The scope and limitations of the Suzuki-Miyaura cross-coupling reactions of 6- and 8-substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylates

Article abstract of DOI:10.1016/S0040-4039(01)01132-7

6- and 8-Aryl-1,2,3,4-tetrahydroisoqinoline-3-carboxylates have been prepared by Suzuki-Miyaura cross-coupling reactions of the triflates or corresponding boronate esters. We have shown for the first time that a one-pot arylation of a triflate via the bor

Full text of DOI:10.1016/S0040-4039(01)01132-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5797–5800
The scope and limitations of the Suzuki–Miyaura cross-coupling
reactions of 6- and 8-substituted
1
,2,3,4-tetrahydroisoquinoline-3-carboxylates
Jeffrey M. McKenna,* John Moliterni and Ying Qiao
Metabolic and Cardiovascular Disease Research, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit,
NJ 07901, USA
Received 9 May 2001; accepted 19 June 2001
Abstract—6- and 8-Aryl-1,2,3,4-tetrahydroisoqinoline-3-carboxylates have been prepared by Suzuki–Miyaura cross-coupling
reactions of the triflates or corresponding boronate esters. We have shown for the first time that a one-pot arylation of a triflate
via the boronate ester can be achieved using an aryl chloride. © 2001 Elsevier Science Ltd. All rights reserved.
During the course of a recent medicinal chemistry
program we became interested in the synthesis of the
tetrahydroisoquinoline derived analogues of meta-
biphenylalanine (m-BiPhe), and further derivatives in
which variations could be made in the remote (with
respect to the parent a-amino acid) aromatic ring. The
use of these constrained analogues of amino acids can
lead to peptidomimetics of greater biological activity
ther complicating this approach would be the lack of
ability to control the regioselectivity of cyclization (8-
or 6-isomer; Fig. 1). Herein we report our efforts
toward regioselective routes to these two isomers and
the generality of our approach to constrained meta-
biarylalanine analogues.
We envisaged that the synthesis of these Tic analogues
would be possible from a common intermediate,
namely meta-tyrosine 1. The inherent advantages
within this strategy were the ease of incorporation of
many functional groups into the isoquinoline nucleus
via recent advances in palladium chemistry and the
mild conditions for the ring formation due to the
phenolic functionality (Scheme 1). Thus, treatment of 1
under Pictet–Spengler conditions yielded the expected
1
and also proteolytic stability. The 1,2,3,4-tetra-
hydroisoqinoline-3-carboxylic acid (Tic) nucleus has
2
3
been successfully used in ACE and renin inhibitors
4
5
and bradykinin and opioid antagonists.
A Pictet–Spengler cyclization of meta-biphenylalanine
to the corresponding 1,2,3,4-tetrahydroisoqinoline-3-
carboxylic acid is plausible, though few examples of a
Pictet–Spengler cyclization exist in which an unacti-
vated aromatic ring has been successfully utilized to
7
6-hydroxyl isomer in excellent yield. Following esterifi-
cation and N-protection the Tic analogue 4 was ready
for introduction of the second aryl unit through a
palladium mediated cross-coupling of its corresponding
triflate. In order to derive the 8-isomer, we brominated
6
direct the tetrahydroisoquinoline ring formation. Fur-
8
meta-tyrosine, thereby directing the subsequent Pictet–
9
Spengler cyclization through the vacant ortho position.
Cyclization, esterification and N-protection were con-
ducted under identical conditions as before yielding 8,
1
easily identified through analysis of its H NMR spec-
trum, a pair of coupled doublets at l 7.34 and 6.73 with
J=8.6 Hz.
Figure 1.
Hydrogenolytic removal of the bromine atom yielded
the desired 8-hydroxy-tetrahydroisoquinoline in excel-
lent yield. The triflates of both derivatives were easily
prepared using trifluoromethanesulfonic anhydride in
*
Corresponding author. Tel.: +1-908-277-4282; fax: +1-908-277-2405;
e-mail: jeffrey.mckenna@pharma.novartis.com
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01132-7

5
798
J. M. McKenna et al. / Tetrahedron Letters 42 (2001) 5797–5800
Scheme 1.
dichloromethane at 0°C. The utility of triflates is well
recognized within the sphere of palladium chemistry,
and their use in biaryl couplings with either boron
that the boron cross-coupling component could be
either a boronic acid or boronate ester, electron rich or
electron deficient, heterocyclic or sterically demanding.
In all cases the desired cross-coupled products were
generated in good to excellent yields (Table 1: 12/13a–
f). Similarly, the palladium catalysed process for the
preparation of the corresponding boronate esters, as
(
Suzuki–Miyaura) and tin (Stille) containing arenes has
10
been extensively demonstrated. We wished to exploit
this knowledge in two ways: firstly, through the Suzuki
reaction of the triflate and secondly to exploit the
generality of the ‘inverse’ Suzuki coupling-strategy
employing a variety of halides and the corresponding
13
reported by Miyaura, proceeded well for both of the
regioisomeric triflates (Table 2: 12/13g). We found this
to be especially true when additional dppf ligand was
added to the reaction to stabilize the palladium cata-
lyst, although the solvent of choice for the two sub-
1
1
boronate esters. This latter aspect was deemed advan-
tageous since the accessibility to a wide variety of
halides is far greater when compared with the corre-
sponding boronic acids or esters. Furthermore, this
approach allowed the possibility of realizing a one-pot
protocol for this arylation via the boronate ester.
1
4–16
strates needed some optimization. (Table 2).
Interestingly the reactivities of the resulting boronate
esters 12g and 13g were drastically different.
1
2
The Suzuki reactions with a variety of boronic acids
Table 1) proceeded well for either the 6- or 8-regioiso-
In examining the reactivity of the 6-isomer 12g (Table
(
3
) we found that the cross-coupling reaction with
meric triflates, yielding the desired biaryl derivatives.
17
iodides, bromides and chlorides yielded the desired
biaryl in good yields through careful choice of the
correct solvent and catalyst. The base had a dramatic
effect on yield, with less dramatic effects seen varying
either the catalyst or solvent, of which the catalyst
We found that the two triflates were able to undergo
the desired cross couplings within 4 h at 90°C. Through
our investigations of the Suzuki–Miyaura reactions for
these constrained amino acid aryl triflates we found
Table 1. Suzuki–Miyaura cross-coupling reactions of triflates 10 and 11
Substrate
Product
Yield (%)
Aryl boronic acid
Substrate
Product
Yield (%)
10
10
10
10
10
10
12a
12b
12c
12d
12e
12f
79
80
76
55
66
83
Phenyl
11
11
11
11
11
11
13a
13b
13c
13d
13e
13f
80
91
88
53
77
54
4-Chlorophenyl
3-Trifluoromethylphenyl
2-Methoxyphenyl
2,4,6-Trimethylphenyl
3-Thiophene
a
a
Conducted using 2,2-dimethyltrimethylene cyclic boronate ester, 1.0 mmol substrate, Pd(PPh3)4 5 mol%, K PO (2.0 equiv.), DMF at 100°C.
3
4

J. M. McKenna et al. / Tetrahedron Letters 42 (2001) 5797–5800
5799
Table 2. Preparation of boronate esters 12g and 13g
With this noted reactivity difference of the boronate
esters in hand, we attempted the utilization of the
Substrate
Product
Yield (%)
Conditionsa
6
-triflate in a one-pot strategy to yield the desired biaryl
15,20
compounds.
Thus, 10 was treated in DMF under
10
10
11
11
10
10
10
12g
12g
13g
13g
12g
12g
12g
17
50
68
35
65
77
69
Dioxane
DMSO
palladium catalysis with bis(pinacolato)diboron and
dppf for 3 h to derive 12g in situ and thereafter with
Dioxane, dppf
DMSO, dppf
Dioxane, dppf
DMSO, dppf
DMF, dppf
3
-iodo-benzotrifluoride and potassium phosphate in an
effort to prepare 12c (Scheme 2). The reaction gener-
ated the desired biaryl 12c in 75% yield and hence we
attempted the identical protocol utilizing 3-chloro-benzo-
trifluoride. The reaction was carried out again in
DMF but with dichlorobis(tricyclohexylphosphino)-
palladium(II) as the catalyst and cesium fluoride as
base for the latter coupling following the in situ prepa-
ration of the boronate ester. Pleasingly the reaction
proceeded to generate 12c in 67% yield.
a
All reactions were carried out using Pd(dppf)Cl2 5 mol%, KOAc
3.0 equiv.), bis(pinacolato)diboron (1.1 equiv.), in the presence or
absence of additional dppf ligand (Pd:L 1:1) as indicated at 80°C.
(
choice seemed to be the more important. Thus, our best
conditions for both rate and yield were the choices of
Hence, as a consequence of the differing reactivity of
the two boronate esters prepared, only for the 6-isomer
DMF as solvent and Pd(dppf)Cl as catalyst.
2
1
0 were we able to perform a one-pot transformation
The 8-isomer 13g failed to yield any cross-coupling
products in DME or DMF under the previous condi-
tions. Through our change of the triflate to boronate
ester within the Tic substrate we speculate that we have
directly impacted its role in the catalytic cycle.
Accordingly, for the Tic triflates, we believe a 14-elec-
via the boronate. We were able to show that this
one-pot protocol was possible both using an iodide and
chloride under appropriate conditions. The one-pot
protocol using the aryl chloride was successful and it
appears that the one-pot protocol is superior to the
sequential process. Thus, access to constrained biaryl-
11
21
tron PdL species to have oxidatively inserted into the
2
alanine a-amino acids is possible through two Suzuki–
CꢀO bond of the triflate and thereafter transmetallation
and reductive elimination proceeded to yield the desired
cross-coupled biaryl. In the latter boronate ester case
the Tic nucleus, in contrast, would now be incorporated
during the transmetallation step of the catalytic cycle.
We propose that the now coordinatively saturated 16-
electron palladium species R-PdL -OR is unable to
2
undergo transmetallation with this 8-boronate ester due
to steric and not electronic limitations. We only recover
from the reaction the homodimer of the initial halide.
In attempts to drive this reaction we employed a strong
base in a polar aprotic solvent and two variations of the
counter-ion of the base. Increasing base strength within
the Suzuki reaction is known to facilitate the reaction,
particularly when the boronic acid or ester is sterically
1
8
encumbered.
Ag(I)X, or Tl(I)X herein) have also been indicated to
aid the reactions by facilitating the transmetallation
Alternatively, insoluble metal halide
(
1
9
step. In our hands, all of these reaction conditions
Scheme 2.
failed to yield cross-coupling products of 13g.
Table 3. Suzuki–Miyaura cross-coupling reactions of boronate esters 12g and 13g
Substrate
Product
Solvent
Catalyst
Halide
Base
Yield (%)
12g
12g
12g
12g
12g
12g
12g
13g
13g
13g
13g
12h
12h
12h
12h
12i
12i
12i
13i
13i
13i
13i
DME
DME
DMF
DMF
DMF
DMF
NMP
DME
DMF
Benzene
Benzene
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(PPh3)4
3I-PhCO Et
K PO
55
27
62
45
66
57
69
2
3
4
3I-PhCO Et
K CO
2
2
3
3I-PhCO Et
K PO
2
3
4
3I-PhCO Et
K PO
2
3
4
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(PCy ) Cl
2
3I-Benzotrifluoride
3Br-Benzotrifluoride
3Cl-Benzotrifluoride
3I-Benzotrifluoride
3I-Benzotrifluoride
3I-Benzotrifluoride
3I-Benzotrifluoride
K PO
3
4
4
K PO
3
CsF
3
2
Pd(dppf)Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
K PO
No Reaction
No Reaction
No Reaction
No Reaction
3
4
K PO
3
4
Ag CO
2
3
Tl CO
2
3

5
800
J. M. McKenna et al. / Tetrahedron Letters 42 (2001) 5797–5800
Miyaura strategies. We will report our findings toward
the realization of an enantioselective synthesis of these
and similar derivatives in due course.
10. Tsuji, J. Palladium Reagents and Catalysts: Innovations in
Organic Synthesis; Wiley & Sons: New York, 1995;
Chapter 4, pp. 125–290.
1
1
1. Suzuki, A. J. Organomet. Chem. 1999, 147–168.
2. Representative example: The triflate 10 (0.440 g, 1.00
mmol), 3-thiopheneboronic acid (0.150 g, 1.17 mmol),
Pd(PPh ) (0.015 g, 5 mol%), 2N Na CO (1.2 ml, 2.40
Acknowledgements
3
4
2
3
mmol), toluene:EtOH (4:1; 5 ml) were combined and
purged, then heated at 90°C for 24 h. Following parti-
tioning between water and EtOAc, washing and drying
the crude product was subjected to SiO2 eluting with
The authors thank Dr. Fariborz Firooznia for helpful
discussions.
EtOAc:hexane (1:5) to yield 12f (0.310 g, 83%); mp
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