M. Bandini, G. P. Miscione et al.
scription. Unfortunately, this class of interactions cannot be correctly
treated by the most popular DFT functionals (for instance, B3LYP),
which are inaccurate for interactions where medium-range correlation ef-
fects are dominant.[21] Even if p–p interactions can be satisfactorily de-
scribed by the MP2 method, this approach is unfeasible for the large
model system used here, because it would require too much CPU time
for practical and extensive usage. However, a new hybrid functional (de-
noted as MPWB1K) has recently been proposed by Trulhar.[22] This func-
tional has been demonstrated to be capable of treating medium-range
correlation effects and to provide a good estimate of the p–p interactions
and reaction energetics[23,24] using reasonable amounts of CPU time.
Thus, all DFT computations reported in the present paper were carried
out with the Gaussian 03 series of programs[25] using the MPWB1K[22]
functional and the DZVP basis set.[26] The DZVP basis is a local spin
density (LSD)-optimized basis set of double-zeta quality, which includes
polarization functions and is suitable for describing weak hydrogen
bonds and p interactions such as those occurring in the system investigat-
ed here. The transition vector of the various transition states was ana-
lyzed by means of frequency computations.
3J
1H), 4.13–4.26 (m, 2H), 4.81 (s, 2H), 5.06 (br, 1H), 7.21–7.31 (m, 2H),
7.46 (s, 2H), 7.51 (s, 1H), 7.80 ppm (d, 3J(H,H)=8.1 Hz, 1H); 13C NMR
(50 MHz, [D]CHCl3): d=14.1, 35.8, 47.3, 61.5, 69.7, 110.1, 111.1, 121.8,
122.8, 123.5, 126.5, 127.2, 135.8, 159.3, 170.3 ppm; ESI-MS: m/z (%): 274
[M+1]+.
(H,H)=12.0 Hz, 1H), 3.02 (dd, 3J(H,H)=16.8 Hz, 3J
ACHTUNGTRENUNGN ACHTUNRTGENNGNU ACHTNUGTRENUN(GN H,H)=9.3 Hz,
AHCTUNGTRENNUNG
Typical procedure for the PTC intramolecular aza-Michael addition (1l
and 1m): Method A: A sample vial was charged with reagent grade tolu-
ene (6 mL), the indolyl-ester 3l or 3m (50 mmol) and catalyst 4a (3 mg,
5 mmol). An aqueous solution of KOH (25%, 6 mL, 0.5 equiv) was added
to the mixture by syringe and immediately cooled to ꢀ458C. The reac-
tion was stirred at the same temperature for 16 h, then the solvent was
evaporated under reduced pressure. The crude product was purified di-
rectly through a pad of silica. Method B: same conditions but at RT.
Data for 1l:[15] Yield: 82%; flash chromatography (c-Hex/AcOEt=8:2);
ee=54%; [a]D =ꢀ20.1 (c=1.3 in chloroform); HPLC analysis: OD
column (210 nm), RT, method: n-Hex/IPA=90:10, flow 1.0 mLminꢀ1
,
t(major) =21.3 min, t(minor) =25.6 min.
Data for 1m:[15] Yield: 77%; flash chromatography (c-Hex/AcOEt=
85:15); ee=56%; [a]D =+4.6 (c=1.5 in chloroform); HPLC analysis:
OD column (214 nm), RT, method: n-Hex/IPA=90:10, flow
1.0 mLminꢀ1, t(minor) =14.9 min, t(major) =19.4 min.
Typical procedure for the PTC intramolecular aza-Michael addition (1i
and 1j): A sample vial was charged with reagent grade toluene (6 mL),
the indolyl-ester 3 (50 mmol) and catalyst 4a (3 mg, 5 mmol). An aqueous
solution of KOH (25%, 6 mL, 0.5 equiv) was added to this mixture by sy-
ringe, and immediately cooled to ꢀ458C. The reaction was stirred at the
same temperature for 16 h, then the solvent was evaporated under re-
duced pressure. The crude product was purified directly through a pad of
silica.
Acknowledgements
(S)-Ethyl-2-[2-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahydropyrazinoACTHNUTRGNE[UNG 1,2-
a]indol-4-yl]acetate (1i): Yellow solid; flash chromatography (c-Hex/
AcOEt=8:2); m.p. 78.5–80.88C; yield: 97%; ee=90%; [a]D =+4.6 (c=
0.9 in chloroform); HPLC analysis: AD column (214 nm), 408C, method:
Acknowledgement is made to the MIUR (Rome), FIRB Project (Proget-
tazione, preparazione e valutazione biologica e farmacologica di nuove
molecole organiche quali potenziali farmaci innovativi), Universitꢀ di Bo-
logna and Fondazione del Monte di Bologna e Ravenna.
n-Hex/IPA=70:30, flow 1.0 mLminꢀ1
,
t
(S) =15.9 min,
G
t
(R) =23.0 min;
1H NMR (300 MHz, [D]CHCl3): d=1.19 (t, 3J
3
2.53 (m, 2H), 3.59 (d, J
G
3H), 4.12 (d, 3J
(H,H)=14.1 Hz, 1H), 6.87 (d, 3J
7.29–7.32 (m, 5H), 7.71 ppm (d, 3J
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
[1] a) D. J. Faulkner, Nat. Prod. Rep. 2002, 19, 1–48; b) A. Kleeman, J.
Engel, B. Kutscher, D. Reichert, Pharmaceutical Substances, 4th ed.,
Thieme, New York, 2001; c) J. Sundberg, Pyrroles and Their Benzo-
derivatives: Synthesis and Applications in Comprehensive Heterocy-
clic Chemistry, Vol. 4 (Eds.: A. R. Katritzky, C. W. Rees), Pergamon,
Oxford, 1984, pp. 313–376; d) A. Joule, Indole and its Derivatives in
Science of Synthesis: Houben-Weyl Methods of Molecular Transfor-
mations, Vol. 10 (Ed.: E. J. Thomas), Thieme, Stuttgart, 2000; Chap-
ter 10.13.
A
ACHTUNGTRENNUNG
(75 MHz, [D]CHCl3): d=13.9, 35.8, 47.2, 48.1, 48.7, 55.2, 61.0, 107.0,
109.5, 114.2, 120.9, 122.9, 124.7, 127.7, 128.3, 128.6, 130.1, 135.3, 159.3,
159.6, 170.4 ppm; ESI-MS: m/z (%): 393 [M+1]+.
(S)-Ethyl-2-[2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrazinoACTHNUTRGNE[UNG 1,2-
a]indol-4-yl]acetate (1j): Pale white solid; flash chromatography (c-Hex/
AcOEt=8:2); m.p. 88.3–91.78C; yield: 85%; ee=84%; [a]D =+2.4 (c=
1.7 in chloroform); HPLC analysis: AD column (214 nm), 408C, method:
b) R. Dalpozzo, G. Bartoli, Curr. Org. Synth. 2005, 2, 163–178; c) S.
ble, M. G. Saumier, E. T. Pelkey, T. L. S. Kishbaugh, Y. Liu, J. Jiang,
H. A. Trujillo, D. J. Keavy, D. A. Davis, S. C. Conway, F. L. Switzer,
S. Roy, R. A. Silva, J. A. Obaza-Nutatis, M. P. Sibi, N. V. Moskalev,
T. C. Barden, L. Chang, W. M. Habeski, B. Pelcman, W. R. Spon-
holtz III, R. W. Chau, B. D. Allison, S. D. Garaas, M. S. Sinha, M. A.
1493–1519; e) S. Agarwal, S. Cꢅmmerer, S. Filali, W. Froçhner, J.
[3] a) K. A. Jørgensen, Synthesis 2003, 1117–1125; b) M. Bandini, A.
3544; d) Y.-F. Sheng, A.-J. Zhang, X.-J. Zheng, S.-L. You, Chin. Org.
Chem. 2008, 28, 605–616; e) B. Poulsen, K. A. Jørgensen, Chem.
J. Org. Chem. 2010, 6, DOI: 10.3762/bjoc.6.6.
n-Hex/IPA=70:30, flow 1.0 mLminꢀ1
1H NMR (200 MHz, [D]CHCl3): d=1.14 (t, 3J
(d, 3J(H,H)=7.4 Hz, 2H), 3.59 (d, 3J
(H,H)=13.0 Hz, 1H), 3.90–4.07 (m,
3H), 4.87 (d, 3J(H,H)=14.6 Hz, 1H), 4.34 (d, 3J
(H,H)=14.6, 1H), 4.87–
4.96 (m, 1H), 5.17 (d, 3J(H,H)=14.6 Hz, 1H), 7.01–7.09 (t, 3J
(H,H)=
8.0 Hz, 2H), 7.17 (dt, 3J(H,H)=8.0, 3J
(H,H)=1.8 Hz, 1H), 7.32–7.39 (m,
5H), 7.70 ppm (d, 3J(H,H)=8.0 Hz, 1H); 13C NMR (75 MHz, [D]CHCl3)
d=14.2, 36.0, 47.5, 48.5, 49.0, 61.3, 107.5, 109.8, 116.0 (d, J=21.8 Hz),
121.3, 123.2, 125.1, 128.0, 128.3, 130.8 (d, J=7.8 Hz), 134.2 (d, J=
206.3 Hz), 159.9, 162.7 (d, J=244.5 Hz), 170.6 ppm; ESI-MS: m/z (%):
381 [M+1]+.
,
t
(S) =17.3 min,
t(R) =28.8 min;
AHCTUNGTRENNUNG
U
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
R
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Typical procedure for the PTC intramolecular aza-Michael addition (1k):
Indolyl ester 3k (20 mg, 0.07 mmol) was dissolved in toluene (4 mL) in a
10 mL round-bottomed flask equipped with a magnetic stirrer. After the
addition of the catalyst 3a (4 mg, 10 mol%), solid tBuOK (8.2 mg,
0.07 mmol) was added. After 1 h stirring at room temperature the start-
ing material was consumed (judged by TLC), and the reaction mixture
brought to dryness under vacuum and purified by flash chromatography.
(ꢀ)-Ethyl-2-(1-oxo-3,4-dihydro-1H-[1,4]oxazino
ACHTUNGTNER[NUNG 4,3-a]indol-4-yl)acetate
(1k): Pale yellow viscous oil; flash chromatography (c-Hex/AcOEt=
8:2); yield: 75%; ee=59%; [a]D =ꢀ12.5 (c=0.4 in chloroform); HPLC
analysis: AD column (214 nm), RT, method: n-Hex/IPA=80:20, flow
1.0 mLminꢀ1
,
t
(minor) =10.9 min,
t
(major) =13.3 min; 1H NMR (300 MHz,
(H,H)=7.2 Hz, 3H), 2.81 (dd, 3J
(H,H)=4.8 Hz,
3
[D]CHCl3): d=1.27 (t, J
A
ACHTUNGTRENNUNG
12472
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12462 – 12473