Scheme 2 illustrates the extension of the acyl-Pictet–Spengler
reaction in multiphasic scCO2/CO2-expanded liquid media to
include the synthesis of tetrahydro-b-carbolines. Reaction of
tryptamine 2218 with CO2 and DBC affords 23 which reacts with
HCHO in the presence of TFA to furnish 24 in 61% overall yield.
The application of this general strategy for utilizing amines in
other C–N bond-forming reactions in environmentally-friendly
media is under investigation.
Table 2 Synthesis of tetrahydroisoquinolines
We thank the Cambridge-MIT Institute (CMI) for generous
financial support and Dr Michael T. Timko and Russ Lachance
for helpful discussions concerning reactor design and operation.
Carbonate R1
Entry Amine (equiv.)
Yield
Acida Product (%)b
R2
1
2
3
4
5
6
7
8
13
1
1
1
1
1
1
1
1
1
1
1
Me (2.0)
Me (2.0)
Me (2.0)
Me (7.5)
Me (2.0)
Me (7.5)
Me (2.0)
Me (7.5)
Me (2.0)
Bn (2.0)
Bn (2.0)
Bn (2.0)
H
H
H
H
Ph
Ph
i-Pr
i-Pr
H2SO4 14
H2SO4 15
52
54
62
63
56
69
53
71
49
67
71
57
Notes and references
TFA
15
1 (a) R. S. Oakes, A. A. Clifford and C. M. Rayner, J. Chem. Soc., Perkin
Trans. 1, 2001, 917; (b) P. G. Jessop and W. Leitner, Chemical Synthesis
Using Supercritical Fluids, Wiley-VCH, Weinheim, New York, 1999; (c)
W. Leitner, Top. Curr. Chem., 1999, 206, 107.
2 (a) R. D. Weinstein, A. R. Renslo, R. L. Danheiser, J. G. Harris and
J. W. Tester, J. Phys. Chem., 1996, 100, 12337; (b) A. R. Renslo,
R. D. Weinstein, J. W. Tester and R. L. Danheiser, J. Org. Chem., 1997,
62, 4530; (c) R. D. Weinstein, A. R. Renslo, R. L. Danheiser and
J. W. Tester, J. Phys. Chem. B., 1999, 103, 2878.
3 C. K. Y. Lee, A. B. Holmes, B. Al-Duri, G. A. Leeke, R. C. D. Santos
and J. P. K. Seville, Chem. Commun., 2004, 2622.
4 C. J. Smith, T. R. Early, A. B. Holmes and R. E. Shute, Chem.
Commun., 2004, 1976 and references therein.
H2SO4 15
H2SO4 16
H2SO4 16
H2SO4 17
H2SO4 17
9
CO2Mec H2SO4 18
H
Et
Ph
10
11
12
a
TFA
TFA
19
20
H2SO4 21
b
9.0 M H2SO4 or 50% v/v TFA in H2O. Isolated yields of
c
products purified by column chromatography. Reaction with
(MeO)2CHCO2Me as methyl glyoxylate equivalent.
5 S. Campestrini and U. Tonellato, Curr. Org. Chem., 2005, 9, 31.
6 S. Kainz, A. Brinkmann, W. Leitner and A. Pfaltz, J. Am. Chem. Soc.,
1999, 121, 6421.
7 A. Fu¨rstner, L. Ackermann, K. Beck, H. Hori, D. Koch,
K. Langemann, M. Liebl, C. Six and W. Leitner, J. Am. Chem. Soc.,
2001, 123, 9000.
8 T. Matsuda, T. Harada and K. Nakamura, Green Chem., 2004, 6, 440.
9 For examples, see: (a) P. G. Jessop, Y. Hsiao, T. Ikariya and R. Noyori,
J. Am. Chem. Soc., 1996, 118, 344; (b) K. Wittmann, W. Wisniewski,
R. Mynott, W. Leitner, C. L. Kranemann, T. Rische, P. Eilbracht,
S. Kluwer, J. M. Ernsting and C. J. Elsevier, Chem. Eur. J., 2001, 7,
4584; (c) M. Shi, S.-C. Cui and Q.-J. Li, Tetrahedron, 2004, 60, 6163.
10 (a) W. M. Whaley and T. R. Govindachari, In Organic Reactions,
R. Adams, Ed., John Wiley and Sons, New York, 1951, vol. 6, p 151; (b)
E. D. Cox and J. M. Cook, Chem. Rev., 1995, 95, 1797.
11 (a) D. B. Dell’Amico, F. Calderazzo, L. Labella, F. Marchetti and
G. Pampaloni, Chem. Rev., 2003, 103, 3857; (b) H. Fischer,
O. Gyllenhaal, J. Vessman and K. Albert, Anal. Chem., 2003, 75, 622.
12 (a) M. Yoshida, N. Hara and S. Okuyama, Chem. Commun., 2000, 151;
(b) M. Alba, J.-C. Choi and T. Sakakura, Chem. Commun., 2001,
2238.
13 P. Tundo and M. Selva, Acc. Chem. Res., 2002, 35, 706.
14 For the conversion of amines to methyl carbamates with DMC and
CO2, see: (a) M. Aresta and E. Quaranta, Tetrahedron, 1991, 47, 9489;
(b) M. Selva, P. Tundo and A. Perosa, Tetrahedron Lett., 2002, 43, 1217;
(c) M. Selva, P. Tundo, A. Perosa and F. Dall’Acqua, J. Org. Chem.,
2005, 70, 2771.
Scheme 2 Synthesis of tetrahydro-b-carbolines via Pictet–Spengler reac-
tion. (a) 5 equiv. CO(OBn)2, scCO2, 130 uC, 130 bar, 24 h; (b) add
1.3 equiv. aq. HCHO, 1.3 equiv. 50% aq. TFA, 80 uC, 160 bar, 24 h.
Both electron-neutral and electron-rich b-arylethylamines partici-
pate in the reaction, which can also be applied to a variety of
aliphatic and aromatic aldehydes. Acyl-Pictet–Spengler reaction
with methyl glyoxylate can be achieved by introducing this
aldehyde in the form of its dimethyl acetal derivative.
Trifluoroacetic acid can be employed in place of H2SO4 to
promote iminium ion formation, and its use leads to somewhat
improved yields due to the sensitivity of some carbamate groups to
sulfuric acid under these conditions. Finally it was noted that the
overall yield for this two-stage process improves somewhat as the
volume of DMC increases from 2.0 to 7.5 equiv. relative to amine.
This effect is attributed to improved selectivity for carbamate
formation over N-methylation as discussed above.
15 Reviewed in: B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi
and C. A. Maryanoff, Chem. Rev., 2004, 104, 1431.
16 Confirmed through control experiments. Styrene product 12 is generated
by N-methylation of 11 by DMC followed by elimination of Me3N.
17 (a) J. Im, M. Kim, J. Lee and H. Kim, J. Chem. Eng. Data, 2004, 49,
243; (b) S. Camy, J.-S. Pic, E. Badens and J.-S. Condoret, J. Supercrit.
Fluid, 2003, 25, 19.
18 Electrophilic addition of the aldehyde to the indole was observed unless
the sulfonamide derivative was employed.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 4465–4467 | 4467