Calcium-catalyzed pictet-spengler reactions

Article abstract of DOI:10.1021/ol802173r

(Chemical Equation Presented) Pictet-Spengler reactions of m-tyramine and aldehydes produced tetrahydroisoquinolines in the presence of a catalytic amount of Ca[OCH(CF₃)₂]₂. This reaction occurs with a variety of aryl, het

Full text of DOI:10.1021/ol802173r

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5289-5291
Calcium-Catalyzed Pictet-Spengler
Reactions
Matthew J. Vanden Eynden and James P. Stambuli*
EVans Chemical Laboratories, Department of Chemistry, The Ohio State UniVersity,
100 West 18th AVenue, Columbus, Ohio 43210
stambuli@chemistry.ohio-state.edu
Received September 17, 2008
ABSTRACT
Pictet-Spengler reactions of m-tyramine and aldehydes produced tetrahydroisoquinolines in the presence of a catalytic amount of Ca[OCH(CF3)2]2.
This reaction occurs with a variety of aryl, heteroaryl, and alkyl aldehydes, producing tetrahydroisoquinolines in high yield and with high
regioselectivity. This calcium-promoted Pictet-Spengler reaction provides a mild alternative to the traditional Brønsted acids typically employed
in these reactions.
The use of calcium complexes as catalysts for organic
transformations has seen a slow but steady growth over the
past decade. Calcium is an attractive Lewis acid catalyst
because of its low toxicity and cost. However, calcium is
not traditionally thought of as a catalyst for organic trans-
formations.1 Recently, groups have employed calcium cata-
lysts to promote alkene hydroaminations2 and hydrophos-
phinations,3 and aldol,4 Michael,5 epoxidation,6 and Tishcenko
reactions.7 In addition, chiral complexes of calcium have
been used as catalysts in enantioselective processes.8
Recently, we have begun a program in our laboratories to
expand the use of calcium complexes in organic synthesis.
Although the role of calcium has been studied greatly in
biochemical processes,9 there are not enough studies related
to the behavior of calcium complexes in organic processes.
However, as a greater awareness of the utility of calcium is
displayed, more chemists will be attracted to study and
employ this underutilized Lewis acid in organic chemistry.
The Pictet-Spengler reaction has been used in the
synthesis of alkaloids as the key step in the formation of
tetrahydroisoquinolines and ꢀ-carbolines.10 Typically, strong
Brønsted acids are used to promote this reaction, and in some
cases, poor regioselectivities are observed. Although activated
substrates containing a catechol functionality undergo Pictet-
Spengler reactions under mildly acidic conditions,11 other less
activated substrates provide low conversions (vide infra).
Lewis acid catalyzed Pictet-Spengler reactions have been
previously reported in the literature.12 Although a large
(1) Alexander, J. S.; Ruhlandt-Serge, K. Eur. J. Inorg. Chem. 2002, 2761.
(2) (a) Crimmin, M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem. Soc.
2005, 127, 2042. (b) Datta, S.; Roesky, P. W.; Blechert, S. Organometallics
2007, 46, 4392.
(3) (a) Crimmin, M. R.; Barrett, A. G. M.; Hill, M. S.; Hitchcock, P. B.;
Procopiou, P. A. Organometallics 2007, 26, 2953. (b) Crimmin, M. R.;
Barrett, A. G. M.; Hill, M. S.; Hitchcock, P. B.; Procopiou, P. A.
Organometallics 2008, 27, 497.
(4) Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.; Yamaguchi,
K.; Shibasaki, M.; Nyori, R. Tetrahedron Lett. 2001, 42, 4669.
(5) Kumaraswamy, G.; Sastry, M. N. V.; Jena, N. Tetrahedron Lett.
2001, 42, 8515.
(9) Sigel, H.; Sigel, A. Metal Ions in Biological Systems. Calcium and
Its Role in Biology; Dekker: New York, NY, 1984.
(6) (a) Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Ramakrishna, G.
ArkiVoc 2005, 15, 53. (b) Kumaraswamy, G.; Sastry, M. N. V.; Jena, N.;
Ravi Kumar, K.; Vairamani, M. Tetrahedron: Asymmetry 2003, 14, 3797.
(7) Crimmin, M. R.; Barrett, A. G. M.; Hill, M. S.; Procopiou, P. A.
Org. Lett. 2007, 9, 331.
(10) (a) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797. (b) Pearson,
W. H.; Lian, B. W. Angew. Chem., Int. Ed. 1998, 37, 1724. (c) Xu, Y.-C.;
Kohlman, D. T.; Liang, S. X.; Eriksson, C. Org. Lett. 1999, 1, 1599. (d)
Zhou, B; Guo, J; Danishefsky, S. J. Org. Lett. 2002, 4, 43. (e) Bailey, P. D.;
Morgan, K. M. J. Chem. Soc., Perkin Trans. 1 2000, 3578. (f) Magnus, P.;
Matthews, K. S.; Lynch, V. Org. Lett. 2003, 5, 2181.
(8) (a) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165.
(b) Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Padmaja, M.; Markon-
daiah, B. AdV. Synth. Catal. 2005, 347, 867. (c) Saito, S.; Tsubogo, T.;
Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364. (d) Kobayashi, S.;
Tsubogo, T.; Saito, S.; Yamashita, Y. Org. Lett. 2008, 10, 807.
(11) (a) Bates, H. A. J. Org. Chem. 1981, 46, 4931. (b) McMurtrey,
K. D.; Meyerson, L. R.; Cashaw, J. L.; Davis, V. E. J. Org. Chem. 1984,
49, 948.
10.1021/ol802173r CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society

Table 1. Screening of Calcium Complexes
Table 2. Scope of Reaction Catalyzed by Ca[(OC(H)(CF3)2]2
entry
catalyst
no catalyst
2 M NaOH
Ca(OH)2
CaF2
CaCI
CaI2
Ca(OTf)2
Ca(OMe)2
Ca(Oi-Pr)2
R
yield (%)a ratio (2:3)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
19
57
16
40
17
43
22
92
93
97
>99
0
9:1
16:1
12:1
8:1
5:1
5:1
6:1
25:1
38:1
100:0
100:0
10 Ca(THF)2(HMDS)2
11 Ca(BDI)
12 Ca(Oi-Pr)2
13 Ca(THF)2(HMDS)2
14 Ca(BDI)
15 Ca(hexafluoroisopropoxide)2
NMe2
NMe2
NMe2
H
0
7
>99
>99
100:0
100:0
16 Ca(hexafluoroisopropoxide)2 NMe2
a
1
Yield and ratio determined by H NMR spectroscopy.
number of Lewis acids were screened in those papers,
calcium complexes were not included in any of the studies.
Kobayashi showed the use of 10 mol % of Yb(OTf)3 in the
presence of 3Å molecular sieves; however, the reaction scope
was narrow, with only three examples reported in 55-98%
yield.12c
a Isolated yields. b Isolated as an 8:1 mixture of isomers.
Using Kobayashi’s conditions as a starting point, m-
tyramine (1) and benzaldehyde were combined in the
presence of 3Å MS and 10 mol % catalyst in CH2Cl2 and
reaction conditions, with benzaldehyde being replaced with
4-(dimethylamino)benzaldehyde. Suprisingly, none of these
cataylsts were reactive using the electron-rich benzaldehyde.
From the simple assumption that increasing the Lewis acidity
at the calcium center should generate a more reactive catalyst,
we synthesized Ca(hexafluoroisopropoxide)2 (4) and applied
it to our reaction conditions. In both cases of aldehydes,
catalyst 4 provided the corresponding products (2a, 2b) in
excellent yield and regioselectivity (entries 15 and 16).
To probe the utility of this catalyst system, we explored
the substrate scope of this process (Table 2). As shown in
the table, the reaction of m-tyramine with various aldehydes
in the presence of 4, produces a variety of 6-hydroxy-
tetrahydroisoquinolines in high yields and regioselectivities.
The existence of electron-donating (entries 2-5) and electron-
withdrawing groups (entries 6-9) on the arenes did not have
an effect on yield or regioselectivity. Interestingly, 2-pyridine
carboxaldehyde was the lone substrate that produced ap-
preciable amounts of both regioisomers (8:1, 6-ol:8-ol) (entry
11). One explanation for the appearance of the 8-ol regioi-
somer in this example may be simultaneous coordination of
the calcium center to the pyridine nitrogen and oxygen of
1
monitored by H NMR spectroscopy (Table 1). Although
activated toward the cyclization reaction, 1 is converted to
the desired product in 19% yield in the absence of catalyst
(entry 1). The addition of sodium hydroxide to the reaction
gave 57% yield of 2a and 3a in a 16:1 ratio. We then
screened a wide range of calcium complexes that were
commercially available or easily prepared.13 Low yields and
selectivity were observed when calcium halides were em-
ployed to promote the reaction (entries 4-6). Calcium
alkoxides, Ca(HMDS)2(THF)2,14 and Ca(BDI)15 gave tet-
rahydroisoquinoline product in high yields and with complete
selectivity as determined by 1H NMR spectroscopy (entries
8-11). The best catalysts were then subjected to similar
(12) (a) Tsuji, R.; Yamanaka, M.; Nishida, A.; Nakagawa, M. Chem.
Lett. 2002, 428. (b) Srinivasan, N.; Ganesan, A Chem. Commun. 2003, 916.
(c) Manabe, K.; Nobutou, D.; Kobayashi, S. Biorg. Med. Chem. Lett. 2005,
13, 5154. (d) Youn, S. J. Org. Chem. 2006, 71, 2521.
(13) See Supporting Information for detailed procedures.
(14) He, X.; Hurley, E.; Noll, B. C.; Henderson, K. W. Organometallics
2008, 27, 3094.
(15) BDI ) CH[CMeNC6H3-2,6-Pri2]2. Chisholm, M. H.; Gallucci, J. C.;
Phomphrai, K. Inorg. Chem. 2004, 43, 6717.
5290
Org. Lett., Vol. 10, No. 22, 2008

calcium hydroxide in dichloromethane. We then synthesized
the corresponding metal hexafluoroisopropoxide complexes
and compared their catalytic ability to 4. These complexes
all gave low yields (entries 6-8), except for barium
hexafluoroisopropoxide, which gave the desired product
regioselectively in 88% yield. However, barium bis(hexaflu-
oroisopropoxide) does not catalyze the conversion of 1 and
p-dimethylaminobenzaldehyde to 2b. These results suggest
the calcium cation has a large effect on this transformation
and this is not simply a base-promoted process.
Table 3. Cation Effect
entry
catalyst
yielda
ratio (2:3)
Currently, the exact role of calcium in this process is
unclear. The use of less reactive Pictet-Spengler substrates
such as tryptamine did not produce cyclization to the desired
product under our conditions, as we only observed their
1
2
3
4
5
6
7
8
9
2 M NaOH
2 M KOH
LiOH·H2O
Ba(OH)2
57
55
61
50
15
35
22
15
88
16:1
10:1
30:1
16:1
15:2
25:2
27:2
8:1
1
Ca(OH)2
corresponding imines by H NMR spectroscopy. A similar
result was reported by Kobayashi.12c
Na(hexafluoroisopropoxide)
Li(hexafluoroisopropoxide)
K(hexafluoroisopropoxide)
Ba(hexafluoroisopropoxide)2
Ca(hexafluoroisopropoxide)2
1
In summary, we report a practical method to synthesize
1,2,3,4-tetrahydroisoquinolines that is mediated by a novel
calcium hexafluoroisopropoxide complex. This method pro-
vides a mild alternative to the typical conditions requiring
strong Brønsted acids. Future work in this area involves
identifying the exact role of the calcium catalyst, which
should assist us in expanding the scope of this reaction to
include less reactive tryptamine and tryptophan substrates.
We are also investigating the use of chiral calcium complexes
to effect an enantioselective version of this Pictet-Spengler
reaction.
100:0
100:0
10
a
>99
Yield and ratio were determined by H NMR spectroscopy.
the phenol. This catalyst also promoted the reaction of trans-
cinnamaldehyde with m-tyramine in 96% yield (entry 12),
whereas the Yb(OTf)3 catalyst system gave a complex
mixture of products under similar conditions. The imines of
alkyl aldehydes also underwent cyclization to the corre-
sponding products in high yields (entries 13-15). The use
of pivaldehyde did not allow product formation, and we
attribute this unreactivity to obvious steric reasons (entry 16).
In an effort to further understand the role of calcium in
these reactions, we investigated the influence that other
cations invoked on this reaction. We evaluated a number of
Group I and Group II metal hydroxides under our optimized
reaction conditions (Table 3). The yields observed for all
metal hydroxides did not appear to vary greatly as they
ranged between 50-60%, except for the low yield of calcium
hydroxide, which we attribute to the poor solubility of
Acknowledgment. This work was generously supported
by The Ohio State University. We thank the Ohio BioProd-
ucts Innovation Center (OBIC) for the grant that provided
the Bruker MicroTOF instrument used to obtain mass spectral
data.
Supporting Information Available: Experimental pro-
cedures and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL802173R
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