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F. Berti et al.
Paper
Synthesis
HRMS (ESI): m/z [M + Na+] calcd for C17H15N3O3 + Na: 332.1006;
(3R)-3-(Pyridin-2-ylamino)-3,6-dihydro-2H-pyridine-1-carboxyl-
found: 332.1003.
ic Acid Phenyl Ester (8c)
In a 10 mL flame-dried Schlenk tube, Cp2TiCl2 (127 mg, 0.496 mmol)
was diluted, under argon protection, with of freshly distilled THF (2.5
mL). After the addition of activated Zn dust (66 mg, 0.99 mmol), the
reaction mixture was stirred at r.t. for 50 min and then cooled to
–30 °C. A solution of 2c (61 mg, 0.2 mmol) in MeOH (2.0 mL) was add-
ed over 5 min and the resulting solution was allowed to stir for 30
min at –30 °C. The reaction was quenched with H2O (6.5 mL), fol-
lowed by sat. aq NaHCO3 (2.0 mL), and allowed to reach r.t. The aque-
ous phase was extracted with EtOAc (3 × 8 mL) and the combined or-
ganic layers were dried (MgSO4), filtered, and concentrated. Subse-
quent flash chromatography (hexane–EtOAc, 1:1; Rf = 0.22) afforded
the title compound as a white amorphous semi-solid; yield: 27 mg
(45%); [α]D20 +6.3 (c = 0.24, CHCl3).
(1-Phenyl-1H-pyrrol-2-ylmethyl)carbamic Acid Phenyl Ester (3b)
A pyrex vial was charged with 7b (59 mg, 0.20 mmol), CuCl (4.0 mg,
0.04 mmol), and 1,2-dichloroethane (1.55 mL), and placed in a pre-
heated oil bath at 75 °C. The reaction mixture was allowed to stir for
18 h, filtered through a short pad of Celite, and washed several times
with CH2Cl2. Removal of the solvent gave a semi-solid, which was
subjected to flash chromatography (hexanes–EtOAc, 7:3) to give 3b as
an amorphous solid; yield: 44 mg (70%).
1H NMR (250 MHz, CDCl3): δ = 7.53–7.15 (m, 8 H), 7.03 (d, J = 7.5 Hz, 2
H), 6.84 (dd, J = 2.6, 1.8 Hz, 1 H), 6.33 (s, 1 H), 6.26 (t, J = 3.1 Hz, 1 H),
5.00 (br s, 1 H), 4.42 (d, J = 5.3 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 154.0, 151.1, 139.7, 129.6, 129.4,
129.3, 127.9, 126.1, 125.4, 123.5, 121.7, 109.9, 108.6, 37.7.
HRMS (ESI): m/z [M + Na+] calcd for C18H16N2O2 + Na: 315.1104;
found: 315.1101.
Enantiomeric ratio (>90:<10, not complete baseline separation) was
determined by HPLC on a Daicel Chiralpak AD-H column (hexane–
i-PrOH, 90:10); flow rate 1.0 mL/min; tR (minor) = 17.7 min, tR
(major) = 16.9 min.
1H NMR (250 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.50–6.86 (m, 3 H), 6.60
(dd, J = 12.3, 6.8 Hz, 1 H), 6.44 (d, J = 8.3 Hz, 1 H), 5.99 (d, J = 13.0 Hz, 1
H), 4.58 (s, 1 H), 4.37–3.40 (m, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 157.5, 154.3, 151.4, 148.3, 148.2,
137.8, 137.6, 129.5, 129.3, 127.8, 126.8, 126.4, 125.8, 125.3, 121.7,
113.9, 113.6, 108.3, 108.0, 46.1, 45.6, 43.8.
(1S*,4S*)-7-Phenyl-2,7-diazabicyclo[2.2.1]hept-5-ene-2-carboxyl-
ic Acid Phenyl Ester (7b)
A solution of cycloadduct 2b (93 mg, 0.30 mmol) in CH2Cl2 (2.3 mL)
was added with i-PrOH (69 μL, 0.90 mmol) and CuCl (5.9 mg, 0.06
mmol), and allowed to stir for 18 h at r.t. The reaction mixture was
quenched with sat. aq NH4Cl (3.0 mL) and the aqueous phase was ex-
tracted with CH2Cl2 (3 × 5.0 mL). The combined organic layers were
dried (MgSO4), and concentrated under vacuum. Flash chromatogra-
phy (hexanes–EtOAc, 1:1; Rf = 0.16) afforded pure compound 7b as a
yellowish solid; yield: 62 mg (65%); mp 133–135 °C.
HRMS (ESI): m/z [M + Na+] Calcd for C17H17N3O2 + Na: 318.1213;
found: 318.1217.
Acknowledgment
1H NMR (250 MHz, CDCl3): δ = 7.47–7.06 (m, 10 H), 6.77 (t, J = 7.3 Hz,
1 H), 6.69 (d, J = 7.8 Hz, 2 H), 6.09 (d, J = 10.1 Hz, 1 H), 6.02–5.79 (m, 2
H), 4.52 (dd, J = 12.4, 5.5 Hz, 1 H), 4.22 (br s, 1 H), 3.17–2.84 (m, 1 H).
This work was supported by the University of Pisa.
13C NMR (62.5 MHz, CDCl3): δ = 150.9, 146.2, 133.3, 129.7, 129.6,
127.1, 126.0, 121.8, 118.6, 113.6, 73.2, 47.9, 42.7.
HRMS (ESI): m/z [M + Na+] calcd for C18H16N2O2 + Na: 315.1104;
found: 315.1108.
Supporting Information
Supporting information for this article is available online at
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boxylic Acid Phenyl Ester (7c)
References
A 10 mL pyrex vial was charged with a solution of racemic 2c (62 mg,
0.20 mmol) in MeCN (1 mL). H2O (60 μL, 3.33 mmol) and Mo(CO)6 (65
mg, 0.24 mmol) were added to give a heterogeneous yellow solution.
The reaction mixture was placed in a preheated oil bath at 65 °C and
stirred for 2.5 h. Upon heating, a color change to dark green was ob-
served. The mixture was filtered through a short pad of Celite and
washed several times with CH2Cl2. The filtrate was concentrated and
the residue was purified by flash chromatography (hexanes–EtOAc,
3:7; Rf = 0.26) to give compound 7c as a white solid; yield: 33 mg
(56%); mp 112–114 °C.
1H NMR (250 MHz, CD3CN): δ = 8.10–7.99 (m, 1 H), 7.50–7.13 (m, 5
H), 6.64–6.48 (m, 2 H), 6.08–5.94 (m, 1 H), 5.94–5.75 (m, 2 H), 5.12 (s,
1 H), 4.76–4.61 (m, 1 H), 4.44 (dd, J = 12.4, 5.4 Hz, 1 H), 4.08 (s, 1 H),
2.99 (t, J = 11.4 Hz, 1 H).
(1) (a) Patchett, A. A.; Nargund, R. P. Ann. Rep. Med. Chem. 2000, 35,
289. (b) Marson, C. M. Chem. Soc. Rev. 2011, 40, 5514.
(2) For a review:Murineddu, G.; Asproni, B.; Pinna, G.; Curzu, M.
M.; Dore, A.; Pau, A.; Deligia, F.; Pinna, G. A. Curr. Med. Chem.
2012, 19, 5342.
(3) Selected examples: (a) Devijer, C.; Macours, P.; Braekman, J.-C.;
Daloze, D.; Pasteels, J. M. Tetrahedron; 1995, 51; 10913.
(b) Katritzky, A. R.; He, H.-Y.; Wang, J. J. Org. Chem. 2002, 67,
4951. (c) Vink, M. K. S.; Schortinghius, C. A.; Mackova-Zabelins-
kaja, A.; Fechter, M.; Pöchlauer, P.; Castelijns, A. M. C. F.; van
Maarseveen, J. H.; Hiemstra, H.; Griengl, H.; Schoemaker, H. E.;
Rutjes, F. P. J. T. Adv. Synth. Catal. 2003, 345, 483. (d) Toumi, M.;
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(e) Mortimer, A. J. P.; Pang, P. S.; Aliev, A. E.; Tocher, D. A.;
Porter, M. J. Org. Biomol. Chem. 2008, 6, 2941.
13C NMR (62.5 MHz, CDCl3): δ (major rotamer) = 157.4, 151.0, 148.3,
137.8 133.2, 129.5, 129.4, 127.2, 125.9, 121.9, 113.9, 108.6, 73.1, 46.2,
42.5.
HRMS (ESI): m/z [M + Na+] calcd for C17H15N3O2 + Na: 316.1056;
found: 316.1052.
(4) Yamada, S.; Takahashi, Y. Tetrahedron Lett. 2009, 50, 5395.
(5) Berti, F.; Di Bussolo, V.; Pineschi, M. J. Org. Chem. 2013, 78, 7324.
(6) For a recent example, see:Shi, S.-L.; Wei, X.-F.; Shimizu, Y.;
Kanai, M. J. Am. Chem. Soc. 2012, 134, 17019.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 647–652