A rapid approach to the synthesis of highly functionalized tetrahydroisoquinolines

Full text of DOI:10.1021/jo8025725

SCHEME 1. Proposed Synthesis of Tetrahydroisoquinoline 2
A Rapid Approach to the Synthesis of Highly
Functionalized Tetrahydroisoquinolines
Praew Thansandote, Christina Gouliaras,
Marc-Olivier Turcotte-Savard, and Mark Lautens*
Department of Chemistry, UniVersity of Toronto, 80 St.
George Street, Toronto, Canada M5S3H6
sequence. In this manner, tetrahydroisoquinoline 2 could be
formed from aryl derivative 1 by an intramolecular ortho-
alkylation with a tethered alkyl halide, an intermolecular ortho-
alkylation with an external alkyl halide, and a Heck reaction
with an alkene (Scheme 1). Variants of 1 can be obtained
through a short synthesis and all other reaction components are
readily available.
mlautens@chem.utoronto.ca
ReceiVed NoVember 19, 2008
In our previous studies, we have found that substrates with
all-carbon tethers inhibit Pd-catalyzed intramolecular ortho-
alkylations.6 However, using an oxygen tether is feasible and
leads to rapid syntheses of benzofurans, dibenzofurans, and
dihydrochromenes7 (Figure 1).
A palladium-catalyzed domino ortho-alkylation/alkenylation
forming up to three new C-C bonds furnishes functionalized
tetrahydroisoquinolines in up to 87% yield. Extension to the
formation of tetrahydrobenzoazepines and tetrahydroiso-
quinolinones is presented.
Tetrahydroisoquinoline natural products1 have been shown
to exhibit biological activity, rendering them potential pharma-
ceutical agents.2 Common routes to these compounds include
cyclizations such as the Pictet-Spengler and the Bischler-
Napieralski reactions.3 Although metal-mediated and metal-
catalyzed syntheses of these heterocycles are known,4 very few
methods allow for easy variation of the substituents present in
the benzenoid ring of these compounds.5 Due to our interest in
developing novel routes to common heterocycles, we targeted
the synthesis of variably substituted tetrahydroisoquinolines by
a Pd-catalyzed, norbornene-mediated domino process which can
form up to three carbon-carbon bonds in one synthetic
FIGURE 1. Synthesis of benzofurans, dibenzofurans, and dihydro-
chromenes.
Although benzylic ether substrates are successful, to the best
of our knowledge, Pd-catalyzed ortho-alkylations with benzylic
amine tethers have not been reported. Switching from a benzylic
ether to a benzylic amine appeared to be a straightforward
change, but obtaining appreciable yields of tetrahydroisoquino-
line 2 proved to be challenging. The substituent on nitrogen
was crucial, and the N-Ts-protected 1 proved most reliable.
Other groups that were tested (Bn, PMB, Cbz, and CO2Et)
resulted in substrate decomposition. This may be due to the
lone pairs on nitrogen displacing the halide and the resulting
aziridinium ion failing to cyclize. Performing the reaction under
microwave irradiation using standard conditions7a,8 or with other
ligand and catalyst combinations9 resulted in no product.
Optimizing using N-Ts-1 from these standard conditions (Table
1, entry 1), independently lowering the amounts of Cs2CO3,
n-butyl iodide, DME and tert-butyl acrylate increased or had
(1) (a) Saito, E.; Daikuharo, N.; Saito, N. Heterocycles 2007, 74, 411. (b)
Ma, M.; Zhao, J.; Wang, S.; Li, S.; Yang, Y.; Shi, J.; Fan, X.; He, L. J. Nat.
Prod. 2007, 70, 337. (c) Lane, J. W.; Estevez, A.; Mortada, K.; Callan, O.;
Spencer, J. R.; Williams, R. M. Bioorg. Med. Chem. Lett. 2006, 16, 3180.
(2) (a) Chafeev, M.; Chowdhury, S.; Fu, J.; Kamboj, R.; Hou, D.; Liu, S.
PCT Int. Appl. WO2008046084, 2008. (b) Vohra, R.; Wei, C.-Q.; Gan, Z.;
Demnitz, J.; Ahring, P. K. PCT Int. Appl. WO2007115408, 2007. (c) Defert,
O.; Leysen, D.; Van Rompaey, P. PCT Int. Appl. WO2008049919, 2008. (d)
Chicharro, R.; Alonso, M.; Aran, V. J.; Herradon, B. Tetrahedron Lett. 2008,
49, 2275. (e) Pandey, M. B.; Singh, A. K.; Singh, V. P. Mycobiology 2007, 35,
157.
(6) Flash vacuum pyrolysis with magnesium can form similar products: Aitken,
R. A.; Hodgson, P. K. G.; Morrison, J. J.; Oyewale, A. O. J. Chem. Soc., Perkin
Trans. 1 2002, 402.
(7) (a) Pache, S.; Lautens, M. Org. Lett. 2003, 5, 4827. (b) Jafarpour, F.;
Lautens, M. Org. Lett. 2006, 8, 3601. (c) Alberico, D.; Rudolph, A.; Lautens,
M. J. Org. Chem. 2007, 72, 775.
(8) Microwave irradiation was attempted using the conditions listed in Table
1, entry 1, at 190 °C for 5 min and 170 °C for 10 min, both of which gave
messy reactions with unidentifiable products.
(9) Only Pd(OAc)2 and PdCl2 have been successful catalysts for our
palladium-catalyzed, norbornene-mediated domino reactions, and the latter
catalyst yielded no product. Only tri-2-furylphosphine and triphenylphosphine
have been successful ligands, and the former yielded only traces of product.
(3) For a recent review, see: Chrzanowska, M.; Rozwadowska, M. D. Chem.
ReV. 2004, 104, 3341.
(4) (a) Young, D. D.; Sripada, L.; Deiters, A. J. Comb. Chem. 2007, 9, 735.
(b) Alezra, V.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2001,
42, 2111. (c) Grigg, R.; Inman, M.; Kilner, C.; Ko¨ppen, I.; Marchbank, I.; Selby,
P.; Sridharan, V. Tetrahedron 2007, 63, 6152. (d) Zhang, Z.; Leitch, D. C.; Lu,
M.; Patrick, B. O.; Schafer, L. L. Chem.sEur. J. 2007, 13, 2012, and references
cited therein.
(5) Some exceptions: the first two citations in ref 4 and this non-metal
example: Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo, Z.;
Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720.
10.1021/jo8025725 CCC: $40.75
Published on Web 01/08/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1791–1793 1791

TABLE 1. Optimizationa for Tetrahydroisoquinoline Product 2a
TABLE 3. Scope for Ortho-Blocked Tetrahydroisoquinolines 5
Cs2CO3 DME n-BuI tert-butyl acrylate norbornene yieldb
entry (equiv) (M) (equiv)
(equiv)
(equiv)
(%)
1
2
3
4
5
6
7
5
3
5
5
5
5
3
0.1
0.1
0.1
0.2
0.1
0.1
0.2
10
10
10
10
10
2
5
5
2
5
5
5
2
11
5
5
5
6
-
10
17
19
37
44
46c
entry
substrate
R3
product
yielda (%)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
CO2-t-Bu
CO2Et
CO2Me
5a
5b
5c
5d
5e
5f
5g
5h
5i
70
73
74
30
87
45
63
-
5
6
2
CN
a All reactions conducted with Pd(OAc)2 (10 mol %), PPh3 (20 mol
C(O)NH-t-Bu
2-pyridine
C(O)Me
phenyl
p-MeO-phenyl
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
%), Cs2CO3, n-BuI, tert-butyl acrylate, and norbornene in DME
b
(amounts indicated) at 80 °C for 16 h. 1H NMR yields using
mesitylene as an internal standard. c Isolated yield.
9
-
10
11
12
5j
5k
5l
75
50
30
TABLE 2. Scope for Tetrahydroisoquinolines 2
a Isolated yields.
TABLE 4. Scope for Ortho-Blocked Tetrahydrobenzoazepines 7
entry
R1X
R2
product yielda (%)
1
2
3
4
5
6
n-BuI
n-BuI
n-BuI
CO2t-Bu
C(O)NHt-Bu
CN
2a
2b
2c
2d
2e
2f
46
28
15b
31
38
34
methyl 4-bromobutyrate CO2t-Bu
1-chloro-3-iodopropane CO2t-Bu
2-methyl-1-iodopropane CO2t-Bu
entry
R2
product
yielda (%)
1
2
3
CO-2t-Bu
C(O)NH-t-Bu
C(O)Me
7a
7b
7c
47
38
59
a Isolated yields. b Isolated with minor impurities.
a Isolated yields.
no effect on the yield of 2a (entries 2, 3, 4 and 6). For an
efficient reaction with minimal waste, we maintained the use
of these lower amounts. However, a larger number of equiva-
lents of norbornene was necessary (entry 5). Combining these
independent variations gave us only 46% isolated yield (entry
7).10 We tested the scope using our best conditions to determine
how other substrates would behave (Table 2).
Methyl 4-bromobutyrate, 1-chloro-3-iodopropane, and 2-meth-
yl-1-iodopropane are all successful ortho-alkylators, giving 2d,
2e, and 2f in 31%, 38%, and 34% yields, respectively. Varying
the Heck acceptor to tert-butyl acrylamide and acrylonitrile gave
2b and 2c in lower yields. While the overall yields are not ideal,
the ease of introducing variations at two positions offers some
appeal for parallel synthesis.
could be varied from tert-butyl acrylate to ethyl and methyl
acrylate giving greater than 70% yields (entries 2 and 3). Use
of acrylonitrile resulted in modest yield (entry 4), while N-t-
Bu-acrylamide gave an excellent 87% yield (entry 5). The
presence of an electron-withdrawing group on the alkene appears
crucial since styrene and p-methoxystyrene failed to give the
desired products (entries 8 and 9). Other groups such as methoxy
and chloro can serve as ortho-position blockers. Products 5j
and 5k are formed in good yields, though 5l, containing an
o-chloro group, was lower yielding.
To expand the scope of this methodology we have shown
that larger ring sizes can also be formed (Table 4). The yields
for these reactions are reduced compared to those of the
corresponding tetrahydroisoquinolines, perhaps because the
intramolecular ortho-alkylation requires the formation of a
seven-membered ring. Nevertheless, this approach rapidly forms
substituted tetrahydrobenzoazepines, another important phar-
maceutical scaffold.12
Since having two sites for ortho-alkylation can lead to
selectivity issues, we speculated that eliminating the intermo-
lecular ortho-alkylation would simplify the process and produce
a cleaner reaction. Thus, we synthesized ortho-blocked substrate
4 and subjected it to our optimal conditions.11
We were pleased to observe the formation of tetrahydroiso-
quinoline 5a in 70% yield (Table 3, entry 1). The Heck acceptor
(12) (a) Nordvall, G.; Petersson, C.; Sehgelmeble, F. PCT Int. Appl.
WO2007004959, 2007. (b) Hal, I. H.; Wyrick, S. D. Pat. Appl. US85788200,
1987. (c) Kouznetsov, V.; Palma, A.; Salas, S.; Stashenko, E.; Gisela Montenegro,
N.; Angel Fontela, G. Heterocycl. Commun. 2000, 6, 519. (d) Briner, K.; Camp,
A. M.; Cornell, A.; Mazanetz, M. P.; Rothhaar, R. R.; Victor, F.; Williams,
A. C.; Zhang, D. PCT Int. Appl. WO2007028132, 2007.
(10) A major byproduct is the ortho-alkylation/halogen reduction product
that presumably forms from palladium oxidatively inserting into the alkyl halide
followed by ꢀ-hydride elimination. For more on this reaction, see ref 17.
(11) Compound 1 was not tried under these conditions.
1792 J. Org. Chem. Vol. 74, No. 4, 2009

SCHEME 2. Extension to Tetrahydroisoquinolinones
Tetrahydroisoquinolinones are also common motifs among
pharmaceuticals.13 Functionalized derivatives of these hetero-
cycles are usually synthesized through stepwise sequences,
though palladium-catalyzed domino processes involving aldol-
type condensations or carbonylations yielding ring-fused or
substituted isoquinolinones were recently reported by Alper14
and Da¨ıch.15 Using the present methodology, substituted tet-
rahydroisoquinolinone 9 can be synthesized from precursor 8
in 64% yield (Scheme 2). Compared to the tetrahydroisoquino-
lines, a lower concentration and amount of norbornene but a
higher amount of base and Heck acceptor are required for a
higher yield.
A proposed mechanism is presented in Figure 2.16 Pd(0)
inserts into the C-I bond of 1, followed by carbopalladation
with norbornene to give 10a. C-H activation of an ortho C-H
bond forms 10b. Oxidative addition of the tethered alkyl
bromide chain leads to the Pd(IV) species 10c, and reductive
elimination generates 10d. This process then occurs for the other
ortho C-H bond with an external alkyl halide to give complex
10e. Alternatively, intermolecular ortho-alkylation can happen
before intramolecular ortho-alkylation; at this time, we do not
know which process occurs first. Extrusion of norbornene,
presumably due to unfavorable steric interactions with the
neighboring ortho groups, gives the 2,4-dialkylated Pd(II)
complex 10f. The reduced form of 10f, resulting from an
intramolecular ortho-alkylation followed by a reduction to a
C-H bond, has been observed as a byproduct of these
reactions.17 Finally, a Heck termination with 10f yields product
2. We believe an excess of norbornene is needed to compete
with the direct Heck pathway.
FIGURE 2. Proposed mechanism for the formation of 2.
tetrahydrobenzoazepines and tetrahydroisoquinolones, two other
pharmaceutically important motifs.
Experimental Section
General Procedure for the Synthesis of Tetrahydroisoquino-
lines. To a 5 mL microwave vessel with a magnetic stir bar were
added 1 (99 mg, 0.2 mmol), Cs2CO3 (195.5 mg, 0.6 mmol), PPh3
(10.5 mg, 0.04 mmol), norbornene (113 mg, 1.2 mmol), Pd(OAc)2
(4.50 mg, 0.02 mmol), alkyl iodide (0.4 mmol), and alkene (0.4
mmol). The tube was sealed and flushed with argon, and dry,
degassed DME (1 mL) was added. The reaction was stirred at 80
°C for 16 h and then cooled to room temperature, diluted with ether
(1 mL), quenched with water (1 mL), and extracted with ether (3×)
and brine. The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure to yield the crude
material. Purification by column chromatography (pentanes/ethyl
acetate) gave the pure compounds.
In conclusion, we present a new and concise route to
substituted tetrahydroisoquinolines by a palladium-catalyzed,
norbornene-mediated domino reaction. Though up to three C-C
bonds can be formed in one pot, the reaction proceeds in higher
yields by the presence of an ortho-blocking group. The
methodology was successfully extended to the formation of
(13) (a) Ramamoorthy, S. P.; Shen, Z.; Harrison, B. L. PCT Int. Appl.
WO2006138549, 2006. (b) Montesharei, K.; Lebl, M.; Krahnak, V.; Ni, Y. PCT
Int. Appl. WO2001014879, 2001. (c) Schwink, L.; Stengelin, S.; Gossel, M.;
Hessler, G.; Haack, T.; Lennig, P. PCT Int. Appl. WO2007093366, 2007. (d)
Chen, X.; Chen, X.; Connors, R. V.; Dai, K.; Fu, Y.; Jaen, J. C.; Kim, Y.-J.; Li,
L.; Lizarzaburu, M. E.; Mihalic, J. C.; Shuttleworth, S. J. PCT Int. Ap-
pl.WO2006020959, 2006.
Acknowledgment. We gratefully acknowledge the financial
support of the University of Toronto, the Natural Sciences and
Engineering Research Council of Canada (NSERC), and Merck
Frosst Canada for an IRC. C.G. and P.T. thank NSERC for
USRA and CGSM/CGSD scholarships.
(14) (a) Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987. (b) Zheng, Z.;
Alper, H. Org. Lett. 2008, 10, 4903.
(15) Pin, F.; Comesse, S.; Sanselme, M.; Da¨ıch, A. J. Org. Chem. 2008, 73,
1975.
(16) Mechanism based on our own preliminary studies and the work of
Catellani and coworkers: (a) Catellani, M.; Fagnola, M. C. Angew. Chem., Int.
Ed. 1994, 33, 2421. (b) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem.,
Int. Ed. 1997, 36, 119. (c) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem.
Soc. 2004, 126, 78.
(17) For more information on reductive terminations in Pd-catalyzed,
norbornene-mediated domino reactions, see: (a) Mitsudo, K.; Thansandote, P.;
Wilhelm, T.; Mariampillai, B.; Lautens, M. Org. Lett. 2006, 8, 3939. (b) Wilhelm,
T.; Lautens, M. Org. Lett. 2005, 7, 4053. (c) Catellani, M.; Motti, E.; Della Ca’,
N.; Ferraccioli, R. Eur. J. Org. Chem. 2007, 4153. (d) Deledda, S.; Motti, E.;
Catellani, M. Can. J. Chem. 2005, 83, 741.
Supporting Information Available: Specific experimental
details and characterization data for all unknown compounds.
This material is available free of charge via the Internet at
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JO8025725
J. Org. Chem. Vol. 74, No. 4, 2009 1793