriles from Ketones and TosMIC (1). The fol-
`Synthesis of Nitriles from Ketones and TosMIC (1). The fol(cid:173)
`lowing selected procedures are illustrative. Table I summarizes the
`lowing selected procedures are illustrative. Table I summarizes the
`conditions used in the reactions not described in detail.
`conditions used in the reactions not described in detail.
`2-Cyanoadamantane (2a). Solid t-BuOK (28.0 g, 0.24 mol, 95%,
`2-Cyanoadamantane (2a). Solid t-BuOK (28.0 g, 0.24 mol, 95%,
`Merck) was added portionwise to a stirred and cooled solution of
`Merck) was added portionwise to a stirred and cooled solution of
`adamantanone (15.0 g, 0.10 mol) and TosMIC (25.0 g, 0.13 mol) in a
`adamantanone (15.0 g, 0.10 mol) and TosMIC (25.0 g, 0.13 mol) in a
`mixture of 350 mL of DME and 10 mL of absolute EtOH while
`mixture of 350 mL of DME and 10 mL of absolute EtOH while
`keeping the temperature between 5 and 10 "C. Stirring was continued,
`keeping the temperature between 5 and 10 °C. Stirring was continued,
`first for 30 min without cooling, then for 30 min at 35-40 "C. The
`first for 30 min without cooling, then for 30 min at 35-40 °C. The
`suspension thus obtained was cooled to room temperature with stir-
`suspension thus obtained was cooled to room temperature with stir(cid:173)
`ring. The precipitate (TosK) was removed and extracted with DME.
`ring. The precipitate (TosK) was removed and extracted with DME.
`The combined DME solutions were concentrated to 25-35 mL and
`The combined DME solutions were concentrated to 25-35 mL and
`purified by flushing the concentrate over a 5-cm thick layer of alumina
`purified by flushing the concentrate over a 5-cm thick layer of alumina
`(ca. 200 g, on a Buchner funnel) with 250 mL of petroleum ether (bp
`(ca. 200 g, on a Buchn