Organic Syntheses, CV 8, 204
Submitted by Daniel A. Dickman, Michael Boes, and Albert I. Meyers
1.
Checked by Jeffrey Romine and Leo A. Paquette.
1. Procedure
A.
(S)-N-Formyl-O-tert-butylvalinol (1). In a
100-mL, round-bottomed flask,
20.6 g (200 mmol) of (S)-valinol (Note
1) and
16 g (216 mmol) of ethyl formate (Note
2) are heated at reflux under a
nitrogen atmosphere for 1 hr. Excess
ethyl formate is removed under reduced pressure and the oil is triturated with dry
ether until a yellow solid appears. This material is dissolved in
260 mL of dry dioxane (Note
3) in a
1000-mL pressure bottle (Note
4) equipped with a
magnetic stirring bar and immersed in an
ice–water bath. The bottle is immediately charged with ca.
260 mL of liquid isobutene (Note
5) and
75 mL of boron trifluoride etherate is rapidly added. The
pressure bottle is sealed with a stopper, removed from the
ice bath, and stirred at room temperature for 3 hr (Note
6). In a
fume hood, excess
isobutene is removed from the resulting clear solution by carefully cracking the seal of the stopper. When the gas ceases to discharge, the stopper is removed and the solution is poured into a
1000-mL separatory funnel containing
250 mL of 2 N sodium hydroxide and is extracted twice with
100 mL of dichloromethane. The organic layer is washed with
100 mL of brine and dried over anhydrous
magnesium sulfate. The organic solvent is removed and the residue is distilled (
Kugelrohr tube, 0.05 mm, 80–85°C bath temperature) to give
27–36 g (
75–95%) of
N-formyl-O-tert-butylvalinol (1) as a clear oil (Note
7).
B.
(S)-N,N-Dimethyl-N'-(1-tert-butoxy-3-methyl-2-butyl)formamidine (2). In a
500-mL, round-bottomed flask 26 g (140 mmol) of the formamide from Part A is dissolved in
100 mL of ethanol and
200 mL of a 50% aqueous potassium hydroxide solution is added. The mixture is heated at reflux overnight; on cooling, the reaction separates into colorless aqueous and organic layers. The two layers are extracted 3 times with
100 mL of ether and the combined organic layers are washed with
100 mL of brine. After the solution is dried over anhydrous
potassium carbonate and filtered, the
ether and
ethanol are carefully removed under
aspirator vacuum at ambient temperature. The crude amine is treated with
25 g (210 mmol) of N,N-dimethylformamide dimethyl acetal (Note
8) and the reaction mixture is heated under
argon at 40°C for 1 hr. The solution is concentrated under reduced pressure and the crude product is distilled bulb-to-bulb (0.05 mm, 55–65°C) to give
25.7–27 g (
86–91.5%) of
(S)-N,N-dimethyl-N'-(1-tert-butoxy-3-methyl-2-butyl)formamidine (2) as a colorless liquid (Note
9).
2. Notes
2.
Ethyl formate was purchased from J. T. Baker Chemical Company.
4. A
Kimble bottle (#15096) purchased from VWR Scientific (Cat. No. 16267-101) was employed.
5.
Isobutene was purchased from Matheson Gas Products.
6. The two-layer system became a clear solution within 15 min.
7. The physical properties are as follows: IR (neat) cm
−1: 3300, 1660;
1H NMR (CDCl
3, 300 MHz) δ: 0.79–0.88 (m, 6 H), 1.07 (s, 9 H), 1.82 (m, 1 H), 3.3 (m, 2 H), 3.75 (m, 1 H), 7.94 (d, 1 H,
J = 12), 8.13 (d, 1 H,
J = 1);
[α]D25 −59.6° (EtOH, c 3.5).
9. The physical properties are as follows: IR (neat) cm
−1: 1660;
1H NMR (CDCl
3, 300 MHz) δ: 0.77 (d, 3 H,
J = 6.5), 0.79 (d, 3 H,
J = 6.5), 1.07 (s, 9 H), 1.72 (m, 1 H), 2.6–3.5 (m, 3 H), 2.73 (s, 6 H), 7.14 (s, 1 H);
[α]D25 −15.9° (THF, c 0.98).
3. Discussion
This procedure for the synthesis of
N,N-dimethyl-
N'-alkylformamidines is representative for both chiral and achiral alkyl groups. These compounds are used to activate a wide range of secondary amines toward metalation and alkylation and may be removed to furnish the α-alkylated amines.
2 3
TABLE I
PREPARATION OF N,N-DIMETHYL-N'-ALKYLFORMAMIDINES
|
RNH2 |
% yield |
|
|
95 |
|
98 |
|
98 |
|
96 |
|
98 |
|
It is also possible to simply heat "DMF-acetal" with an amino alcohol (e.g.,
valinol,
leucinol) and obtain the
hydroxy formamidine, which can be directly silylated with
Et3SiCl,
Me3SiCl, or
tert-BuMe2SiCl at 0°C in
dichloromethane (Eq. 2).
2 If these
N,N-dimethylformamidines are required, this procedure has the advantage of eliminating the sometimes troublesome cleavage of a
silyl ether during reaction with CMF–acetal.
In addition to the exchange reaction
5 described previously,
6 formamidines derived from secondary amines can be prepared by forming the
N-formyl derivative, which is treated successively with
boron trifluoride etherate and the appropriate primary amine
2 (Eq. 3, Table II). However, this method is not satisfactory if sensitive groups (e.g., Me
3Si) are present on the amine since they are cleaved by the Meerwein reagent.
TABLE II
PREPARATION OF FORMAMIDINES VIA N-FORMYL DERIVATIVES
|
RNH2 |
(%) |
|
|
98 |
|
94 |
|
98 |
|
97 |
|
The main advantages of using the
tert-butyl ether of the
valinol formamidine are its stability to reaction conditions used in the asymmetric alkylation of amines and its ready recovery from these reactions for further use.
This preparation is referenced from:
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
brine
(S)-N-Formyl-O-tert-butylvalinol (1)
(S)-N,N-Dimethyl-N'-(1-tert-butoxy-3-methyl-2-butyl)formamidine (2)
(L)- or (S)-Valinol
Et3SiCl
Me3SiCl
tert-BuMe2SiCl
N,N-dimethylformamidines
ethanol (64-17-5)
potassium carbonate (584-08-7)
ether (60-29-7)
formamide (75-12-7)
sodium hydroxide (1310-73-2)
nitrogen (7727-37-9)
potassium hydroxide (1310-58-3)
ethyl formate (109-94-4)
dichloromethane (75-09-2)
magnesium sulfate (7487-88-9)
dioxane (5703-46-8)
isobutene (9003-27-4)
lithium aluminum hydride (16853-85-3)
boron trifluoride etherate (109-63-7)
argon (7440-37-1)
silyl ether (13597-73-4)
valinol,
(S)-valinol,
(L)-valinol (2026-48-4)
leucinol
dimethylformamide dimethyl acetal,
N,N-dimethylformamide dimethyl acetal (4637-24-5)
hydroxy formamidine
valinol formamidine
tert-butyl ether (6163-66-2)
N-formyl-O-tert-butylvalinol (90482-04-5)
(S)-N,N-DIMETHYL-N'-(1-tert-BUTOXY-3-METHYL-2-BUTYL)FORMAMIDINE,
Methanimidamide, N'-[1-[(1,1-dimethylethoxy)methyl]-2-methylpropyl]-N,N-dimethyl-, (S)- (90482-06-7)
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved