2-Chloro-2-methylpropanal N-Isopropylimine1

(R = i-Pr, R1 = R2 = Me, X = Cl)

[63364-30-7]  · C7H14ClN  · 2-Chloro-2-methylpropanal N-Isopropylimine  · (MW 147.64) (R = i-Pr, R1 = R2 = Me, X = Br)

[30453-45-3]  · C7H14BrN  · 2-Bromo-2-methylpropanal N-Isopropylimine  · (MW 192.12) (R = t-Bu, R1 = R2 = Me, X = Cl)

[56990-50-2]  · C8H16ClN  · 2-Chloro-2-methylpropanal N-t-Butylimine  · (MW 161.67) (R = Cy, R1 = R2 = Me, X = Cl)

[63364-31-8]  · C10H18ClN  · 2-Chloro-2-methylpropanal N-Cyclohexylimine  · (MW 187.70) (R = Bn, R1 = R2 = Me, X = Cl)

[63547-67-1]  · C11H14ClN  · 2-Chloro-2-methylpropanal N-Benzylimine  · (MW 195.68) (R = t-Bu, R1 = Et, R2 = Me, X = Cl)

[63364-32-9]  · C9H18ClN  · 2-Chloro-2-methylbutanal N-t-Butylimine  · (MW 175.69) (R = t-Bu, R1 = R2 = Et, X = Cl)

[63364-33-0]  · C10H20ClN  · 2-Chloro-2-ethylbutanal N-t-Butylimine  · (MW 189.72) (R = Cy, R1 = R2 = Et, X = Cl)

[63364-34-1]  · C12H22ClN  · 2-Chloro-2-ethylbutanal N-Cyclohexylimine  · (MW 215.76) (R = t-Bu, R1R2 = (CH2)5, X = Cl)

[63364-35-2]  · C11H20ClN  · 1-Chlorocyclohexanecarbaldehyde N-t-Butylimine  · (MW 201.73) (R = Cy, R1R2 = (CH2)5, X = Cl)

[63364-36-3]  · C13H22ClN  · 1-Chlorocyclohexanecarbaldehyde N-Cyclohexylimine  · (MW 227.77) (R = t-Bu, R1 = Me, R2 = Ph, X = Cl)

[63364-37-4]  · C13H18ClN  · 2-Chloro-2-phenylpropanal N-t-Butylimine  · (MW 223.73)

(synthesis of 1-aza-1,3-dienes,2 a-amino acetals,2,3 allylic amines,4 a,b-unsaturated aldehydes,5 a-alkoxy aldimines,6,7 a-t-butyl aldimines,7 a-sulfenylated aldimines,8 1,4-diimines,9 a-cyano enamines,10 b-chloro amines,11 aromatic ketones,12 aziridines,13 2-imidazolidinethiones,14 2-imidazolidinones,15 a-aryl aldehydes,16 2-aza-1,3-dienes;17,18 reductive dechlorination of a-halo aldehydes18)

Alternate Name: N-isopropyl-a-chloroisobutyraldimine.

Physical Data: 2-chloro-2-methylpropanal N-isopropylimine (R = i-Pr, R1 = R2 = Me, X = Cl): bp 47-49 °C/24 mmHg; 2-bromo-2-methylpropanal N-isopropylimine (R = i-Pr, R1 = R2 = Me, X = Br): bp 58-61 °C/14 mmHg; 2-chloro-2-methylpropanal N-t-butylimine (R = t-Bu, R1 = R2 = Me, X = Cl): bp 50-52°/30 mmHg.

Solubility: sol most organic solvents; not compatible with aqueous acidic solutions; basic aqueous solutions cause a slow hydrolysis.

Form Supplied in: 2-chloro-2-methylpropanal N-isopropyl- and N-t-butylimines are commercially available as colorless liquids.

Analysis of Reagent Purity: GC, 1H NMR.

Preparative Methods: aldimines, which are easily accessible from aldehydes and primary amines and which may be prepared in situ, react smoothly with N-Chlorosuccinimide in CCl4 at room temperature to give a-chloro aldimines (eq 1).2 Similarly, a-bromo7 and the labile a-iodo aldimines19 are accessible by reaction of aldimines with N-Bromosuccinimide and N-Iodosuccinimide, respectively (eq 2). Alternatively, the condensation of a-chloro and a-bromo aldehydes with primary amines in the presence of magnesium sulfate,18 Titanium(IV) Chloride,20 or Molecular Sieves28 as dehydrating agent affords the corresponding a-halo aldimines (eq 3).

Handling, Storage, and Precautions: a-chloro aldimines are relatively stable bifunctional reagents which are preferably kept in the refrigerator, well-protected from moisture. a-Bromo aldimines are more labile and only readily accessible with N-t-butyl substituents. a-Iodo aldimines are best freshly prepared and used immediately. The use of a-halo imines in the presence of water is incompatible (except for a fast cyanation reaction; see below). Use in a fume hood.

a-Halo aldimines are protected or modified a-halo aldehydes, but their chemistry is quite different from that of a-halo aldehydes.1,21,22 They are suitable building blocks for a variety of heterocycles and have a high synthetic potential for functional group transformations. Comparable reagents are b-haloenamines.23

Synthesis of 1-Aza-1,3-dienes, a-Amino Acetals, Allylic Amines, and a,b-Unsaturated Aldehydes.

a-Chloroisobutyraldimines react with Sodium Methoxide in methanol to give 1-aza-1,3-dienes and rearranged a-amino acetals (via a 2-methoxyaziridine intermediate) (eq 4).2 Selective formation of 1-aza-1,3-dienes is obtained with Potassium t-Butoxide (eq 5),4 while complete rearrangement into a-amino acetals is achieved by reaction with alcohols without added base (eq 6).2,3 The a-amino acetals serve as precursors for a-(N-alkylamino) aldehydes (eq 6).3 Higher analogs, having at least one a-methyl replaced by ethyl or higher alkyl, do not rearrange but are dehydrochlorinated on treatment with sodium methoxide or potassium t-butoxide (eq 7).2,4 The resulting 1-aza-1,3-dienes are easily converted into allylic amines (eq 8)4 and a,b-unsaturated aldehydes (eq 9).5

Synthesis of a-Alkoxy Aldimines, a-t-Butylaldimines, a-Sulfenylated Aldimines, and 1,4-Diimines.

While the reaction of a-bromo aldimines with alcohols produces rearranged a-amino acetals, the silver-induced alcoholysis affords a-alkoxy aldimines (eq 10).6 In addition to oxygen nucleophiles, the a-halogen in a-chloro aldimines can be displaced by sulfur or carbon nucleophiles, e.g. thiolates (eq 12)7,8 or t-Butyllithium (eq 11).7 Coupling of a-bromo aldimines to give 1,4-diimines via captodative stabilized radical intermediates is accomplished with Lithium Diisopropylamide (eq 13).9 A similar coupling of a-chloro aldimines by Methylcopper to give 1,4-diimines has been reported.12

Synthesis of a-Cyano Enamines,11 Acylation of Arenes under Non-Friedel-Crafts Conditions, and Synthesis of b-Chloro Amines.

Cyanation of a-chloro aldimines leads to a-cyano enamines, which are potential building blocks (eq 14).10 The conversion of a-chloro aldimines with Phenyllithium into alkyl phenyl ketimines and, after hydrolysis, into alkyl phenyl ketones constitutes a mild acylation of arenes under non-Friedel-Crafts conditions (eq 15).12 Electrophilic reduction of a-chloro aldimines by the Borane-Dimethyl Sulfide complex is a route to sterically hindered b-chloro amines (eq 16).11

Synthesis of Aziridines, 2-Imidazolidinethiones, and 2-Imidazolidinones.

Nucleophilic reduction of a-chloro aldimines with Lithium Aluminum Hydride in ether gives ready access to aziridines (eq 17).13 Ambident nucleophiles, such as Potassium Thiocyanate and potassium cyanate, react with a-chloro aldimines in methanol to produce 4-methoxy-2-imidazolidinethiones and 4-methoxy-2-imidazolidinones, respectively (eqs 18 and 19).14,15 The latter heterocycles can be cleanly converted into the corresponding demethoxylated five-membered aza heterocycles,14,15 4-imidazolin-2-ones (eq 19),24 or triimidazohexahydro[1,3,5]triazines (eq 18).25

a-Arylation of Aldehydes, Synthesis of 2-Aza-1,3-dienes, Reductive Dehalogenation of a-Halo Aldehydes, and Synthesis of 3-(1-Chloroalkyl)oxaziridines.

The Friedel-Crafts-type arylation of a-chloro aldimines in the presence of Aluminum Chloride gives rise to a-aryl aldimines, which are hydrolyzed to a-aryl aldehydes (eq 20).16 a-Substituents which stabilize the intermediate a-imidoylcarbenium ions, e.g. phenyl substituents, greatly enhance the yields of this reaction.16,26 Higher alkyl analogs give lower yields of a-arylation products due to competing 1,2-dehydrochlorination to give a,b-unsaturated aldimines. When toluene is used as the arene, the ortho:para regiochemistry is about 7:93.26 This reaction proceeds also with heteroaromatic compounds such as furan (eq 21).26 The reductive conversion of a-halo aldehydes to aldehydes is not easy to accomplish due to the sensitivity of the carbonyl function for reductive processes. However, this conversion can be performed via N-benzyl a-halo aldimines, which undergo 1,4-dehydrohalogenation to give 2-aza-1,3-dienes (eq 22).17,18 The latter heterodienes are easily hydrolyzed to aliphatic and aromatic aldehydes (eq 22).18

Oxidation of a-halo aldimines with m-Chloroperbenzoic Acid produces stable 3-(1-chloroalkyl)oxaziridines (eq 23), which undergo rearrangement with Methyllithium to a-(N-alkylamino) aldehydes (eq 24) and which oxygenate phenyllithium to phenol (eq 24).27

Related Reagents.

Acetaldehyde N-t-Butylimine; 2-(t-Butylamino)-3-methyl-2-butenenitrile; Chloroacetaldehyde; 1-(N,N-Dimethylamino)-2-methyl-1-propene; a-Methacrolein N-t-Butylimine; Methacrolein Dimethylhydrazone; Propionaldehyde t-Butylimine.

1. (a) De Kimpe, N.; Verhé, R. The Chemistry of a-Haloketones, a-Haloaldehydes and a-Haloimines; Wiley: Chichester, 1988. (b) De Kimpe, N.; Verhé, R. In The Chemistry of Functional Groups, Supplement D: The Chemistry of Halides, Pseudo Halides and Azides; Wiley: Chichester, 1983; Chapter 13, p 549.
2. De Kimpe, N.; Verhé, R.; De Buyck, L.; Hasma, H.; Schamp, N. T 1976, 32, 2457.
3. De Kimpe, N.; Boeykens, M.; Boelens, M.; De Buck, K.; Cornelis, J. OPP 1992, 24, 679.
4. De Kimpe, N.; Stanoeva, E.; Verhé, R.; Schamp, N. S 1988, 587.
5. De Kimpe, N.; Stevens, C. BSB 1990, 99, 41.
6. De Kimpe, N.; Stevens, C. T 1990, 46, 6753.
7. De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N. CJC 1984, 62, 1812.
8. De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N. S 1983, 632.
9. De Kimpe, N.; Yao, Z.; Schamp, N. TL 1986, 27, 1707.
10. De Kimpe, N.; Verhé, R.; De Buyck, L.; Hasma, H.; Schamp, N. T 1976, 32, 3063.
11. De Kimpe, N.; Stevens, C. T 1991, 47, 3407.
12. De Kimpe, N.; De Corte, B.; Verhé, R.; De Buyck, L.; Schamp, N. TL 1984, 25, 1095.
13. De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N. RTC 1977, 96, 242.
14. De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N.; De Clercq, J. P.; Germain, G.; Van Meersche, M. JOC 1977, 42, 3704.
15. De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N. BSB 1977, 86, 663.
16. De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N.; Charpentier-Morize, M. TL 1982, 23, 2853.
17. De Kimpe, N.; Yao, Z.; Boeykens, M.; Nagy, M. TL 1990, 31, 2771.
18. De Kimpe, N.; Nagy, M.; Boeykens, M.; Van Der Schueren, D. JOC 1992, 57, 5761.
19. De Kimpe, N.; Yao, Z.; Schamp, N. BSB 1989, 98, 481.
20. De Kimpe, N.; Verhé, R.; De Buyck, L.; Moëns, L.; Schamp, N. S 1982, 43.
21. De Kimpe, N.; Schamp, N. OPP 1979, 11, 115.
22. De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N. OPP 1980, 12, 49.
23. De Kimpe, N.; Schamp, N. OPP 1981, 13, 241.
24. De Kimpe, N.; Stanoeva, E. BSB 1991, 100, 195.
25. Verhé, R.; De Kimpe, N.; De Buyck, L.; Schamp, N. JOC 1978, 43, 5022.
26. De Kimpe, N.; Yao, Z.; Schamp, N. BSB 1989, 98, 481.
27. De Kimpe, N.; De Corte, B. T 1992, 48, 7345.
28. Duhamel, L.; Duhamel, P.; Valnot, J.-Y. CR(C) 1970, 271, 1471.

Norbert De Kimpe

University of Gent, Belgium

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