Ketoform reaction. Synthesis of hindered imines from 2,6-dialkylanilines and ketones

Article abstract of DOI:10.1016/S0040-4039(02)00159-4

Hindered imines are synthesized from 2,6-dialkylanilines, ketones, chloroform and sodium hydroxide in a phase-transfer catalyzed reaction.

Full text of DOI:10.1016/S0040-4039(02)00159-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1965–1967
Ketoform reaction. Synthesis of hindered imines from
2,6-dialkylanilines and ketones
John T. Lai*
Noveon, Inc., 9911 Brecksville Rd, Brecksville, OH 44141, USA
Received 6 November 2001; revised 21 January 2002; accepted 22 January 2002
Abstract—Hindered imines are synthesized from 2,6-dialkylanilines, ketones, chloroform and sodium hydroxide in a phase-trans-
fer catalyzed reaction. © 2002 Elsevier Science Ltd. All rights reserved.
Hindered imines derived from 2,6-di-alkylanilines and
ketones are difficult to prepare. They have been isolated
as silver iodide salts,1 and recently-reported synthetic
methods employ harsh conditions that include the use
of strong Lewis acid catalyst,2 or strong dehydrating
agent.3 In this report, we describe a new method
employing mild, basic conditions where the imines are
easily isolated in high yields. It is one of several appli-
cations from our studies of the ketoform reaction.4
Usually, nucleophiles break the dialkyl carbonꢀoxygen
bond in the oxirane (Scheme 2, path a). However,
2-alkylanilines are an exception.5 They preferentially
break the carbonꢀcarbon bond, leading to the imine
(Scheme 2, path b).
We now report that 2,6-dialkylanilines break only the
carbon–carbon bond of the oxirane in the ketoform
reaction, and hindered imines are the exclusive products
(Scheme 3).
In the ketoform reaction, a ketone, chloroform and
sodium hydroxide provide a reactive 1,1-dialkyl-2,2-
dichlorooxirane intermediate that can be selectively
opened to an acyl chloride with nucleophiles. Further
condensation with the same or different nucleophile
gives a stable product (Scheme 1).
The process involves the mixing of a ketone (0.2 mol),
chloroform (0.15 mol) and 2,6-dialkylaniline (0.1 mol),
the phase-transfer catalyst Aliquot® 336 (0.004 mol)
and 100 ml toluene at 10°C under a nitrogen atmo-
sphere. Sodium hydroxide (50%, 0.5 mol) is then added
Scheme 1.
Scheme 2.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00159-4

1966
J. T. Lai / Tetrahedron Letters 43 (2002) 1965–1967
Scheme 3.
dropwise to keep the temperature below 20°C. After
the addition, the reaction is allowed to continue
overnight at 15°C. The reaction mixture is then
filtered, and the solid removed is rinsed with toluene.
The filtrate is washed with 50 ml water, dried over
magnesium sulfate and concentrated to yield the
crude product which is mainly imine, but can include
some unreacted aniline and ketone. Pure compound
can be obtained by distillation through a Vigraux
column.
In diimine 1i, the syn and anti isomers are present in
1
a 38:62 ratio based on H NMR.
Table 1 shows examples of selected hindered imines
made in this manner.
When R3 and R4 are different, the geometric syn and
anti isomers6 exhibit a ratio of about 15:85 from their
1H NMR spectra, with little influence from the size of
the R groups.
Acknowledgements
The author wishes to thank Miss Debby Filla for her
laboratory work, Dr. George Benedict for the 1H
Table 1.
R1
R2
R3
R4
Bp (°C/torr)
1H NMRa (l, CDCl3)
1.61 (s, 3H), 1.99 (s, 6H), 2.21 (s, 3H), 6.8–7.3 (m, 3H)
0.98 and 1.25 (2t, 18/82 ratio, 3H), 1.61 and 2.20 (2s, 82/18, 3H) 91 (64)
1.98 (s, 6H), 2.16 and 2.47 (2q, 18/82, 2H), 6.8–7.1 (m, 3H)
Yieldb (%)
1a
1b
Me
Me
Me
Me
Me
Me
Me
Et
85–8/5
84–7/1
\95 (77)
1c
1d
Me
Me
Me
Me
Me
Me
-(CH2)5-
i-Bu
118–23/7.5
–
110–2/1
128–31/0.9
1.5–2.0 (m, 8H), 2.00 (s, 6H), 2.54 (t, 2H), 6.8–7.0 (m, 3H)
0.81 and 1.05 (2d, 13/87, 6H), 1.60 and 2.20 (2s, 13/87, 3H), 2.00 62
(s, 6H), 1.9–2.4 (m, 3H), 6.8–7.0 (m, 3H)
0.83 and 0.91 (2t, 15/85, 3H), 1.1–2.3 (m, 8H), 1.62 and 2.21 (2s, 43 (20)
85/15, 3H), 1.91 and 2.45 (2t, 15/85, 2H), 1.99 (s, 6H), 6.8–7.0
(m, 3H)
\95 (79)
Me
Me
Me
1dc Me
i-Bu
n-Hex
73 (43)
1e
Me
1f
Me
Et
i-Pr
-(CH2)5-
Et
137–43/1
120–5/6
1.12 (d, 3H), 1.66 (d, 3H), 1.5–2.0 (m, 8H), 2.55 (t, 3H), 2.55
(hept, 1H), 6.9–7.1 (m, 3H)
1.00 and 1.26 (2t, 15/85, 3H), 1.13 (t, 6H), 1.64 and 2.22 (2s,
85/15, 3H), 2.00 and 2.48 (2q, 15/85, 2H), 2.2–2.3 (m, 4H),
6.9–7.1 (m, 3H)
\95 (81)
1g
Et
Me
83 ( 67)
1h
1i
Et
Et
-(CH2)5-
140–5/1
1.14 (t, 6H), 1.5–2.6 (m, 14H), 6.9–7.1 (m, 3H)
\95 (76)
(155–60)d
1.58–1.60 (2s, 38/62, 6H), 1.89 (s, 12H), 2.23 (s, 6H)
95 (40)
a Bruker WH-200 spectrometer.
b Yield as measured by GC, with the isolated yield in parenthesis. The large differences between the two yields in 1b, 1d and 1e are due to the
close proximity between the boiling points of the aniline and the imine, thus it is difficult separation. Correct mass ion from chemical ionization
mass spec by a Finnigan MAT spectrometer: 0.0009; infrared spectra of neat or KBr pellet all show peaks at 1665–1775 cm−1
c 0.4 mol of MIBK is used instead of 0.2 mol of ketone used for the rest of the syntheses.
d Melting point, after recrystallization from hexanes.
.

J. T. Lai / Tetrahedron Letters 43 (2002) 1965–1967
1967
NMR service and Dr. Robert Lattimer for mass spec-
tra. He is greatly indebted to Dr. Paul Nicholas for
proof-reading the revised draft.
Scand. 1992, 46, 1211.
3. Love, B. E.; Ren, J. J. Org. Chem. 1993, 58, 5556.
4. (a) Lai, J. T. Tetrahedron Lett. 2001, 42, 557; (b) Lai, J.
T. Synthesis 1984, 122; (c) Son, P.; Lai, J. T. J. Org.
Chem. 1981, 46, 323; (d) Lai, J. T. J. Org. Chem. 1980,
45, 754.
5. Lai, J. T. J. Org. Chem. 1980, 45, 3671.
6. Wurmb-Gerlich, v. D.; Vogtle, F.; Mannschreck, A.;
Staab, H. Liebigs Ann. Chem. 1967, 708, 36.
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