Gold-catalyzed N,O-functionalization of 1,4-diyn-3-ols with: N -hydroxyanilines to form highly functionalized pyrrole derivatives

Article abstract of DOI:10.1039/c8cc00330k

This work describes new N,O-functionalization of 1,4-diyn-3-ols with N-hydroxyanilines to yield highly functionalized pyrrole derivatives. In a postulated mechanism, N-hydroxyaniline attacks the more electron-rich alkynes via regioselective N-attack to form unstable ketone-derived nitrones that react with their tethered alkynes via an intramolecular oxygen-transfer to form α-oxo gold carbenes. This new method is applicable to a short synthesis of a bioactive molecule, a PDE4 inhibitor.

Full text of DOI:10.1039/c8cc00330k

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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Gold-catalyzed N,O-functionalizations of 1,4-diyn-3-ols with N-
hydroxyanilines to form highly functionalized pyrrole derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Yu-Chen Hsu, Shu-An Hsieh, Po-Hsuan Li and Rai-Shung Liu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
This work describes new N,O-functionalizations of 1,4-diyn-3-ols tethered alkynes in a non-cycloaddition route, notably through
with N-hydroxyanilines to yield highly functionalized pyrrole a distinct oxygen-transfer reaction.8,9 In our previous work,
derivatives. In a postulated mechanism, N-hydroxyaniline attacks gold catalysed reactions of nitrones with ynamides proceeded
at the more electron-rich alkynes via a N-attack regioselectivity to through different 1,2-oxoamination reactions, in which
form unstable ketone-derived nitrones that react their tethered
alkynes via an intramolecular oxygen-transfer to form -oxo gold
nitrones were hydrolysed to liberate free
aldehydes.9b
Previous work
α
LAu+
Ph
H
O-attack
( 1 )
N
carbenes. This new method is applicable to a short synthesis of an
bioactive molecule, PDE4 inhibitor.
R
R
N
OH
H
nitrone/alkene cycloaddition
R1
Nitrones are versatile building blocks to access N,O-
containing molecules through their stereoselective [3+2]-
cycloadditions with alkene and allenes.1 Nitrone species are
R1
N
R1
R2
H
R2
R2
X
N-attack
H
O
( 2 )
X
X
O
R
N
N
HO
Ph
LAu+
R
commonly generated in situ from
a mixture of N-
H
H
nitrone/allene cycloaddition
R
hydroxyanilines with aldehydes; in contrast, ketone-derived
nitrones are generally kinetically unstable2a unless an electron-
withdrawing group is present.2b-2e Zhang and coworkers
reported gold-catalyzed intermolecular reactions of N-
hydroxyanilines with terminal alkynes to afford indole
products; the key step involves an O-attack of N-
hydroxyanilines at gold π-alkynes [Eq. (1)].3,4 As opposed to the
O-attack mode, we reported an alkene-controlled N-attack of
N-hydroxyanilines at the π-alkynes of 1,6-enynes to generate
unstable ketone-derived nitrones that reacted instantaneously
with their tethered alkenes to enable novel [2+2+1]-annulation
O
R
R
H
.
O
N-attack
X
LAu+
R'
X
( 3 )
X
N
N
H
R'
OH
N
Ph
anti-form
kinetically favored
R'
H
Ph
This work: nitrone/alkyne redox reaction
OH
HO
-
R2
R2
R3
LAu+
N-attack
( 4 )
R2
R3
R1
O
R3
R1
N
+
H
N
N
R1
O
Ar
products
[Eq.
(2)].5,6
Such
gold-catalyzed
N,O-
Ar
Ar
OH
functionalizations with N-hydroxyanilines is further applicable
to 6-allenyl-1-ynes to form the same nitrones that were
trapped with their tethered allenes to afford benzoazepin-4-
ones stereoselectively [Eq. (3)].7 This work reports new gold-
catalyzed N,O-functionalizations of 1,4-diyn-3-ols with N-
hydroxyanilines, delivering pyrrole derivatives efficiently [Eq.
(4)]. Notably, the key ketone-derived nitrones reacted with the
The utility of this synthesis provides a short entry to highly
functionalized pyrrole frameworks, which are found as the
core structures in several bioactive and natural products; the
examples are shown in Figure 1.10 Herein, a short synthesis of
PDE4 inhibitor is demonstrated in this work.
Fig.1 Representative bioactive and natural products
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Table
1
optimizes the reactions of 3-methyl-1,5-
diphenylpenta-1,4-diyn-3-ol (1a) with N-hydroxyaniline (2a
)
using various gold catalysts. We tested the reaction with
tBuMePhosAuCl/AgNTf2 (10 mol %) in DCE at room
temperature, affording pyrrole 3a in only 11% with a 69%
recovery of initial 1a. To improve the product yields, Zn(OTf)2
(30 mol%) was added to this reaction to increase the yield of
Bu)2(o-biphenyl)AuCl (10-20 mol %)/AgNTf2 (50 mol %); the
results are summarized in Table 2. As the tertiary carbon were
substituted with R2 = n-propyl, i-propyl and styryl, the resulting
products 3b-3d were obtained in 48-73% yield (entry 2-4). In
entries 5-8, different symmetric aryl-substituted diynols 1e-1h
were tested; electron-donating substituents R1 = R3 = 4-XC6H4
(X = Me, OMe) were operable with 10 mol % LAuCl to afford
compounds 3g and 3h in 58% and 66% yields respectively
whereas electron-withdrawing analogues 3e and 3f (X = Cl,
CF3)
3a to 43% (entry 2).
A high loading, 20 mol % of
tBuMePhosAuCl/AgNTf2 together with Zn(OTf)2 led to a high
consumption of 1a to deliver 3a in 58% (entry 3). With
tBuMePhosAuCl (20 mol%), we employed AgNTf2 with 50 mol
% to obtain 3a in 71% yield. With 50 mol % AgNTf2, we altered
gold catalysts LAuCl (20 mol %, L = IPr, P(t-Bu)2(o-biphenyl),
PPh3), finding that P(t-Bu)2(o-biphenyl)AuCl was the best
catalyst to produce 3a in 78% yield (entries 5-7). We tested the
reactions with 10 mol % P(t-Bu)2(o-biphenyl)AuCl/AgNTf2, but
0
giving 3a in 20-21% yields at 25 C and 60 0C (entries 8-9). The
Table 2. Reactions with various 3-alkyl-1,4-diyn-3-ols
use of P(t-Bu)2(o-biphenyl)AuCl/AgSbF6 maintained the same
high efficiency (entry 10). We employed a low loading (15 mol
%) of P(t-Bu)2(o-biphenyl)AuCl and AgNTf2 (50 mol %) to
decrease the yield of 3a in 48% yield (entry 11). The use of this
catalyst composition in other solvents gave 3a in the following
results: 41% in DCM, 8% in THF and 47% in CH3NO2. We also
performed catalytic reactions with p-TSA, Zn(OTf)2, Cu(OTf)2
and Sc(OTf)3, with Zn(OTf)2 being the most productive to afford
3a in 39% yield (see Table S1). The molecular structure of
compound 3a was determined by X-ray diffraction.11
n mol% LAuClb
Ph
N
OH
R1
O
50 mol% AgNTf2
PhNHOH
R2
R3
R1
Ph
R3
DCE, rt
R2
2a
3a
1
X
Ph
N
S
Ph
Ph
O
O
O
N
N
Ph
X
Me
S
Me
1) 3a (X = Me, 2h, 78%, 20) X-ray
2) 3b (X = n-Pr, 4h, 55%, 20)
3) 3c (X = i-Pr, 7h, 48%, 20)
4) 3d (X = styryl, 1.5h, 73%, 20)
9) 3i (2h, 21%, 10;
5) 3e (X = Cl, 5.5h, 41%, 20)
6) 3f (X = CF3, 5h, 22%, 20)
X
1.5h, 49%, 20)
7)
3g
(X = Me, 1h, 58%, 10)
8) 3h (X = OMe, 2h, 66%, 10;
5min, 91%, 20)c
Me
Ph
N
Ph
N
S
Ph
N
Ph
Table 1. Optimization of the reaction condition
O
O
O
O
N
Ph
OH
Ph
Me
Me
S
N
Me
Me
O
+
PhNHOH
10) 3j (3h, 46%, 10;
11) 3k (3.5h, 31%, 20)
13) 3m (2h, 41%, 10;
12) 3l (1.5h, 25%, 10;
Me
0.05M
Cl
Ph
Ph
2h, 69%, 20)
1.5h, 67%, 20)
2h, 33%, 20)
Ph
2a
1a
MeO
3aa
Me
X
Ph
Ph
S
Ph
O
N
Ph
N
isolated yield
(%)
O
O
N
N
Temp
(°C)
Catalyst
(mol%)
Lewis acid
(mol%)
Time
(h)
O
Entry
Solvent
DCE
Me
1a
3a
nBu
Me
Me
Me
L1AuCl(10)/AgNTf2(10)b
L1AuCl(10)/AgNTf2(10) Zn(OTf)2 (30) DCE
L1AuCl(20)/AgNTf2(20) Zn(OTf)2 (30) DCE
L1AuCl(20)/AgNTf2(50)
IPrAuCl(20)/AgNTf2(50)
L2AuCl(20)c/AgNTf2(50)
PPh3AuCl(20)/AgNTf2(50)
L2AuCl(10)/AgNTf2(10)
L2AuCl(10)/AgNTf2(10)
OMe
rt
rt
1
2
3
4
5
6
7
8
9
9
5
5
3
7
2
5
8
6
2
4
69
34
15
8
56
0
48
62
53
0
11
43
58
71
28
78
39
21
20
77
48
23) 3w (10min, 93%, 10)c
X
17) 3q (1.5h, 49%, 10;
18) 3r (X = H, 3.5h, 51%, 10)
19) 3s (X = OMe, 3h, 47%, 10)
20) 3t (X = Me, 4h, 63%, 10)
21) 3u (X = Cl, 6h, 32%, 10)
22) 3v (X = CF3, 7h, 12%, 10)
14) 3n (X = H, 1.5h, 71%, 10)
15) 3o (X = Cl, 1.5h, 62%, 10)
16) 3p (X = Me, 2h, 66%, 10)
1.5h, 63%, 20)
rt
rt
rt
rt
rt
rt
60
rt
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
C6H6
Ph
Ph
Ph
Ph
Ph
Ph
O
N
O
N
O
S
N
O
N
Ph
S
Ph
Me
Me
Me
Me
a
a'
a'
a
24) 3x (2h, a/a' = 10/7, 51%, 20)
25) 3y (1.5h, a/a' = 10/1, 73%, 10)
10 L2AuCl(20)/AgSbF6(50)
11 L2AuCl(15)/AgNTf2(50)
12 L2AuCl(15)/AgNTf2(50)
rt
30
1 (0.05M, 1.0 equiv). 2a (3.0 equiv). a Product yields are given after purification from a silica column. b L =
P(t-Bu)2(o-biphenyl). c 1.5equiv PhNHOH
rt
rt
rt
rt
4
4.5
7
35
43
76
36
45
41
8
13 L2AuCl(15)/AgNTf2(50)
14 L2AuCl(15)/AgNTf2(50)
15 L2AuCl(15)/AgNTf2(50)
DCM
THF
required 20 mol % gold catalysts to deliver the desired
products 3e and 3f in 41% and 22% yields respectively. For
diynol 1h, gold catalyst at a 20 mol % loading enabled a
complete reaction within 5 minutes, yielding 3h in 91% yield.
We tested the reaction of species 1i (R1, R3 = 2-thienyl) and 1j
(R1, R3 = 3-thienyl), delivering the desired products 3i and 3j in
49% and 69% yields respectively (entries 9 and 10). For alkyl-
substituted diyne and alkenyl diyne derivatives 1k and 1l, their
corresponding reactions were performed with 20 mol %
catalyst to afford pyrrole derivatives 3k and 3l in poor yields
(31-33% entries 11 and 12). In the non-symmetric aryl-
substituted diynes, we tested substrates 1m-1p with 10-20
mol % catalysts to afford the following products in satisfactory
CH3NO2
4
47
1a (0.05M, 1.0 equiv). 2a (3.0 equiv). a Product yields are given after purification
from a silica column. b L1 = 2-Di-tert-butylphosphino-2'-methylbiphenyl. c L2 = P(t-
Bu)2(o-biphenyl). d IPr = 1,3-bis (diisopropylphenyl) imidazol-2-ylidene.
Under the optimized condition, we examined the effects of
the alkoxy groups of diynols 1aa-1ac (R = Me, Bu and PhCH2),
yielding compound 3a in relatively low yields (52-59%) [Eq.
(5)]. The high efficiency of a hydroxyl group as in species 1a is
probably attributed to its good leaving property.
We assessed the scope of this pyrrole synthesis with various
3-alkyl-1,4-diyn-3-ol
1 and N-hydroxyaniline 2a using P(t-
2 | J. Name., 2012, 00, 1-3
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of amine, as facilitated by its tethered alkyne.5,7 Resulting
ketone-derived nitrones II again coordinates with gold to
effect a dehydration; this step is facilitated with AgNTf2 or
Zn(OTf)2 to ionize a hydroxyl leaving group. A subsequent
Angew. Chem. Int. Ed., 2012, 51, 6870-6873; e) H. Fan, J.
Peng, M. T. Hamann, J. F. Hu, Chem. Rev., 2008, 108,
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A. Tafi, F. Manetti, Bioorg. Med. Chem., 2004, 12, 1453-1458.
11 Crystallographic data of compounds 3a and 4c were
deposited at X-ray crystallographic Data Centers: CCDC
1580644 (3a); CCDC 1580618(4c).
intramolecular oxygen transfer of species IV yields
carbenes
that undergoes an aza-Nazorav cyclization12 to
yield observed products 3o via intermediate VI
α-oxo gold
V
.
12 For gold-catalyzed aza-Nazorav cyclizations, see: a) S. K.
Pawar, R. L. Sahani, R.-S. Liu, Chem. Eur. J. 2015, 21, 10843-
In summary, we have developed novel gold-catalyzed N,O-
functionalizations of 1,4-diyn-3-ols13,14 with N-hydroxyanilines
to form highly functionalized pyrrole derivatives. The loading
of gold catalysts relies on the types of N-hydroxyanilines;
electron-deficient types can be catalysed satisfactorily with a
10 mol % loading. The mechanism of these reactions proceeds
via an initial formation of nitrones, but their reactions with the
tethered alkynes occur via an oxygen-transfer process.
10850; b) R. L. Sahani, R.-S. Liu, Angew. Chem. Int. Ed. 2017
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56, 1026-1030; c) A.-H. Zhou, Q. He, C. Shu, Y.-F. Yu, S. Liu, T.
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S. K. Hashmi, Angew. Chem. Int. Ed. 2016, 55, 794-797; e) H.
Jin, B. Tian, X. Song, J. Xie, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2016, 55, 12688-12692.
13 For gold-catalyzed intermolecular reactions of N-
hydroxyamines with allenes, see: a) R. K. Kawade.; P.-H.
Huang, S. N. Karad,; R.-S. Liu, Org. Biomol. Chem. 2014, 12,
737–740; b) J.-M. Chen; C.-J. Chang; Y.-J. Ke; R.-S. Liu, J. Org.
Chem. 2014, 79, 4306–4311.
Notes and references
14 For gold-catalyzed reactions of 1,4-diyn-4-ol derivatives, see
T. Wang, S. Shi, M. M. Hansmann, E. Rettenmeier, M.
Rudolph, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2014, 53,
3715-3719.
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Org. Lett. 2008, 10, 4493−4496; c) E. Winterfeldt, W. Krohn,
H. Stracke, Chem. Ber. 1969, 102, 2346−2361; d) A. Pernet-
Poil-Chevrier, F. Cantagrel, K. Le Jeune. C. Philouze, P. Y.
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Cantagrel, S. Pinet, Y. Gimbert, P. Y. Chavant, Eur. J. Org.
Chem. 2005, 2694−2701.
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see D. B. Huple, S. Ghorpade, R.-S. Liu, Adv. Syn. Catal. 2016
358, 1348-1367.
,
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Biomol. Chem. 2009, 7, 3733-4752; b) A. Mukherjee, R. B.
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4 | J. Name., 2012, 00, 1-3
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Table of Contents:
This work describes new
N
,
O
-functionalizations of 1,4-diyn-3-ols with
N
-hydroxyanilines to
-hydroxyaniline
-attack regioselectivity to form unstable
ketone-derived nitrones that react their tethered alkynes via an intramolecular oxygen-transfer
to form oxo gold carbenes. This new method is applicable to a short synthesis of an bioactive
molecule, PDE4 inhibitor.
yield highly functionalized pyrrole derivatives. In a postulated mechanism,
attacks at the more electron-rich alkynes via a
N
N
α-