Consecutive three-component synthesis of (hetero)arylated propargyl amides by chemoenzymatic aminolysis-Sonogashira coupling sequence

Article abstract of DOI:10.1039/c4ob02386b

A novel chemoenzymatic three-component synthesis of (hetero)arylated propargyl amides in good yields based upon Novozyme 435 (Candida antarctica lipase B (CAL-B)) catalyzed aminolysis of methyl carboxylates followed by Sonogashira coupling with (hetero)aryliodides in a consecutive one-pot fashion has been presented. This efficient methodology can be readily concatenated with a CuAAC (Cu catalyzed alkyne azide cycloaddition) as a third consecutive step to furnish 1,4-disubstituted 1,2,3-triazole ligated arylated propargyl amides. This one-pot process can be regarded as a transition metal catalyzed sequence that takes advantage of the copper source still present from the cross-coupling step.

Full text of DOI:10.1039/c4ob02386b

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Consecutive three-component synthesis of
(hetero)arylated propargyl amides by
chemoenzymatic aminolysis–Sonogashira
coupling sequence†
Cite this: DOI: 10.1039/c4ob02386b
Sidra Hassan, Anja Ullrich and Thomas J. J. Müller*
A novel chemoenzymatic three-component synthesis of (hetero)arylated propargyl amides in good yields
based upon Novozyme® 435 (Candida antarctica lipase B (CAL-B)) catalyzed aminolysis of methyl carb-
oxylates followed by Sonogashira coupling with (hetero)aryliodides in a consecutive one-pot fashion has
been presented. This efficient methodology can be readily concatenated with a CuAAC (Cu catalyzed
alkyne azide cycloaddition) as a third consecutive step to furnish 1,4-disubstituted 1,2,3-triazole ligated
arylated propargyl amides. This one-pot process can be regarded as a transition metal catalyzed
sequence that takes advantage of the copper source still present from the cross-coupling step.
Received 12th November 2014,
Accepted 27th November 2014
DOI: 10.1039/c4ob02386b
www.rsc.org/obc
coupling–cycloisomerization sequences7 that can be expanded
to three-component syntheses of blue-luminescent 5-(3-
Introduction
Propargyl amides are particularly interesting as biologically indolyl)oxazoles8 and PtCl2 induced intramolecular cycliza-
active functionalities and as synthetic building blocks. Protein tions of N-propargyl indole-2-carboxamides to give azepino-
derived propargyl amides have been studied to irreversibly [3,4-b]indol-1-ones.9
inhibit cysteine proteases1 while systems containing rigid pro-
The combination of chemical and enzymatic transform-
pargylated aryl cores have been demonstrated to be active as ations offers numerous opportunities for designing new synth-
structurally modified homodimeric gonadotropin releasing eses. Therefore, these chemoenzymatic transformations have
hormone receptor (GnRHR) antagonist dimers with rigid func- recently received considerable attention and many applications
tionalities such as bistriazole with a hydrophilic polyethylene have been found on chiral resolution of racemic or meso sub-
glycol (PEG) spacer2 or a propargylated aryl system as a strates to furnish enantiomerically enriched chiral building
spacer.3 Synthetically these compounds were prepared by blocks for organic syntheses in a catalytic fashion.10 In con-
coupling propargylated amino acid derivatives with the arylio- trast to chemoenzymatic continuous flow processes,11 the
dides.3 Likewise, deoxynucleoside derivatives of N-trifluoro- concatenation of enzymatic and chemical catalyzed steps in a
acetyl propargyl amides were synthesized.4
one-pot fashion thus furnishing novel types of chemoenzy-
As synthetic building blocks, propargyl amides have been matic sequences remains a major challenge. While the one-pot
employed as monomers for the synthesis of chromophore combination of enzymes and transition metal catalysis is
labeled poly(N-propargyl amides) as stimulus responsive con- dominated by dynamic kinetic resolution as an important tool
jugated polymers.5 Optically active N-propargyl amides bearing in asymmetric synthesis,12 chemoenzymatic one-pot sequences
hydroxyl groups have been synthesized and polymerized for involving Pd-catalyzed coupling13 or Cu-catalyzed alkyne–azide
studying their secondary structure and chiral-recognition.6 cycloaddition (CuAAC)14,15 are still in their infancy. Recently,
Furthermore, propargyl amides are excellent substrates in we have disclosed
a
consecutive three-component
sequence consisting of CAL-B (Candida antarctica lipase B)
catalyzed aminolysis of methyl esters with propargyl amine
furnishing propargyl amides and CuAAC to give amide
ligated 1,4-disubstituted 1,2,3-triazoles in good to
excellent yields. Here we communicate the first consecutive
three-component syntheses of (hetero)arylated propargyl
amides by chemoenzymatic aminolysis–Sonogashira coupling
sequence.
Lehrstuhl für Organische Chemie, Institut für Organische Chemie und
Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße
1, D-40225 Düsseldorf, Germany. E-mail: ThomasJJ.Mueller@uni-duesseldorf.de;
Fax: +49 (0)211 8114324; Tel: +49 (0)211 8112298
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization, and 1H and 13C NMR spectra of compounds 5 and 7.
See DOI: 10.1039/c4ob02386b
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efficiently established for Sonogashira coupling16,17 were not
successful in the model reaction (Table 1, entries 7 and 8).
Results and discussion
We have previously reported on the efficient CAL-B catalyzed However, Pd(PPh3)4 as the Pd(0) catalyst precursor was proven
aminolysis for the synthesis of propargyl amides as a milder to be superior (Table 1, entries 5, 9–15).
alternative to the base catalyzed process that occurs with a
The choice of the base was equally important. It turned out
remarkable chemoselectivity with α-heteroatom substituted that 1,1,3,3-tetramethyl guanidine (TMG), successfully
methyl carboxylates.15 Encouraged by the excellent compatibil- employed in Pd-catalyzed coupling–cyclization syntheses of
ity of CAL-B catalyzed aminolysis with copper catalysis in a indoles from ortho-iodo anilines18,19 and in domino sequences
single reaction vessel we set out to concatenate this aminolysis involving N-propargyl sulfoximines,20 was the most favorable
step with Sonogashira coupling to access (hetero)arylated pro- amidine base that not only gave good yields of propargyl
pargyl amides in a diversity-oriented one-pot sequence.
amide 5a but also drastically reduced the reaction times at
First the Sonogashira coupling of propargyl amide 3a, 45 °C (Table 1, entry 15). Moreover, it is sufficient to employ
formed by CAL-B aminolysis of methyl ester 1a with propargyl- an equimolar amount of TMG to achieve full conversion. There-
amine (2),15 and iodo benzene (4a) to furnish 3-phenylpropar- fore, with these conditions for the coupling step in hand, the
gyl amide 5a was optimized as a model reaction with respect stage was set to combine the CAL-B catalyzed aminolysis with
to a suitable catalyst system, base, solvent and temperature the Sonogashira coupling in a consecutive one-pot fashion.
(Scheme 1, Table 1).
Upon the Novozyme® 435 catalyzed aminolysis of methyl
In comparison with standard Sonogashira conditions, pro- carboxylates 1 with propargyl amine (2) in MTBE (methyl tert-
pargyl amides are apparently peculiar since all Pd(II) catalyst butylether) at 45 °C, the formed propargyl amide 3 was sub-
precursors have failed to give reasonable yields (Table 1, sequently reacted with (hetero)aryl iodides 4 in the presence of
entries 1–4). Even novel carbene ligands that have been DMF as a cosolvent, TMG as a base and catalytic amounts of
Pd(PPh3)4 and CuI at 45 °C to give 3-(hetero)arylpropargyl
amides 5 in a three-component one-pot fashion in moderate to
excellent yields (Scheme 2, Table 2).
Taking into account the already established substrate scope
of the Novozyme® 435 catalyzed aminolysis15 the general sub-
stitution pattern is equally well accepted in this chemo-
enzymatic sequence. Moreover, also a free phenol moiety in
substrate 1i is well tolerated furnishing the propargyl amide 5j
in remarkably high yield (Table 2, entry 10). The same holds
true for methyl chloroacetate (1m), which is transformed to
give the corresponding propargyl amide 5o in excellent yield
(Table 2, entry 15). Most importantly, the chemoselectivity of
Scheme 1 Formation of propargyl amide 3a by CAL-B catalyzed
the aminolysis of the more electrophilic methyl carboxylate in
substrate 1p underlines the superiority of applying CAL-B as a
aminolysis of methyl ester 1a and the optimization of the Sonogashira
coupling of propargyl amide 3a and iodo benzene (4a).
Table 1 Optimization of the Sonogashira reaction of propargyl amide 3a and iodo benzene (4a) giving rise to 3-phenylpropargyl amide 5a
Yield of
Entry
Catalyst system
Solvent
Base/additive
T, t
5aa (%)
b
1
2
3
4
5
6
7
8
2 mol% PdCl2(PPh3)2, 4 mol% CuI
2 mol% PdCl2(PPh3)2, 4 mol% CuI
2 mol% PdCl2(PPh3)2, 4 mol% CuI
2 mol% PdCl2(PPh3)2, 4 mol% CuI
5 mol% Pd(PPh3)4, 1 mol% CuI
2.5 mol% Pd2(dba)3·CHCl3, 10 mol% P(2-furyl)3
2.5 mol% Pd2(dba)3·CHCl3, 10 mol% IPr·HClc
5 mol% Pd(OAc)2, 10 mol% IPr·HClc
THF
NEt3 (1.0 equiv.)
NEt3 (1.0 equiv.)
rt to 50 °C, 24 h
rt to 70 °C, 24 h
rt to 70 °C, 24 h
rt to 70 °C, 24 h
45 °C, 6 h
45 °C, 24 h
45 °C, 24 h
—
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DMF
MeCN
MeCN
13
25
33
75
Pyrrolidine (1.0 equiv.)
Pyrrolidine (1.5 equiv.)
Pyrrolidine/DMF (1 : 4 v/v)
NaOt-Bu (2.0 equiv.)
NaOt-Bu (2.0 equiv.)
K2CO3 (2.0 equiv.),
TBAC (2.0 equiv.)
b
—
—
—
b
b
MeCN
45 °C, 24 h
9
2 mol% Pd(PPh3)4, CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NEt3 (1.0 equiv.)
rt, 24 h
53
67
56
85
57
69
83
10
11
12
13
14
15
2 mol% Pd(PPh3)4, 4 mol% CuI
2 mol% Pd(PPh3)4, 4 mol% CuI
2 mol% Pd(PPh3)4, 4 mol% CuI
2 mol% Pd(PPh3)4, 4 mol% CuI
2 mol% Pd(PPh3)4, 4 mol% CuI
2 mol% Pd(PPh3)4, 4 mol% CuI
DIPEAd (1.5 equiv.)
Pyrrolidine (1.0 equiv.)
Pyrrolidine (1.5 equiv.)
DABCOe (1.0 equiv.)
DBUf (1.0 equiv.)
45 °C, 6 h
45 °C, 8 h
45 °C, 4 h
45 °C, 8 h
45 °C, 8 h
45 °C, 1 h
TMGg (1.0 equiv.)
a Isolated yield after chromatography on silica gel. b No product formation. c IPr·HCl: 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride.
d DIPEA: diisopropylethylamine. e DABCO: 1,4-diazabicyclo[2.2.2]octane. f DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene. g TMG: 1,1,3,3-tetramethyl
guanidine.
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catalyst in the sequence. However, it should be noted that
2-iodopyridine and 1,3-diiodobenzene failed to undergo the
Sonogashira step under the optimized conditions.
Finally, we have combined the chemoenzymatic amino-
lysis–Sonogashira coupling with a terminal CuAAC step fur-
nishing propargyl amide functionalized 1-aryl 4-benzyl 1,2,3-
triazoles 7 in good yields (Scheme 3). Commencing with the
CAL-B catalyzed aminolysis, the propargyl amides 3 are reacted
with p-iodo[(trimethylsilyl)ethynyl]benzene (4i) to give the
TMS-protected 3(p-ethynyl)phenyl propargyl amides 8, which
Scheme 2 Consecutive three-component synthesis of 3-(hetero)aryl-
propargyl amides 5 by CAL-B catalyzed aminolysis–Sonogashira coup-
ling sequence.
Table 2 Chemoenzymatic three-component synthesis of 3-(hetero)arylpropargyl amides 5
Entry
1a
Methyl ester 1
(Hetero)aryl iodide 4
R2 = Ph (4a)
3-(Hetero)aryl propargyl amide 5
R1 = p-MeOC6H4CH2CH2 (1a)
2a
3a
R1 = C6H5CH2 (1b)
4a
1b
R2 = p-MeO2CC6H4 (4b)
4a
5a
R1 = C6H5CH2CH2 (1c)
4a
R1 = E-C6H5CHvCH (1d)
R2 = p-MeOC6H4 (4c)
6a
R1 = C6H5CuC (1e)
4a
7b
R1 = C6H5OCH2 (1f)
4a
4a
4a
4b
8b
R1 = C6H5NHCH2 (1g)
R1 = C6H5SCH2 (1h)
9b
10a
R1 = p-HOC6H4CH2CH2 (1i)
11a
1h
4c
12b
13a
R1 = (CH2)5NCH2 (1j)
R1 = Me(CH2)5CH2 (1k)
R2 = p-H3CCOC6H4 (4d)
4c
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Table 2 (Contd.)
Entry
14a
Methyl ester 1
(Hetero)aryl iodide 4
3-(Hetero)aryl propargyl amide 5
R1 = F3CCONHCH2 (1l)
4a
15b
16a
R1 = ClCH2 (1m)
R1 = 2-furyl (1n)
4b
R2 = 2-thienyl (4e)
17a
18a
19b
R1 = 2-thienyl (1o)
4e
1n
R2 = 5-OHC-2-furyl (4f)
R1 = p-(MeO2CCH2CH2)C6H4OCH2 (1p)
4f
a 24 h time for CAL-B catalyzed aminolysis. b 4 h time for CAL-B catalyzed aminolysis.
Scheme 3 Consecutive four-component synthesis of 3-(4-1,2,3-triazolyl)phenyl propargyl amides 7 by CAL-B catalyzed aminolysis–Sonogashira
coupling-CuAAC sequence.
are rapidly desilylated by potassium fluoride to furnish the peptidomimetics in a one-pot fashion. Furthermore, the
ethynyl derivatives 9. The presence of the Sonogashira cocatalyst potential to concatenate CuAAC as a third step opens up new
CuI and benzyl azide (6) terminates the sequence by a CuAAC avenues for the rapid alignment of various functionalities in
giving rise to the formation of functionalized 1,2,3-triazoles 7 in the sense of diversity-oriented synthesis of complex chromo-
the sense of a transition metal catalyzed one-pot sequence.21
phores.22 Studies directed to further expand and develop this
chemoenzymatic sequence are currently underway.
Conclusions
Experimental
Chemoenzymatic three-component synthesis of methyl 4-(3-
(3-(4-hydroxyphenyl)propanamido)prop-1-yn-1-yl) benzoate (5j)
(typical procedure)
In conclusion, we have disclosed a novel chemoenzymatic one-
pot synthesis of 3-(hetero)arylpropargyl amides 5 by CAL-B
catalyzed aminolysis–Sonogashira coupling sequence. This
combination of enzyme-metal catalyzed methodology is well
suited for application to more sophisticated peptides and aryl To a solution of propargylamine (2) (55 mg, 1.00 mmol) in dry
halides as a bioorganic tool for the efficient generation of MTBE (2.0 mL) in a screw-cap Schlenk vessel, methyl p-hydroxy
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dihydrocinnamate (1i) (216 mg, 1.20 mmol) and Novozyme® 10.0 mL). The combined organic layers were dried with anhy-
435 (108 mg, 50% w/w of substrate 1i) were successively added drous Na2SO4 and after column chromatography on silica gel
and the reaction was allowed to shake in an incubating shaker (n-hexane/ethyl acetate) 245 mg (58%) of analytically pure com-
at 45 °C for 24 h. After the complete conversion (monitored by pound 7b was obtained as a yellow solid, Mp 147 °C.
1
TLC), DMF (2.0 mL) was added to the reaction mixture which
Yellow solid. Mp 147 °C. H NMR (300 MHz, d6-DMSO): δ =
3
was then flushed with argon for 15 min. Then methyl p-iodo- 4.21 (d, J = 5.6 Hz, 2 H), 4.54 (s, 2 H), 5.65 (s, 2 H), 6.97–7.00
benzoate (4b) (262 mg, 1.00 mmol), TMG (115 mg, (m, 3 H), 7.28–7.39 (br m, 7 H), 7.45 (d, 3J = 8.4 Hz, 2 H),
3
1.00 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and CuI (8 mg, 7.59–7.62 (m, 1 H), 7.86 (d, J = 8.4 Hz, 2 H), 8.69 (s, 1 H).13C
0.04 mmol) were successively added to the reaction mixture NMR (75 MHz, d6-DMSO): δ = 28.5 (CH2), 53.1 (CH2), 66.8
under argon and the reaction was allowed to shake at 45 °C for (CH2), 81.3 (Cquat), 87.7 (Cquat), 114.7 (CH), 121.2 (CH), 121.5
1 h. The reaction mixture was filtered to remove the enzyme (Cquat), 122.1 (CH), 125.3 (CH), 127.9 (CH), 128.2 (CH), 129.5
beads. Then, brine (5.0 mL) was added to the filtrate, followed (CH), 130.7 (Cquat), 132.0 (CH), 135.9 (Cquat), 145.9 (Cquat),
by extraction with ethyl acetate (3 × 10.0 mL). The combined 157.6 (Cquat), 167.7 (Cquat). MALDI-MS: m/z = 423 ([M + H]+). IR
organic layers were dried with anhydrous Na2SO4 and after (ATR) ˜ν [cm−1] = 3034 (w), 2922 (w), 2910 (w), 2856 (w), 1662
column chromatography on silica gel (n-hexane/ethyl acetate), (s), 1598 (w), 1587 (w), 1519 (m), 1489 (s), 1456 (w), 1435 (w),
288 mg (85%) of analytically pure compound 5j was obtained 1409 (w), 1350 (w), 1286 (w), 1242 (s), 1226 (s), 1170 (w), 1080
as a colorless solid, Mp 151 °C.
(w), 1060 (w), 1047 (w), 1028 (w), 1018 (w), 1001 (w), 835 (m),
3
1H NMR (300 MHz, DMSO-d6): δ = 2.35 (t, J = 7.9 Hz, 2 H), 798 (m), 756 (s), 721 (s), 657 (w), 603 (w). Anal. calcd for
2.72 (t, 3J = 7.9 Hz, 2 H), 3.85 (s, 3 H), 4.13 (d, 3J = 5.5 Hz, 2 H), C26H22N4O2 (422.5): C 73.92, H 5.25, N 13.26; Found: C 74.06,
3
3
6.64 (d, J = 8.4 Hz, 2 H), 6.99 (d, J4,3 = 8.4 Hz, 2 H), 7.54 (d, N 5.32, H 13.47.
3
3
3J = 8.5 Hz, 2 H), 7.94 (d, J = 8.5 Hz, 2 H), 8.38 (t, J = 5.5 Hz,
1 H), 9.14 (s, 1 H). 13C NMR (75 MHz, DMSO-d6): δ = 28.5
(CH2), 30.1 (CH2), 37.2 (CH2), 52.3 (CH3), 80.7 (Cquat), 90.6
(Cquat), 115.0 (CH), 127.1 (Cquat), 129.0 (CH), 129.1 (Cquat),
129.3 (CH), 131.2 (Cquat), 131.6 (CH), 155.4 (Cquat), 165.6
(Cquat), 171.3 (Cquat). EI-MS (m/z (%)): 337 (M+, 13), 336 ([M −
Acknowledgements
The authors cordially thank CLIB Graduate Cluster for the
financial support (scholarship of S.H.) and the Fonds der
Chemischen Industrie.
H]+, 22), 230 (C13H12NO3 , 100), 188 (C11H10NO2 , 19),
120 (C8H8O+, 20), 107 (C7H7O+, 52). IR (ATR) ˜ν [cm−1] = 3385
(m), 3291 (m), 2966 (m), 2951 (w), 2924 (w), 2845 (w), 1705 (s),
1632 (s), 1601 (w), 1533 (m), 1516 (s), 1435 (m), 1362 (w), 1344
(m), 1288 (m), 1279 (s), 1259 (m), 1225 (s), 1198 (m), 1175 (m),
1103 (m), 1011 (w), 966 (w), 862 (m), 831 (w), 816 (m), 766 (s),
684 (m), 640 (w). Anal. calcd for C20H19NO4 (337.4): C 71.20,
H 5.68, N 4.15; Found: C 70.96, H 5.38, N 4.07.
+
+
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