Gold(i) operational in synergistic catalysis for the intermolecular α-addition reaction of aldehydes across allenamides

Article abstract of DOI:10.1039/c5cc09529h

The intermolecular reaction of allenamides with aldehydes is reported. The designed approach relies on gold(i) and organocatalysis for activating the allenamides and the aldehydes respectively. Conditions to achieve an enantioselective version of this int

Full text of DOI:10.1039/c5cc09529h

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DOI: 10.1039/C5CC09529H
Journal Name
COMMUNICATION
Gold(I) Operational in Synergistic Catalysis for the Intermolecular
α-Addition Reaction of Aldehydes across Allenamides
Received 00th January 20xx,
Accepted 00th January 20xx
a
Alberto Ballesteros, Pablo Morán-Poladura and Jose M. González*
DOI: 10.1039/x0xx00000x
www.rsc.org/
1
1
The intermolecular reaction of allenamides with aldehydes is Scheme 1). Likewise, allene functionality has been used as
reported. The designed approach relies on gold(I) and the precursor for the allyl appendage in a synergistic approach
organocatalysis for activating the allenamide and the aldehyde to the same intramolecular process, which combines palladium
12
respectively. Conditions to achieve an enantioselective version of and organocatalysis.
Furthermore, gold and enamine
this intermolecular reaction are defined.
catalysis were early found useful for the direct intramolecular
α-vinylation reactions of aldehydes with alkynes. Allenamides
13
Synergistic catalysis creates opportunities for designing
carbon-carbon bond-making processes through polar reactions
in which, simultaneously, synthetic catalytic access to the
nucleophile and electrophile is granted. Thus, the reactivity of
the precursors would be triggered by two different catalysts in
synchronized but independent selective cycles. On this
conceptual basis, unique catalytic approaches have been
are subject of current attention for the development of new
1
4
gold-catalyzed reactions. Now, we report the ability of gold-
catalysis to merge with organocatalysis to accomplish an
intermolecular α-addition reaction of aldehydes across
allenamides, resulting in a new allylation event based on the
principles of synergistic catalysis.
Far from kinetic constrains associated with the coordination of
the two different catalytic cycles, competitive aldol
condensation and allenamide [2+2] reactions must be carefully
controlled. Initial trials focused on the reactivity of N,4-
dimethyl-N-(1,2-propadienyl)benzenesulfonamide 1a and 4-
1
established. The development of methodology for the
enantioselective intermolecular α-allylic alkylation reactions of
2
aldehydes is among those processes. Often, the proposed
reaction comprises trapping a catalytically generated allylic
intermediate by an in situ formed enamine; typically, the
former species roots from a productive metal-catalyzed
activation of an allylic precursor, while the reactivity of the
methyl-N-phenyl-N-(1,2-propadienyl) 1b towards butanal 2a
,
in search for catalysts that would afford the desired cross-
adducts. Previous studies proved that (2,4-tBu C H O) PAuNTf
2
2
6
3
3
3,4
aldehyde is triggered by an organocatalyst. Conceptually
(I) is an efficient gold catalyst for the allenamide [2+2]
5
1
5
differentiate catalytic systems have been recognized from
reaction, and also that the rate of dimerization of
combining asymmetric organocatalysis with metal catalysis,
6
-
t B
u
which resulted in processes of practical utility. Moreover, gold
-
t Bu
P
Au(NCCH3)
a
catalysis has been a major player in advancing contemporary
( )
SbF
6
7
synthetic organic methodology. In this respect, the merger of
O
8
O
(10 mol%)
gold catalysis with organocatalysis is well established and
NMe
Me
Me
H
OHC
9
Bn
relevant examples of cascade catalysis have been disclosed.
N
H
(20 mol%
)
OH
However, its potential to devise synergistic approaches to the
PhCO
H (20 mol%); THF
2
X
.
X
intermolecular aldehyde α-allylic alkylation reactions remains
X
:
NTs (38 h) 93% trans/cis 8/1; ee 90%(trans), 88%(cis)
:
10
ref 11
(
)
rans c s: 2/1; ee 89%(trans), 83%(cis)
elusive. Worth noting, the intramolecular process has been
elegantly approached combining organocatalysis and cationic
gold catalysis, using an alcohol as the required allyl donor (see
X
:
B
n
C(CO
2
)
2
79% t
/
i
(
b)
CF
3
F
3
C
O
CF
3
(
30
mol%)
H
OHC
NH
OTIPS
c
CF
mo
l%)
3
a.
Pd(OA
)
2
(5
Departamento de Química Orgánica e Inorgánica and Instituto Universitario de
Química Organometálica “Enrique Moles”
Universidad de Oviedo. C/ Julián Clavería 8, 33006 Oviedo (Spain);
E-mail: jmgd@uniovi.es.
MeO C
CO M
e
º
,
60
C
o uene
,
,
2
2
t
l
20 h 72%
ee
rans
)
.
MeO C
CO Me
2
ref 12
rans c s:
2
(
)
t
/
i
13/1;
82%(t
Electronic Supplementary Information (ESI) with further experimental details and
characterization data available. See DOI: 10.1039/x0xx00000x
Scheme 1. Synergistic catalysis: Intramolecular aldehyde α-allylation reaction.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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COMMUNICATION
Journal Name
Table 1. Optimization of intermolecular allenamide-aldehyde cross-reaction
allenylsulfonamides is dependent on the additional substituent
bonded to nitrogen, with aliphatic chains reacting under
View Article Online
DOI: 10.1039/C5CC09529H
O
milder conditions. Furthermore, the electrophilic nature of
suggests that a certain degree of acidity would be beneficial to
avoid catalysts passivation as the consequence of a likely
I
LAuNTf2 (5 mol%)
Me
.
-
L Pro 20 mol%
N
+
O
(
)
Ts
sol
vent
NTs
Me
1
a
2a
unproductive complexation of
Satisfyingly, it was discovered that
I
with the organocatalyst.
and L-proline
3
a
-
-
i Pr
-
tBu
i Pr
t Bu
I
tB
u
P
O
P
N
N
synergistically work to furnish the target intermolecular α-
aldehyde functionalization reaction with allenamides, yet in
modest yield (Scheme 2). The reaction was conducted by slow
PPh
3
-
-
-
i Pr
t Bu
i Pr
3
L
1
L
2
L3
L
4
addition of the allenamide
1
for a period of 15 minutes over a
a
b
Entry
Gold cat.
I (L: L1)
Solvent
T (ºC)
60
60
60
60
60
60
60
60
60
40
60
60
60
t (h)
24
24
5.5
5.5
2
Yield (%)
solution containing the catalysts and the excess of aldehyde, to
minimize allenamide dimerization. The use of stoichiometric
aldehyde (1 equiv) and organocatalyst did not result in
c
1
2
3
4
5
6
7
8
9
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
THF
2
2
2
2
2
2
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
25
d
II (L: L2)
III (L: L3)
IV (L: L4)
Cl
Cl
Cl
Cl
Cl
17
improved formation of
The absence of any of the two catalysts translates in lack of
formation of . Next, different experimental conditions and
3, but in lowering the yield by a third.
15
24
7
3
several catalyst modifications were tested, in an attempt to
improve the efficiency of this new C-C bond-forming event.
Representative data are summarized in Table 1.
The reaction takes place diminishing the catalyst loading by
half but requires longer time. IPrAuNTf2 (IV) is the more active
catalyst (entries 1-6), and acetonitrile is a convenient media to
conduct the target transformation (entries 7-13). Increasing
the amount of 2a up to 5 equiv and modifying the protocol for
mixing reactants and catalysts (2a being stirred with proline
before adding IV and 1a) resulted in improved yield for
forming 3a (entry 14). A control experiment replacing the gold 11
catalyst by HNTf2 was performed for 3-phenylpropanal. The
desired product was formed in only 11% (see ESI), highlighting
the merit of merging gold and organocatalysis for triggering 13
AuCl
3
PtCl
4
1
6
IV
6.5
6
40
37
42
37
35
40
38
58
IV
Toluene
IV
CH
3
2
CN
Cl
1.7
21
7.8
22
10
IV
CH
2
IV
tBuOCH
3
12
IV
1,4-dioxane
IV
CH
3
3
CO
2
Et
21.5
2.3
the process. Although enantiopure L-Pro was used, 3a was
e
14
IV
CH
CN
20
obtained racemic. It might reflect an insufficient bulkiness of
the carboxylic functionality to allow the required productive
facial discrimination along the attack of the enamine to the Based on H NMR analysis of crude reaction, adding 1,3,5-trimethoxybenzene
gold-activated allenamide, at the time of 1a lacking properly
located hydrogen-bond acceptors for the key step. Alternative
organocatalysts were tested under this experimental protocol.
In all cases, the aldehyde-allenamide cross-reaction either
failed or was less efficient than for proline. Representative
examples are collected in Scheme 3 (yield from 1,3,5-
trimethoxybenzene as internal standard). On this basis, the
a
b
Monitoring the disappearance of 1a by TLC, unless otherwise specified.
1
c
d
as internal standard. 1a remains partly unreacted (25%). 12% of 1a
unreacted. 5 equiv of 2a stirred with the organocatalyst for 10 min, and then
IV and 1a were added. The reaction was quenched adding Ph P.
3
e
O
IPrAuNTf
rganocatalyst 20 mol%
)
(IV) (5 mol%)
(
Me
.
2
N
+
O
O
Ts
,
º
C
,
.
2
a (5
equiv
)
CH
3
CN 20
NTs
Me
1
a
(
1
equiv 0 2 M)
3
a
potential of the simultaneous catalytic activation of
1
and
2
by
OTMS
OTMS
Ar
O
OMe
Ph
N
Ph
Ph
N
H
N
H
N
IPrAuNTf and L-Pro was explored. The conditions in entry 14,
2
H
H
Ar
OMe
Ph
,
-
Table 1 were chosen to check the scope of this addition to
allenamides that, by prior standard reduction before isolation,
resulted in the different alcohols depicted in Scheme 4.
Linear and β-branched aldehydes react towards allenamides to
(A
r:3 5 CF3 C H
2
6 3
) )
(
a 7% 23 h
3a 4% 24 h
3a 10% 24 h
( )
3
a 10% (23 h)
3
(
)
(
)
,
(
1
a recovere
,
1a recovered 57
,
1a recovered 72
,
a recovere
d
50%)
d
43%)
(
%)
(
%)
(
1
16
H
H
Ph
O
N
N
Me
OTBS
Ph
OTBS
O
N
H
N
H
M
e
e
Ph
M
e
N
H
N
H
Me
Ph
M
-
-
--
a 12% 24 h
a
a
4 h
)
3
a 9% (24 h)
3
( )
,
3
(2 h)
3
(
,
(1a recovered 49%)
tBu
tBu
(1
a recovered 59%
)
O
(
I)
OH
O
CO
2
H
O
PAuNTf2
N
N
Ph
N
N
H
R1
(10
mol%
-
)
H
H
H
2
.
3
NH2
Ph
CH CO
3
2
O
N
Ts
+
L Pro 20 mol%
s
.
(
)
NT
a
3
a
3
a
a 5
2
3
h
)
3
15% (24 h)
1% (24 h)
5% 24 h
)
,
3
8% (
(
,
º
R1
1a recovered 25%
,
1a recovered 78%
,
a recovere
ClCH CH Cl 60
C
(
)
(
)
(1
d
48%)
2
2
a R1
:
e
e u v
3
a
R1
:
Me,
,
95
m n,
i
30%
32%
1
M
(
2
q i
2
Scheme 3. Organocatalysts activity for 2a addition to IPrAuNTf -activated 1a.
)
b R1 Ph
:
2a
3b R1 Ph 50
i
m n,
:
1
Scheme 2. Intermolecular allenamide reaction with aldehyde: initial results.
2
| J. Name., 2012, 00, 1-3
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Journal Name
furnish the target adducts (3a
COMMUNICATION
.
1
IPrAuNTf
2
(IV) (5 mol%)
-
3l) as the result of this
CO
2
H
View Article Online
OTBS
DOI: 10.1039/C5CC09529H
intermolecular C-C bond-forming carbonyl α-functionalization
process. For a given aldehyde, an N-alkyl allenamide gives
higher yield than an N-aryl-substituted one; for instance, see
the formation of 3g vs. 3j. At the same time, aldehydes giving
conjugated enamines offer better performance than simple
linear ones (3g against 3a). Although quaternary centres can
be assembled the yields range only from modest to moderate.
Alternatively, excellent results are obtained from suitable
partners, such as for getting 3k from aldehyde 2f and 1d.
OH
N
H
Ph
Ph
F
.
q
(0 5 i
e
u v
)
20
mo
l%)
,
(
Me
.
O
Toluene 20 ºC
+
N
Ph
Ts
.
Ph
NaBH4, CH
OH
NTs
Me
(
2
eq
uiv
)
2
3
3
g
1
a
2f
,
,
3
0 min 37% 64% ee
,
,
60 min 62% 56% ee
,
,
1
20 min 63% 54% ee
Scheme 5. Activation of TBS-masked diaryl prolinol for adding 2f to 1a.
Next, the search for alternative experimental conditions was
further pursued with the aim of overcoming the limitations
evidenced by the first generation. Attention was paid to
prepare quaternary centres in respectable chemical yield and
to accomplish an enantioselective version. On the basis of the
above quoted findings, an acid additive could help to broach
the potential of other common but better space-shielding
2
gold by HNTf was tested for preparing 3p. The desired adduct
was formed in 18% yield (vs. 72%, Table 2). Interestingly, it
works nicely for accessing the racemic product using a highly
enolizable aldehyde, modifying the first generation conditions
in Scheme 4 (3p now isolated in convenient 51% yield, see ESI).
As depicted in Table 2, the efficiency of the diarylprolinol
frame was further tested using two different O-protected silyl
17
organocatalyst. Under this assumption, some molecules early
tested (Scheme 3) could be proper catalysts for this purpose.
In this preliminary screening, attention was paid to render
diaryl prolinol silyl ethers active catalyst for this synergistic
1
9
derivatives. As early noticed, the more sterically demanding
TIPS-masked prolinol affords improved stereocontrol although
only modest chemical yield. Conversely, using the related TBS-
protected organocatalyst, the quaternary center is formed in
excellent yield although in lower, but still respectable,
enantiomeric excess for the different α-aryl propanals assayed.
A tentative proposal that accounts for the formation of the
observed products matching the characteristic of this new C-C
bond-forming event and lining up with previous mechanistic
18
transformation. The reaction in presence of different acids
was tested, and ortho-fluorobenzoic acid is a beneficial
additive, as illustrated in Scheme 5 for the synthesis of 3g from
1a and aldehyde 2f. Extended reaction time gives 3g in higher
yield but concomitant loss of steroselectivity is noticed, likely
due to its partial epimerization under the reaction conditions.
Exploring the utility of this protocol for preparing quaternary
stereocenters is an attractive option. The reaction is sluggish
but, as epimerization is not operating, the amount of acid can
be increased up to 1 equiv to speed the reaction. Also, the
more polar acetonitrile was chosen as the solvent, and the
results are collected in Table 2. A control experiment replacing
2
0
insights in the field is graphically outlined in Scheme 6.
Activation of allenamide by gold(I) gives rise to the required
electrophile, which is trapped by the in situ formed enamine
from reacting aldehyde with the organocatalyst. The
2
1
Brønsted acid facilitates both, the enamine formation and the
regeneration of both types of active catalysts.
Table 2. Quaternary stereocenters from enantioselective addition of 2 to 1.
.
.
r
u
mo
l%)
IPrAuNTf
-
(IV) (5 mol%)
2
OH
R3
1
IP A NTf2 (IV) (5
1
R3
CO2H
F
L Pro (20 mol%)
OR
R1
.
O
,
º
N
H
Ph
OH
Ar
N
Ts
+
CH
BH4, CH
3
CN 20
C
R2
R2
Ph
.
Me
(20 mol%)
CH3CN, 20 ºC
(1 equiv)
2
N
a
3
OH
NTs
R1
-
2(a-j)
-
1
(a g)
3(a s)
Me
.
O
N
T
+
A
r
M
e
a R1
d R
:
e
; 1b R1 Ph; 1 R1 CH
:
c
:
R2 Et
2d R iP
2g R Ph
2i R p M C H
:
,
R
r
,
3
:
3
2
:
B
:
u
,
R
3
:
3
-
H; 2 R2
c
:
2
M
:
e
,
,
R3
R
:
:
H
H
s
.
2
NaBH4, CH OH
3
1
1
1
1
M
2
Cy;
2
a
H; 2b R
NT
s
1
:
:
:
n
e
1
:
-
r
-
-
,
:
H; 2 R2
e
,
:
3
(2
equiv
)
2
:
B
n
B
; 1
R
p B C H
6
4
;
R
R
H; 2f R Ph
-
-
s
1
-
e
-
(p Tol);
g R p M O C H
(PMP)
OH
-
,
R3
1a
2g
3p
Me
2
:
3
:
e
2
:
:
e
;
j
f R p M C H
6
4
R
M
; 2h R p Cl C H
6
4
M
1
-
e
-
2
:
-
e
-
4,
3
:
M
e
; 2j R p M O C H R3
2
:
-
e
-
4,
:
M
e
6
4
6
R
6
OH
OH
OH
OH
a
b
Entry
Ar / 2
R
t (h)
3 (%)
ee (%)
76
Ts
Ts
Ts
Ts
N
Ts
N
N
N
N
1
2
3
4
5
6
7
8
a
C H / 2g
TBS
TIPS
TBS
TIPS
TBS
TIPS
TBS
TIPS
4
3p 72
3p 25
3s 73
3s 32
3q 27
3q 23
3r 80
3r 35
6
5
a 63% Me
3c 70% Me
3d 52% Me
Me
%
3
3b 32% Ph
OH
3e 5
9
OH
OH
OH
OH
C
6
H
5
/ 2g
3
86
Ts
Ts
Ph
Ts
Ph
N
T
s
Ph
3j 61% Ph
T
s
p-MeOC
6
6
H
4
/ 2j
/ 2j
4
68
Ph
N
N
Ph
N
N
3
i 71%
B
n
3
f 74% Me
3g 78% Me
3h 55% Cy
p-MeOC
H
4
7
80
OH
OH
OH
OH
OH
Br
p-ClC
6
H
4
/ 2h
8
24
Ts
N
-
ol Ph
Ph
Ts
N
Ph
Ph
Ph
p T
PMP
N
N
N
3
k 94%
3l 88%
3m 27% Ts
3n 42%
3o 47% T
s
p-ClC H / 2h
8
60
Ph
Cy
OH
T
s
6
4
OH
OH
OH
p-MeC
6
H
4
/ 2i
/ 2i
2.25
7
60
Ts
N
Ts
N
Ts
Ts
N
N
Me
Me
Me
Me
p-MeC
6
H
4
82
Me
3
p 27%
Cl
3q 28%
3r 46%
MeO
3s 25%
b
Monitoring reaction progress until disappearance of 1a. Isolated yield.
Scheme 4. Intermolecular aldehyde 1 α-addition reaction to allenamides 2.
This journal is © The Royal Society of Chemistry 20xx
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COMMUNICATION
Journal Name
Acc. Chem. Res., 2014, 47, 925; (e) R. DVoierweAl,rticlAe.OnMline.
O
H
2
O
N
Echavarren, Chem. Rev., 2015, 115, 9028.
DOI: 10.1039/C5CC09529H
O
OH
.
R1
8
9
C. J. Loh, D. Enders, Chem. Eur. J., 2012, 18, 10212.
R1
2
(a) D. M. Barber, A. Ďuriš, A. L. Thompson, H. J. Sanganee, D.
Ts
[
N
[A
u
]
O
R2
J. Dixon, ACS Catal., 2014, 4, 634; (b) D. Hack, C. C. J. Loh, J.
O
N
NTf
2
]
N
H
OH
M. Hartmann, G. Raabe, D. Enders, Chem. Eur. J., 2014, 20
,
T
s
O
OH
N
3
917; (c) A. Ďuriš, D. M. Barber, H. J. Sanganee, D. J. Dixon,
R2
A
u
]
R1
[
R1
Chem. Commun., 2013, 49, 2777; (d) D. M. Barber, H. J.
Sanganee, D. J. Dixon, Org. Lett., 2012, 14, 5290; (e) C. C. J.
1
.
[
NTf
2
]
O
NTf
2
AuL
NTs
N
T
s
N
Loh, J. Badorrek, G. Raabe, D. Enders, Chem. Eur. J., 2011, 17
3409; (f) S. Belot, K. A. Vogt, C. Besnard, N. Krause, A.
Alexakis, Angew. Chem. Int. Ed., 2009, 48, 8923.
,
R2
2
R
H
2
O
T
s
O
1
N
R2
R1
1
0 Synergistic catalysis using aldehyde/gold/amine: (a) α-
vinylidenation: Z. Wang, X. Li, Y. Huang, Angew. Chem. Int.
Ed., 2013, 52, 14219; (b) Ynone synthesis: Z. Wang, L. Li, Y.
Huang, J. Am. Chem. Soc., 2014, 136, 12233.
Scheme 6. Proposed gold-organocatalyzed synergistic C-C bond-formation
In short, a C-C bond-forming reaction by adding the Cα-H bond
of an aldehyde to the distal bond of an allenamide is
presented. The reaction relies on the power of synergistic
catalysis merging gold with organocatalysis. Its usefulness to
approach the preparation of quaternary carbon-stereocenters
is covered and an asymmetric version presented.
The authors thank financial support by the Spanish MINECO
Grant CTQ-2013-41511-P and the Principality of Asturias
Grant FC-15-GRUPIN14-013). A.B. is grateful to the Asturias
1
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6 Added 2 ranges from 2 to 5 equiv. See the accompanying ESI.
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Terminology used for catalytic systems is defined in ref. 1.
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