Synthesis of CF3-containing 1,2,3,4-tetrahydroisoquinoline-3- phosphonates via regioselective ruthenium-catalyzed co-cyclotrimerization of 1,7-aza-diynes

Article abstract of DOI:10.1055/s-0033-1339173

An efficient access to novel trifluoromethyl-substituted phosphonate analogues of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (TIC) derivatives based on regioselective ruthenium--catalyzed co-cyclotrimerization of functionalized 1,7-diynes with vario

Full text of DOI:10.1055/s-0033-1339173

LETTER
▌1517
lSetyternthesis of CF3-Containing 1,2,3,4-Tetrahydroisoquinoline-3-Phosphonates
via Regioselective Ruthenium-Catalyzed Co-cyclotrimerization of 1,7-Aza-
diynes
Synthesis of CF -Containing 1,2,3,4-Tetrahydroisoquinoline-3-Phosphonates
a
a
b
b
a
3
Maria A. Zotova, Daria V. Vorobyeva, Pierre H. Dixneuf, Christian Bruneau, Sergey N. Osipov*
a
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Str. 28, 119991 Moscow, Russia
Fax +7(499)1355085; E-mail: osipov@ineos.ac.ru
b
Centre of Catalysis and Green Chemistry, UMR 6226 CNRS-Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
Received: 04.04.2013; Accepted after revision: 07.05.2013
inhibitor quinapril,15 commercialized as Accupril, which
is currently used for the treatment of hypertension and
congestive heart failure (Figure 1).
Abstract: An efficient access to novel trifluoromethyl-substituted
phosphonate analogues of 1,2,3,4-tetrahydroisoquinoline-3-carbox-
ylic acid (TIC) derivatives based on regioselective ruthenium-
catalyzed co-cyclotrimerization of functionalized 1,7-diynes with
various alkynes has been developed using RuClCp*cod and pre-
ferably Grubbs second-generation catalysts.
On top of this, the introduction of CF3 groups into biolog-
ically relevant compounds has nowadays become an im-
portant tool in drug discovery.16 Indeed, many
biologically active compounds, for example, the antide-
pressant Prozac and the anticancer agent Casodex, contain
the CF3 groups as an additional essential motif.17 There-
fore, the development of efficient methods for the prepa-
ration of new TIC analogues, especially their CF3
derivatives, as potential enzyme inhibitors and unique
building blocks for peptide modification, is of great im-
portance.
Key words: α-aminophosphonates, 1,7-azadiynes, alkynes, cyclo-
trimerization, ruthenium catalysis
α-Aminophosphonates and related α-aminophosphonic
acids are structural analogues of the corresponding α-ami-
no acids.1–3 They contain a tetrahedral phosphonic acid
moiety that mimics the transition state of nucleophilic
substitution reactions at the carboxyl group of natural
amino acids,4 which makes them efficient competitors for
the active sites of enzymes and other cell receptors. As a
consequence, α-aminophosphonates have found a multi-
tude of applications in medicinal, agricultural, and indus-
trial chemistry.1–8
An efficient protocol for the preparation of protected α-
trifluoromethyl-substituted derivatives of tetrahydroiso-
quinoline-3-carboxylic acid (TIC) has been elaborated via
[2+2+2] cycloaddition of α-CF3-α-amino esters bearing
two terminal alkyne chains with another alkyne. In the
case of terminal alkynes the reaction led to the formation
of an inseparable mixture in a ratio 1:1 of 5(7)-regioiso-
mers.18 We now report on a convenient and selective ac-
cess to a hitherto unknown class of phosphonate
analogues of TIC, based on N-propargylation of α-al-
kynyl-α-CF3-α-aminophosphonates 119 followed by co-
cyclotrimerization20 with terminal alkynes and for the first
time via catalytic regioselective formation of the meta-
arene isomer promoted by two types of ruthenium cata-
lysts: RuClCp*COD and preferably the alkene-metathesis
Grubbs second-generation catalyst (Grubbs II, Scheme 1).
On the other hand, the 1,2,3,4-tetrahydroisoquinoline core
is found in organic molecules that exhibit a wide array of
biological activities, including antihypertensive,9 antitu-
mor,10 and antimalarial11 properties. Among them, the
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (TIC),
being a constrained analogue of phenylalanine, attracts a
special attention as an important building block to con-
struct highly selective enzyme inhibitors,12 antagonists of
integrins,13 and δ-opioid receptors14 with a broad spec-
trum of remarkable pharmacological activity. The most
successful example of the TIC core utilization in drug de-
sign is the discovery of angiotensin-converting enzyme
Ph
R2
R2
C(O)R1
CO2H
P(O)(OR1)2
R4
R4
N
N
N
R3
R3
N
H
CO2Et
O
inhibitors of enzymes,
antagonists of integrins
and opioid receptors
Accupril (by Pfizer)
unknown
this work
Figure 1 Bioactive TIC derivatives and their unknown phosphonate analogues
SYNLETT 2013, 24, 1517–1522
Advanced online publication: 17.06.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339173; Art ID: ST-2013-B0304-L
© Georg Thieme Verlag Stuttgart · New York

1518
M. A. Zotova et al.
LETTER
Ar
Ar
CF3
P(O)(OEt)2
CF3
P(O)(OEt)2
Ar
CF3
P(O)(OEt)2
N
HN
Cbz
1
N
R1
Cbz
Cbz
CF3-TICP
Scheme 1 Access to phosphonate analogues of TIC
The
investigation
of
the
catalytic
alkyne the cyclotrimerization products 3b and 3c have been ob-
cyclotrimerization21 started with the reaction of terminal tained in good yield as a mixture of their 6- and 7-alkylat-
1,7-diyne 2a with acetylene. For this purpose, the N-al- ed regioisomers in a 1:1 ratio (Scheme 2).
kylation of propargyl-containing α-CF3-α-aminophospho-
nate 1a with propargyl bromide has been initially
performed. As a result, we found that the best conversion
(91%) of aminophosphonate 1a into 1,7-azadiyne 2a can
In attempts to induce the regioselectivity of the [2+2+2]-
cycloaddition process, we have investigated the reactions
of 1,7-azadiynes 5, containing an internal triple bond,
with terminal alkynes such as hexyne, octyne, and phenyl-
be achieved using 1.4 equivalents of NaH in DMF in the
acetylene. The derivatives 5 (Scheme 3, Table 1) have
presence of a five-fold excess of propargyl bromide. The
been prepared starting from readily available aryl-
reaction has been monitored by 19F NMR spectroscopy.
containing aminophosphonates 4,19 and then crude
Taking into account the high NMR yield of 2a and the dif- compounds 5 (purity >90%) were used for ruthenium-
ficulty of its purification, crude 2a (>90% purity), quanti- catalyzed cyclotrimerization step. It turned out that the cy-
tatively obtained by the standard workup procedure, has cloaddition of 1,7-azadiynes 5 with hexyne-1 and octyne-
been further utilized for the cyclotrimerization steps. 1 proceeded at 80 °С in dichloroethane in the presence of
Thus, we found that [2+2+2] cycloaddition of 2a with 5 mol% of RuClCp*cod and led to reaction completion af-
acetylene (1 atm) occurres at room temperature in dichlo- ter three hours to afford the corresponding CF3-substitut-
roethane after eight hours in the presence of 5 mol% ed tetrahydroisoquinoline-3-phosphonic acid derivatives
RuClCp*COD affording the corresponding bicyclic phos- 6 in moderate yields. In all cases the meta isomers 6 were
phonate 3a in 62% overall yield for the two steps (Scheme formed as major cyclotrimerization products with remark-
2).
able regioselectivity (meta/ortho from 92:8 to 94:6)
(Scheme 3, Table 1).
The same conditions have proved to be acceptable for the
reaction of 2a with 1-hexyne and 1-octyne. In both cases,
CF3
acetylene (1 atm)
P(O)(OEt)2
N
Cbz
3a 62%
F3C
(EtO)2(O)P
F3C
(EtO)2(O)P
1. NaH, DMF
2. Br
RuClCp*COD (5 mol%)
DCE, r.t., 8 h
NH
N
Cbz
CF3
Cbz
2a
1a
P(O)(OEt)2
R
R
N
Cbz
3b R = Bu 61%
3c R = Hex 65%
Scheme 2 Synthesis of diyne 2a and tetrahydroisoquinolines 3a–c
Ar
CF3
P(O)(OEt)2
N
R
Cbz
Ar
Ar
meta-6
F3C
(EtO)2(O)P
F3C
(EtO)2(O)P
1. NaH, DMF
R
+
NH
2. Br
RuClCp*COD (5 mol%)
DCE, 80 °C
N
Ar
Cbz
CF3
Cbz
R
3 h
P(O)(OEt)2
4
5
N
Cbz
ortho-6
Scheme 3 Synthesis of diynes 5a,b and tetrahydroisoquinolines 6a–f
Synlett 2013, 24, 1517–1522
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of CF3-Containing 1,2,3,4-Tetrahydroisoquinoline-3-Phosphonates
1519
Ru=C bonds.22 The less hindered Ru=C bond of B is ex-
pected to give a regioselective [2+2] cycloaddition with
the alkyne triple bond, via a metathesis step, affording the
less hindered adduct C, with the R group away from the
bulky RuCp* group (Scheme 4).
Table 1 Synthesis of Tetrahydroisoquinolines 6a–f via
RuClCp*COD Catalysis
Entry Ar
R
Yield of 6 (%)a meta/orthob
1
2
3
4
5
6
Ph
Bu
6a 60
6b 57
6c 51
6d 42
6e 39
6f 41
93:7
92:8
93:7
94:6
93:7
93:7
The new biscarbene ruthenium intermediate C corre-
sponds to the tautomer D closed to the transition state
leading to the reductive elimination step. The different re-
activity of the two Ru=C bonds in B is responsible for the
observed regioselectivity and is due to both electronic and
steric effects, as the Ar group in the Ar–C=Ru moiety is
known to stabilize the Ru=C carbene bond22b and the al-
kyne couples with the less hindered C=Ru bond to avoid
steric interaction with both RuCp* and Ar.
Ph
C6H13
Ph
Ph
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Bu
C6H13
Ph
a Isolated yield for two steps after purification by chromatography on
silica gel.
b Determined by 19F NMR spectroscopy.
The Ru=C carbene bond character of intermediate B and
C led us to evaluate a possible more active ruthenium–
alkylidene catalyst, the Grubbs second-generation cata-
lyst already shown to be efficient for enyne ring-closing
metathesis, whereas the Grubbs first-generation (Grubbs
I) catalyst could perform specific intramolecular cy-
clotrimerization of alkynes.23 As the Grubbs first-genera-
tion catalyst was shown not to be the most efficient for the
The action of precatalyst RuClCp*cod can be rationalized
as described in Scheme 4. The first step corresponds to the
oxidative coupling of the diyne to give the ruthenacyclo-
pentadiene A, close to the transition state, leading to its
more stable tautomer B with the carbene character of
Ar
F3C
(EtO)2(O)P
[Ru]Cp*
F3C
(EtO)2(O)P
N
R
Ar
Cbz
A
N
Ar
[Ru]Cp*
Cbz
F3C
(EtO)2(O)P
N
Cbz
[Ru]Cp*
Ar
B
F3C
(EtO)2(O)P
R
N
Ar
Cbz
R
F3C
6
[Ru]Cp*
R
Ar
(EtO)2(O)P
F3C
[Ru]Cp*
R
N
(EtO)2(O)P
Cbz
N
H
Cbz
C
D
Scheme 4 Proposed mechanism for regioselective cyclotrimerization catalyzed by RuClCp*COD
Ar
CF3
P(O)(OEt)2
N
Ar
R
R
Cbz
meta-6
F3C
(EtO)2(O)P
1. NaH, DMF
2. Br
R
4
+
N
Grubbs II (5 mol%)
DCE, 80 °C
3 h
Ar
Cbz
CF3
5
P(O)(OEt)2
N
Mes
N
N
Cl
Mes
Cbz
ortho-6
Grubbs II
Ru
Cl
PCy3
Scheme 5 Synthesis of Bicyclic Derivatives 6 from Alkynyl Phosphonates 4
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1517–1522

1520
M. A. Zotova et al.
LETTER
cyclotrimerization of terminal diynes containing the ami- triple bond to form the first cycle and intermediate F.23 A
noester moiety,18 the Grubbs second-generation catalyst, cascade of intra- and intermolecular, as well as ring-clos-
containing a bulky and an electron-rich NHC ligand, was ing metathesis steps, which are related to the well-estab-
evaluated in the search for regioselectivity of alkyne inter- lished enyne and olefin metathesis, would finally result in
actions. As a result, it was found that the 5 mol% of the liberation of the ruthenium benzylidene catalyst and in
Grubbs second-generation catalyst smoothly proceeds at the preferred formation of the corresponding meta isomer
60 °C for 3–4 hours to promote the cyclotrimerization (Scheme 6). The addition of the alkylidene bond to the ex-
leading to the desired phosphorylated TIC derivatives24 in ternal alkyne in G is expected to afford the alkenylidene
significantly better isolated yields (60–77%) with an ex- H reacting intramolecularly to generate the meta isomer
cellent regioselectivity meta/ortho from 92:8 to 95:5 and the alkylidene ruthenium catalyst, thus causing the
(Scheme 5, Table 2).
chemo- and regioselectivity of this process.
To obtain free cyclic aminophosphonates selective re-
moval of protection groups from amino and phosphonic
acid functions could be applied via standard protocols
commonly used in peptide chemistry. Thus, the Cbz pro-
tective group could be easily removed by catalytic hydro-
genation on 10% Pd/C in methanol at room temperature
for two hours to afford NH-phosphonates 7 and 8 in good
yields. Subsequent treatment of 8 with trimethylsilyl bro-
mide led to the formation of the desired free amino phos-
phonic acid 9 as hydrogen bromine salt (Scheme 7).
Table 2 Synthesis of Tetrahydroisoquinolines 6a–f via Grubbs II
Catalysis
Entry Ar
R
Yield of 6 (%)a meta/orthob
1
2
3
4
5
6
Ph
Bu
6a 77
6b 68
6c 63
6d 72
6e 75
6f 60
93:7
94:6
93:7
92:8
95:5
95:5
Ph
C6H13
Ph
Ph
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Bu
In conclusion, we have developed a convenient method
for crossed cyclotrimerization of phosphonate containing
1,7-azadiyne and terminal alkyne mediated by two ruthe-
nium catalysts, RuClCp*cod, the precursor of biscarbene
complex, and the Grubbs second-generation alkene me-
tathesis catalyst which revealed the most efficient catalyt-
ic activity. This catalytic protocol offers an efficient
access to a hitherto unknown family of functionalized
phosphorus analogues of 1,2,3,4-tetrahydroisoquinoline-
3-carboxylic acid (TIC) derivatives with the regioselec-
tive formation of the arene ring bearing meta substituents
arising from diyne and terminal alkyne.
C6H13
Ph
a Isolated yield for two steps after purification by chromatography on
silica gel.
b Determined by 19F NMR spectroscopy.
In this case, the preferred addition of ruthenium alkyli-
dene bond to the less substituted alkyne moiety of the 1,7-
diyne 5 should lead to the alkenyl alkylidene ruthenium
moiety E then interacting intramolecularly with the other
F3C
Ar
(EtO)2(O)P
Ru
N
F3C
Ar
Ar
Cbz
(EtO)2(O)P
F3C
N
(EtO)2(O)P
Ru
Ph
E
Cbz
N
Ph
Cbz
preferred
addition
F
[Ru
Ph
R
Ar
F3C
R
(EtO)2(O)P
Ru
Ph
Ar
Ar
F3C
(EtO)2(O)P
N
N
F3C
(EtO)2(O)P
Cbz
R
N
N
G
R
Cbz
Cbz
Ru
meta isomer
H
Ph
Mes
N Mes
Cl
[Ru
=
Ru
Ph
Cl
Ph
PCy3
Scheme 6 Proposed mechanism for cyclotrimerization catalyzed by Grubbs second-generation catalyst
Synlett 2013, 24, 1517–1522
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of CF3-Containing 1,2,3,4-Tetrahydroisoquinoline-3-Phosphonates
1521
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Ar
Ar
CF3
P(O)(OEt)2
CF3
P(O)(OEt)2
H2, Pd/C
MeOH
R
N
N
R
Cbz
H
3a, 6a
7 R = Ar = H 94%
8 R = Bu, Ar = Ph 85%
Ph
CF3
Me3SiBr
P(O)(OH)2
MeCN–EtOH
N
⋅HBr
Bu
H
9 80%
Scheme 7 The synthesis of free aminophosphonate
(15) Markina, N. A.; Mancuso, R.; Neuenswander, B.;
Lushington, G. H.; Larock, R. C. ACS Comb. Sci. 2011, 13,
265.
Acknowledgment
(16) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, 2004. (b) Uneyama, K. Organofluorine
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in Medicinal Chemistry and Chemical Biology; Wiley-
Blackwell: Chichester, 2009. (d) Schlosser, M. Angew.
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This work was financially supported by RFBR (grant No. 12-03-
00557) and GDRI (grant No. 12-03-93111) in the frame of bilateral
collaboration between CNRS France and Russian Academy of
Sciences.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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(24) Typical Procedure for Compound 6
A degased solution of dyine-containing aminophosphonate
(0.39 mmol), alkyne (1.55 mmol, 4 equiv), and Grubbs II
catalyst (0.02 mmol, 5 mol%) in dry CH2Cl2 (8 mL) was
stirred under heating at 60 °C for 3 h. After cooling to r.t., the
solvent was removed under reduced pressure, and the crude
product was purified by column chromatography on silica
gel (eluent: CH2Cl2–EtOAc) to afford the product.
Selected Data for Compound 6b
1H NMR (300 MHz, CDCl3): δ = 0.98 (t, J = 7.3 Hz, 3 H,
CH3), 1.07 (t, J = 7.1 Hz, 3 H, CH3), 1.17 (t, J = 6.5 Hz, 3 H,
CH3), 1.32–1.45 (m, 2 H, CH2), 1.61–1.71 (m, 2 H, CH2),
2.68 (t, J = 7.6 Hz, 2 H, CH2), 3.52–3.56 (m, 2 H, CH2),
© Georg Thieme Verlag Stuttgart · New York
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M. A. Zotova et al.
LETTER
3.89–4.20 (m, 4 H, OCH2), 4.76 (br s, 2 H, CH2), 5.21 (d, J
= 12.2 Hz, 1 H, OCH2), 5.35 (d, J = 12.2 Hz, 1 H, OCH2),
Hz), 22.4, 33.6, 35.3, 43.4, 47.3, 62.7 (d, J = 8.8 Hz), 64.0
(m), 64.8 (dq, J = 28.7, 154.8 Hz), 67.9, 124.7, 125.9 (qd, J
= 12.8, 288.9 Hz), 127.1, 127.2 (d, J = 6.6 Hz), 128.1, 128.2,
128.3, 128.4, 129.2, 129.4, 136.2, 140.2, 140.6, 141.6,
155.7, 171.1. Anal. Calcd for C32H37F3NO5P: C, 63.67; H,
6.18; N, 2.32. Found: C, 63.28; H, 5.88; N, 2.54.
7.08–7.21 (m, 2 H, ArH), 7.32–7.52 (m, 10 H, ArH). 19
F
NMR (282 MHz, CDCl3): δ = 9.81 (s, 3 F, CF3). 31P NMR
(161 MHz, CDCl3): δ = 16.63 (q, J = 3.3 Hz). 13C NMR (151
MHz, CDCl3): δ = 13.9, 15.8 (d, J = 6.6 Hz), 16.2 (d, J = 5.5
Synlett 2013, 24, 1517–1522
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