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DOI: 10.1055/s-0029-1219537
Direct Stereoselective Synthesis of 1-Amino-2,5-diarylcyclohexanecarboxylic Acid Derivatives Based on a [5+1] Annulation of Divinyl Ketone and Isocyanoacetate
Publikationsverlauf
Publikationsdatum:
18. Februar 2010 (online)
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Abstract
A 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed stereoselective [5+1] annulation of divinyl ketones and isocyanoacetate was disclosed, which provided a facile and efficient route to 1-amino-2,5-diarylcyclohexanecarboxylic acids as novel constrained cyclohexane analogues of phenylalanine.
Key words
isocyanoacetate - divinyl ketones - [5+1] annulation - 1-amino-2,5-diarylcyclohexanecarboxylic acid - DBU
- Supporting Information for this article is available online:
- Supporting Information
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References and Notes
General Experimental
Procedure for Cyclohexane Analogues of Phenylalanine 3 (3f as an
Example)
To the mixture of 1f (392
mg, 1.0 mmol) and ethyl isocyanoacetate 2 (0.132
mL, 1.2 mmol) in DMF (5 mL) was added 1,8-diazabicyclo [5.4.0]undec-7-ene
(DBU, 0.015 mL, 0.1 mmol) in one portion at r.t. The reaction mixture was
stirred at r.t., and the reaction mixture was monitored by TLC.
After the substrate 1f was consumed, the
resulting mixture was poured into ice water (30 mL) under stirring. The
precipitated solid was collected by filtration, washed with H2O
(3 × 10 mL), and dried in vacuo to afford
the crude product 3f, which was purified
by flash chromatography (silica gel, PE-Et2O = 3:1,
v/v) to give 3f (460 mg, 91%).
Compound 3f: white solid; mp 145-146 ˚C. ¹H
NMR (500 MHz, CDCl3): δ = 0.94
(t, J = 7.5
Hz, 3 H), 2.73 (dd, J = 16.5,
3.5 Hz, 1 H), 2.98-3.09 (m, 2 H), 3.13 (dd, J = 16.5,
12.5 Hz, 1 H), 3.76-3.89 (m, 3 H), 3.94 (dd, J = 12.5,
3.5 Hz, 1 H), 7.04 (d, J = 7.5
Hz, 2 H), 7.15 (d, J = 7.5
Hz, 2 H), 7.45 (d, J = 7.5
Hz, 2 H), 7.48 (d, J = 7.5 Hz,
2 H). ¹³C NMR (125 MHz, CDCl3): δ = 13.4,
41.0, 41.8, 42.7, 50.0, 63.0, 71.3, 122.6, 122.9, 130.1, 130.4,
131.8, 131.9, 135.2, 135.4, 163.9, 166.0, 206.3. MS (ES): m/z = 504.1 [M + 1]+.
Anal. Calcd for C22H19Br2NO3:
C, 52.30; H, 3.79; N, 2.77. Found: C, 52.42; H, 3.71; N, 2.63.
CCDC 753606 (3f) and CCDC 753605 (4d) contain the supplementary crystallographic data for this paper, respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centra via www.ccdc.cam.ac.uk/data_request/cif.
11
General Experimental
Procedure for
N
-Formyl Cyclohexane
Analogues of Phenylalanine 4 (4d as an Example)
To
the mixture of 3j (396 mg, 1.0 mmol) in
CH2Cl2 (5.0 mL) was added TFA (0.089 mL, 1.2
mmol) in one portion at r.t. Then the reaction mixture was stirred
at r.t. After the substrate 3j was consumed
as indicated by TLC, the resulting mixture was poured onto ice water
(30 mL) under stirring, following by basification with sat. aq NaHCO3 solution
to adjust the pH value of the solution to 7, and extracted with
CH2Cl2 (3 × 30
mL), the combined organic phase was washed with brine, dried over
anhyd MgSO4, and concentrated in vacuo to give the pure
product 4d (406 mg, 98%).
Compound 4d: white solid; mp 136-139 ˚C. ¹H
NMR (500 MHz, CDCl3): δ = 1.33
(t, J = 7.0
Hz, 3 H), 2.31 (s, 3 H), 2.58-2.70 (m, 2 H), 3.46 (dd, J = 17.5,
15.0 Hz, 1 H), 4.03-4.09 (m, 1 H), 4.13-4.30 (m,
3 H), 4.60 (dd, J = 15.0,
2.5 Hz, 1 H), 6.39 (s, 1 H), 6.91 (d, J = 8.0
Hz, 2 H), 6.93 (d, J = 7.5 Hz,
2 H), 7.09 (d, J = 8.0
Hz, 2 H), 7.25 (d, J = 7.5
Hz, 2 H), 8.03 (d, J = 1.5
Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 14.0,
21.0, 39.3, 41.0, 42.3, 44.7, 63.2, 69.1, 128.1, 128.6, 129.1, 129.2,
133.4, 134.0, 136.3, 137.7, 160.9, 171.6, 210.5. MS (ES): m/z = 414.1 [M + 1]+.
Anal. Calcd for C23H24ClNO4: C,
66.74; H, 5.84; N, 3.38. Found: C, 66.99; H, 5.90; N, 3.20.