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DOI:10.15227/orgsyn.067.0133

Organic Syntheses, Coll. Vol. 8, p.231 (1993); Vol. 67, p.133 (1989).

N-BENZYL-N-METHOXYMETHYL-N-(TRIMETHYLSILYL)
METHYLAMINE AS AN AZOMETHINE YLIDE EQUIVALENT:
2,6-DIOXO-1-PHENYL-4-BENZYL-1,4-DIAZABICYCLO[3.3.0]
OCTANE[Pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione, tetrahydro-2-phenyl-5-(phenylmethyl)-,cis-]

Submitted by Albert Padwa and William Dent1.
Checked by Bruce Lefker and Albert I. Meyers.

1. Procedure
A. N-Benzyl-N-(trimethylsilyl)methylamine. An oven-dried, 100-mL, one-necked, round-bottomed
flask equipped with a magnetic stirring bar and a reflux condenser is charged with 12.58 g (0.1 mol) of
chloromethyltrimethylsilane (Note 1). Benzylamine (Note 2) (33.1 g, 0.3 mol) is added with stirring andthe resulting solution is heated at 200°C for 2.5 hr. At the end of this time a 0.1 N sodium hydroxide
solution is added in order to hydrolyze the white organic salt that had formed. The mixture is extractedwith ether and the ether layer is dried over magnesium sulfate and concentrated under reduced pressure.
The residue is distilled under reduced pressure through a 6-in. Vigreux column to give 11.6–15.3 g (58–72%) of N-benzyl-N-(trimethylsilyl)methylamine, bp 68–72°C (0.7–0.8 mm) (Note 3).
B. N-Benzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine. A 25-mL, round-bottomed flask
equipped with a stirring bar is charged with 6.0 g (74 mmol) of a 37% aqueous formaldehyde solution(Note 4). The solution is cooled to 0°C and 10.0 g (51.7 mmol) of N-benzyl-N-(trimethylsilyl)
methylamine is added dropwise with stirring. After the solution is stirred for 10 min at 0°C, 6 mL (0.15mol) of methanol (Note 5) is added in one portion. Potassium carbonate (4.0 g) is added to the mixture
to absorb the aqueous phase. The mixture is stirred for 1 hr, the nonaqueous phase is decanted, anadditional 2.0 g of potassium carbonate is added, and the mixture is stirred at 25°C for 12 hr. Ether isadded to the mixture and the solution is dried over potassium carbonate, filtered, and concentrated under
reduced pressure (Note 6). The residue is distilled at reduced pressure to give 6.8–8.6 g (54–69%) of Nbenzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine as a colorless liquid, bp 77–80°C (0.5 mm)(Note 7).

C. 2,6-Dioxo-1-phenyl-4-benzyl-1,4-diazabicyclo[3.3.0]octane. An oven-dried, 250-mL, onenecked, round-bottomed flask equipped with a magnetic stirring bar is charged with 10.0 g (0.042 mol)of N-benzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine and 100 mL of anhydrous acetonitrile(Note 8). N-Phenylmaleimide (Note 9) (7.3 g, 0.042 mol) is added, followed by 1.7 g (0.063 mol) of
lithium fluoride (Note 10). The reaction mixture is sonicated (Note 11) for 3 hr and poured into 100 mLof water. The mixture is extracted with three 100-mL portions of ether. The organic extracts arecombined and washed with 100 mL of saturated sodium chloride solution, dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The residue is chromatographed on a silica
gel column (300 g) using a 35% ethyl acetate:hexane mixture (ca. 1500 mL) as the eluant to give 9.2–
9.6 g (72–75%) of 2,6-dioxo-1-phenyl-4-benzyl-1,4-diazabicyclo[3.3.0]octane as a pale yellow solid,
mp 97–98°C (Note 12).

2. Notes
1. Chloromethyltrimethylsilane is purchased from Petrarch Systems, Inc. and is used withoutpurification.
2. Benzylamine, purchased from Aldrich Chemical Company, Inc., is distilled and stored overpotassium hydroxide.
3. The submitters report bp 89–90°C (5 mm). The 1H NMR spectrum (CDCl3, 90 MHz) is as follows δ:
0.10 (s, 9 H), 2.00 (s, 2 H), 3.78 (s, 2 H) and 7.28 (s, 5 H).
4. Formaldehyde (37% solution in water) is purchased from Aldrich Chemical Company, Inc. Sufficientaqueous 10% sodium hydroxide solution (1–5 drops) is added until the pH reaches 7.
5. Purified-grade methanol, purchased from Fisher Scientific Company, is used.
6. The submitters found it easier to pump down the crude mixture overnight under reduced pressure toensure that all the methanol is removed. If not, the residue tends to bump uncontrollably upon
distillation.
7. The spectral properties are as follows: IR (neat) cm−1: 3095, 3064, 3030, 2900, 1605, 1495, 1450,1422, 1385, 1362, 1245, 1070, 925, 845, 740, 700; 1H NMR (CDCl3, 90 MHz) δ: 0.10 (s, 9 H), 2.13 (s,2 H), 3.20 (s, 3 H), 3.72 (s, 2 H), 3.95 (s, 2 H) and 7.22 (m, 5 H).
8. Anhydrous acetonitrile, purchased from Aldrich Chemical Company, Inc., is distilled over calcium
hydride and stored over Linde 4A molecular sieves.
9. N-Phenylmaleimide is purchased from Aldrich Chemical Company, Inc., and used withoutpurification.
10. Lithium fluoride is purchased from Fisher Scientific Company.
11. A Branson ultrasonic cleaner (2.8 L, 13 × 23 × 10 cm), purchased from Fisher Scientific Company,
is used for sonication. Without sonication, the yield drops by ca. 10–15%.
12. The spectral properties are as follows: IR (neat) cm−1: 3145, 3000, 2950, 2900, 2800, 1760, 1700,1575, 1490, 1445, 1380, 1310, 1200, 1155, 880, 840, 740, 700; 1H NMR (CDCl3, 90 MHz) δ: 2.3–2.7(m, 2 H), 3.2–3.6 (m, 4 H), 3.60 (s, 2 H), 7.0–7.7 (m, 10 H).

3. Discussion
The preparation of pyrrolidines has received extensive attention by synthetic chemists in recent
years, in part because of the interesting biological activities exhibited by several polysubstituted
pyrrolidines.2 Little attention has been given to one of the most conceptually simple ways of pyrrolidine
formation: a 1,3-dipolar cycloaddition of an azomethine ylide with an olefin. This is not surprising since
few methods exist for the preparation of nonstabilized azomethine ylides.3,4,5,6,7,8,9,10,11,12,13 Silylsubstituted amines of type 1 represent conjunctive reagents that can be considered as the equivalent of anonstabilized azomethine ylide. These reagents have recently been found to undergo 1,3-dipolar
cycloaddition to olefins to give pyrrolidine derivatives in good yield.14,15,16 The present procedureprovides a convenient route for the synthesis of a variety of five-membered ring nitrogen heterocycles
using different dipolarophiles. Some representative examples are given in Table I. Advantages of thepresent method over existing methodologies include mild conditions, high yield, and simplicity of thecycloaddition. Trimethylsilyl triflate or trimethylsilyl iodide can also be used.12 However, these reagentsare expensive and require longer reaction times.

TABLE ICYCLOADDITION OF 1 WITH ELECTRON-DEFICIENTDIPOLAROPHILES
Dipolarophile

Product% Yield

90

90

90

92

80

91

We have found that sonication of the reaction mixture decreases the time needed for reaction andalso substantially increases the yield. This is probably related to an increase in the solubility of lithium
fluoride in acetonitrile or is a consequence of surface effects on the metal.
N-Benzyl-N-methoxymethyl-N-(trimethylsily)methylamine undergoes stereospecific cycloaddition
with dimethyl maleate and fumarate. The cycloaddition behavior of an unsymmetrically substituted α-methoxysilylamine has also been examined and found to occur with high overall regioselectivity. The stereospecificity
and regioselectivity of the reaction is consistent with a concerted 1,3-dipolar cycloaddition reaction.
17

References and Notes
1. Department of Chemistry, Emory University, Atlanta, GA 30322.
2. "The Alkaloids, A Specialist Periodical Report," The Royal Society of Chemistry: London. 1983, Vol. 13.
3. Vedejs, E.; Martinez, G. R. J. Am. Chem. Soc. 1979, 101, 6452; 1980, 102, 7993.
4. Achiwa, K.; Sekiya, M. Tetrahedron Lett. 1982, 23, 2589; Heterocycles 1983, 20, 167; Chem. Lett. 1981, 1213.
5. Achiwa, K.; Motoyama, T.; Sekiya, M. Chem. Pharm. Bull. 1983, 31, 3939.
6. Terao, Y.; Imai, N.; Achiwa, K. Sekiya, M. Chem. Pharm. Bull. 1982, 30, 3167.
7. Tsuge, O.; Kanemasa, S.; Kuraoka, S.; Takenaka, S. Chem. Lett. 1984, 279; 1984, 281.
8. Tsuge, O.; Kanemasa, S.; Hatada, A.; Matsuda, K. Chem. Lett. 1984, 801; Tsuge, O.; Kanemasa. S.; Takenaka, S. Bull.
Chem. Soc. Jpn. 1983, 56, 2073.
9. Tsuge, O.; Oe, K.; Kawaguchi, N. Chem. Lett. 1981, 1585.
10. Tsuge, O.; Ueno, K. Heterocycles 1983, 20, 2133; 1982, 19, 1411.
11. Grigg, R.; Basanagoudar, L. D.; Kennedy, D. A.; Malone, J. F.; Thianpatanagul, S. Tetrahedron Lett. 1982, 23, 2803;
Grigg, R.; Gunaratne, H. Q. N.; Kemp, J. Tetrahedron Lett. 1984, 25, 99.
12. Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117.
13. Chen. S. F.; Ullrich, J. W.; Mariano, P. S. J. Am. Chem. Soc. 1983, 105, 6160.
14. Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235.
15. Padwa, A.; Dent, W.; Nimmesgern, H.; Venkatramanan, M. K.; Wong, G. S. K. Chem. Ber. 1986, 119 , 813.
16. Parker, K. A.; Cohen, I. D.; Padwa, A.; Dent, W. Tetrahedron Lett. 1984, 25, 4917.
17. "1,3-Dipolar Cycloaddition Chemistry," Padwa, A.; Ed.; Wiley: New York, 1984.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)potassium carbonate (584-08-7)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether (60-29-7)acetonitrile (75-05-8)
sodium hydroxide (1310-73-2)
formaldehyde (50-00-0)
sodium chloride (7647-14-5)
potassium hydroxide (1310-58-3)

magnesium sulfate (7487-88-9)
benzylamine (100-46-9)
pyrrolidine (123-75-1)
hexane (110-54-3)
calcium hydride (7789-78-8)
Dimethyl fumarate (624-49-7)
N-Phenylmaleimide (941-69-5)
trimethylsilyl iodide (16029-98-4)
trimethylsilyl triflate (27607-77-8)
chloromethyltrimethylsilane (2344-80-1)
2,6-Dioxo-1-phenyl-4-benzyl-1,4-diazabicyclo[3.3.0]octane
lithium fluoride (7789-24-4)
dimethyl maleate (624-48-6)
α-methoxysilylamine
N-BENZYL-N-METHOXYMETHYL-N-(TRIMETHYLSILYL)METHYLAMINE (93102-05-7)
N-benzyl-N-(trimethylsilyl)methylamine
Pyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione, tetrahydro-2-phenyl-5-(phenylmethyl)-, cis- (87813-00-1)
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