Dealkoxylation ofN-alkoxyamides without an external reductant driven by Pd/Al cooperative catalysis

Article abstract of DOI:10.1039/d0ob01815e

Lewis acid-assisted palladium-catalysed dealkoxylation ofN-alkoxyamides has been developed. This reaction proceeded smoothly with a range ofN-alkoxyamides in the absence of an external reductant, thereby establishing a convenient and reductant-free protocol. In addition, a gram-scale reaction could be achieved. Preliminary mechanistic investigations indicated that β-hydrogen elimination from a palladium alkoxide intermediate generated an intramolecular hydride source.

Full text of DOI:10.1039/d0ob01815e

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Dealkoxylation of N-alkoxyamides without an
external reductant driven by Pd/Al cooperative
Cite this: DOI: 10.1039/d0ob01815e
catalysis†
Received 2nd September 2020,
Accepted 14th September 2020
Hirotsugu Suzuki,
Takahiro Shiomi, Kenji Yoneoka and Takanori Matsuda
*
DOI: 10.1039/d0ob01815e
rsc.li/obc
Lewis acid-assisted palladium-catalysed dealkoxylation of resulted in the formal reduction of the amides, along with the
N-alkoxyamides has been developed. This reaction proceeded formation of formaldehyde. Although these reductants and
smoothly with a range of N-alkoxyamides in the absence of an bases allow facile cleavage of the alkoxy groups from
external reductant, thereby establishing a convenient and reduc- N-alkoxyamides under very mild conditions, excess amounts of
tant-free protocol. In addition, a gram-scale reaction could be reductants or bases are required for these reactions. In
achieved. Preliminary mechanistic investigations indicated that
β-hydrogen elimination from a palladium alkoxide intermediate
generated an intramolecular hydride source.
N-Alkoxyamides are an important class of synthetic intermedi-
ates for a range of organic transformations.1 In particular,
N-methoxy-N-methylamides, which are known as Weinreb
amides, have unique properties as acylating reagents that sup-
press the overalkylation of reaction products by forming
remarkably stable five-membered cyclic intermediates
(Scheme 1a).2 This exceptional feature allows the transform-
ation of readily available and stable N-alkoxyamides3 into
useful aldehydes and ketones in a single step. Recently,
Scheme 1 Transformation of N-alkoxyamides: (a) nucleophilic addition
of organometallic reagents and (b) dealkoxylation of N-alkoxyamides.
N-alkoxyamides have emerged as versatile directing groups for
C–H bond functionalisation, and various transformations
employing N-alkoxyamides are currently available.4 While
N-alkoxyamides are commonly used in various organic reac-
tions, the dealkoxylation of N-alkoxyamides has not been
explored enough yet (Scheme 1b).
Conventional dealkoxylation of N-alkoxyamides requires
stoichiometric metal-based reductants such as SmI2,5 Na/Hg6
and lithium powder7 (Scheme 2a). An organic, neutral super
electron donor has been developed as a stoichiometric reduc-
tant, and it gives results comparable to those obtained using
metal-based reductants.8 Base-mediated formal reduction of
N-alkoxyamides has also evolved as a method for dealkoxyla-
tion.9 Treatment of N-alkoxyamides with lithium diisopropyl-
amide,9a or tert-butyldimethylsilyl triflate and triethylamine9b
Department of Applied Chemistry, Tokyo University of Science, 1-3 Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan. E-mail: mtd@rs.tus.ac.jp
†Electronic supplementary information (ESI) available: Experimental procedures
and characterisation data for new compounds. See DOI: 10.1039/d0ob01815e
Scheme 2 Dealkoxylation of N-alkoxyamides.
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addition, these reducing reagents are sometimes expensive, tive protocol for avoiding the use of such stoichiometric
difficult to handle, and hazardous. Ruthenium-catalysed deal- reagents (Scheme 2b). Dealkoxylation proceeded in alcoholic
koxylation of N-alkoxyamides has been reported as an alterna- solvents, which also behaved as a stoichiometric reductant.10
Although the catalytic reactions require only green and cheap
alcohols as stoichiometric reductants, it is necessary to add a
substoichiometric amount of Zn–Cu for activating the ruthe-
nium catalyst. Herein, we report the palladium-catalysed deal-
Table 1 Optimisation of reaction conditionsa
koxylation of N-alkoxyamides in the absence of an external
reductant as a convenient and reductant-free protocol for deal-
koxylation (Scheme 2c). To the best of our knowledge, this is
the first report on the catalytic dealkoxylation of
N-alkoxyamides without any external reductants.11
We began our investigation using N-methoxy-N-methyl-
Entry
Lewis acid
Solvent
Yield (%)
benzamide (1a) as a model substrate, which was heated in
toluene at 150 °C in the presence of the Pd(dba)2/DPPBz cata-
lyst (Table 1). After 6 h, the desired secondary amide 2a was
formed in a moderate yield (entry 1). We then screened alu-
minium Lewis acids as co-catalysts in order to activate the N–O
bond.12 The addition of aluminium(III) chloride (AlCl3) sup-
pressed the reaction completely (entry 2). Trialkylaluminium
or trialkoxyaluminium dramatically improved the yields
(entries 3–6), and the best result was obtained when triiso-
butylaluminium (Ali-Bu3) was employed as a co-catalyst (entry
4).13 Solvent screening (entries 7–12) revealed that cyclopentyl
methyl ether (CPME) was the optimal solvent for affording the
desired product in an excellent yield (entry 9).14 In addition,
this demethoxylation reaction could reach completion with
reduced catalyst loadings (entry 13).
1
2
3
4
5
6
7
8
—
AlCl3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
p-Xylene
1,4-Dioxane
CPME
33
NR
87
98
83
94
86
86
99
85
84
61
99
AlMe3
Ali-Bu3
Al(OEt)3
Al(Oi-Pr)3
Ali-Bu3
Ali-Bu3
Ali-Bu3
Ali-Bu3
Ali-Bu3
Ali-Bu3
Ali-Bu3
9
10
11
12
13b
Diglyme
DMF
DMSO
CPME
a Reaction conditions:
(4 mol%) and Lewis acid (10 mol%) in CPME (0.3 M) at 150 °C for 6 h,
unless otherwise noted. b Pd(dba)2/DPPBz (2 mol% each) and Ali-Bu3
(5 mol%) were used as catalysts. The reaction time was 20 h.
1 (0.3 mmol), Pd(dba)2 (4 mol%), DPPBz
Table 2 Palladium-catalysed demethoxylation of N-methoxyamidesa
a Reaction conditions: 1 (0.3 mmol), Pd(dba)2 (4 mol%), DPPBz (4 mol%) and Ali-Bu3 (10 mol%) in CPME (0.3 M) at 150 °C for 6 h, unless other-
wise noted. The yields represent the average yield of two reaction runs. b Pd(dba)2 (8 mol%), DPPBz (8 mol%) and Ali-Bu3 (20 mol%) were used
(20 h). c The reaction time was 18 h. d Pd(dba)2 (8 mol%), DPPBz (8 mol%) and Ali-Bu3 (20 mol%) were used (18 h).
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With the optimised reaction conditions in hand, we investi- bearing electron-donating and electron-withdrawing groups
gated the scope of demethoxylation (Table 2). Introduction of 1f–j were well tolerated under the optimal conditions.
methyl groups at the para- and meta-positions of the benzene Heteroaryl-substituted substrates 1k–o were also converted
ring (1b–d) did not affect the efficiency of transformations. into the desired secondary amides with high efficiency.
However, the reactivity decreased with o-methylbenzamide 1e, Cinnamamide 1p afforded the corresponding product without
and increased catalyst loadings were required to obtain a the reduction of the olefin moiety.10 It is worth noting that the
reasonable yield of the desired secondary amide. Benzamides demethoxylation of enolisable N-methyl-N-methoxyamides 1q–
s proceeded smoothly, and no side reactions were observed.
To further demonstrate the applicability of demethoxyla-
tion, other alkoxyamides were examined. Under the optimal
conditions, sulfonamide 3 gave the desired secondary sulfona-
mide 4 in a high yield (Scheme 3a). Moreover, phosphorami-
date 5 was found to be a promising substrate for the
demethoxylation to afford the corresponding product in a
good yield (Scheme 3b). In both cases, an N–O bond was selec-
tively cleaved, while the other heteroatom–heteroatom bonds
remained intact. In contrast to previous studies, reductant-free
demethoxylation was applicable to a wide range of N-methoxy-
N-methylamides, without the occurrence of any side reactions
or over-reactions. Furthermore, a gram-scale reaction was per-
formed with 1a in diglyme, and the desired product 2a was
obtained in 78% yield (Scheme 4).15
To gain insight into the reaction mechanism, a control
experiment was conducted (Scheme 5). When N-butoxy-N-
Scheme 3 Palladium-catalysed demethoxylation of sulfonamide 3 and
phosphoramidate 5.
methylbenzamide (1t) was subjected to the standard reaction
conditions, butanal and its aldol condensation product were
produced along with the desired secondary amide 2a. These
byproducts may have been generated via the β-hydrogen elim-
ination from a palladium alkoxide intermediate. The results
reveal that an α-hydrogen atom with respect to the oxygen
atom of the alkoxy group functions as a hydride source.11,16
A plausible mechanism for the reductant-free demethoxyla-
tion is proposed on the basis of a previous report11 and our
Scheme 4 A gram-scale reaction.
preliminary mechanistic investigations (Scheme 6). The carbo-
nyl oxygen of alkoxyamide 1 coordinates to the aluminium
Lewis acid to form A, thereby weakening the N–O bond.
Subsequently, oxidative addition of the N–O bond to Pd(0) gen-
erates palladium alkoxide B, which undergoes β-hydrogen
elimination to generate palladium hydride intermediate C and
formaldehyde. Finally, reductive elimination from the inter-
Scheme 5 Palladium-catalysed debutoxylation of N-butoxy-N-methyl-
mediate C affords secondary amide 2 and simultaneously
regenerates the catalytically active Pd(0) species.
benzamide (1t) (conditions: 4 mol% Pd(dba)2, 4 mol% DPPBz, 10 mol%
Ali-Bu3, CPME, 150 °C, 6 h).
Scheme 6 The plausible reaction mechanism for reductant-free demethoxylation.
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S. F. McHardy and J. E. Murry, J. Am. Chem. Soc., 1995, 117,
7289–7290.
Conclusions
In summary, we achieved the demethoxylation of N-alkoxyamides
in the presence of a Pd/Al cooperative catalytic system. The reac-
tion proceeded with various N-alkoxyamides including a sulfona-
mide and a phosphoramide in the absence of an external reduc-
tant. The N–O bond was selectively reduced, and there were no
side reactions or over-reactions. Preliminary mechanistic investi-
gations revealed that β-hydrogen elimination of a palladium
alkoxide intermediate generated an intramolecular hydride
source. Further studies on palladium-catalysed reductant-free
demethoxylation are ongoing in our laboratory.
6 (a) R. Sword, S. O’Sullivan and J. A. Murphy, Aust. J. Chem.,
2013, 66, 314–322; (b) J. E. Jackson, B. N. O’Brien,
S. K. Kedzior, G. R. Fryz, F. S. Jalloh, A. Banisafar,
M. A. Caldwell, M. B. Braun, B. M. Dunyak and J. L. Dye,
Tetrahedron Lett., 2015, 56, 6227–6230.
7 M. Yus, G. Radivoy and F. Alonso, Synthesis, 2001, 914–918.
8 S. P. Y. Cutulic, J. A. Murphy, H. Farwaha, S.-Z. Zhou and
E. Chrystal, Synlett, 2008, 2132–2136.
9 (a) S. L. Graham and T. H. Scholz, Tetrahedron Lett., 1990,
31, 6269–6272; (b) G. E. Keck, S. F. McHardy and
J. A. Murry, Tetrahedron Lett., 1993, 34, 6215–6218.
10 H. Fukuzawa, Y. Ura and Y. Kataoka, J. Organomet. Chem.,
2011, 696, 3643–3648.
11 For nickel-catalysed reductant-free dealkoxylation of aryl
alkyl ethers, see: M. Tobisu, T. Morioka, A. Ohtsuki and
N. Chatani, Chem. Sci., 2015, 6, 3410–3414.
Conflicts of interest
There are no conflicts to declare.
12 For the decrease in the activation energy of an aryl C–O
bond cleavage by aluminium Lewis acids, see: (a) X. Liu,
C.-C. Hsiao, I. Kalvet, M. Leiendecker, L. Guo,
F. Schoenebeck and M. Rueping, Angew. Chem., Int. Ed.,
2016, 55, 6093–6098; (b) P. Kelley, G. A. Edouard, S. Lin and
T. Agapie, Chem. – Eur. J., 2016, 22, 17173–17176.
Notes and references
1 S. Balasubramaniam and I. S. Aidhen, Synthesis, 2008,
3707–3738.
2 (a) S. Nahm and S. M. Weinreb, Tetrahedron Lett., 1981, 22,
3815–3818; (b) J. A. Murphy, A. G. J. Commeureuc,
T. N. Snaddon, T. M. McGuire, T. A. Khan, K. Hisler,
M. L. Dewis and R. Carling, Org. Lett., 2005, 7, 1427–1429;
(c) C. O. Kangani, D. E. Kelley and B. W. Day, Tetrahedron
Lett., 2006, 47, 6289–6292.
13 For recent examples of transition metal/aluminium
cooperative catalysis, see: (a) P. A. Donets and N. Cramer,
J. Am. Chem. Soc., 2013, 135, 11772–11775; (b) S. Okumura,
S. Tang, T. Saito, K. Semba, S. Sakaki and Y. Nakao,
J. Am. Chem. Soc., 2016, 138, 14699–14704; (c) S. Okumura
and Y. Nakao, Org. Lett., 2017, 19, 584–587; (d) F. Inoue,
T. Saito, K. Semba and Y. Nakao, Chem. Commun., 2017, 53,
4497–4500; (e) Q.-S. Liu, D.-Y. Wang, Z.-J. Yang, Y.-X. Luan,
J.-F. Yang, J.-F. Li, Y.-G. Pu and M. Ye, J. Am. Chem. Soc.,
2017, 139, 18150–18153; (f) S. Okumura, T. Komine,
E. Shigeki, K. Semba and Y. Nakao, Angew. Chem., Int. Ed.,
2018, 57, 929–932; (g) Y.-X. Wang, S.-L. Qi, Y.-X. Luan,
X.-W. Han, S. Wang, H. Chen and M. Ye, J. Am. Chem. Soc.,
2018, 140, 5360–5364; (h) T. Zhang, Y.-X. Luan, S.-J. Zheng,
Q. Peng and M. Ye, Angew. Chem., 2020, 59, 7439–7443.
14 The yield was dramatically decreased when the reaction
was performed at 130 °C for 6 h (36% yield).
3 (a) A. Basha, M. Lipton and S. M. Weinreb, Tetrahedron
Lett., 1977, 18, 4171–4172; (b) J. M. Williams, R. B. Jobson,
N. Yasuda, G. Marchesini, U.-H. Dolling and
E. J. J. Grabowski, Tetrahedron Lett., 1995, 36, 5461–5464;
(c) T. Shimizu, K. Osako and T. Nakata, Tetrahedron Lett.,
1997, 38, 2685–2688; (d) P.-Q. Huang, X. Zheng and
X.-M. Deng, Tetrahedron Lett., 2001, 42, 9039–9041.
4 (a) F. Yang and L. Ackermann, Org. Lett., 2013, 15, 718–720;
(b) Y. Wang, C. Li, Y. Li, F. Yin and X.-S. Wang, Adv. Synth.
Catal., 2013, 355, 1724–1728; (c) G. Li, L. Wan, G. Zhang,
D. Leow, J. Spangler and J.-Q. Yu, J. Am. Chem. Soc., 2015,
137, 4391–4397; (d) R. Das and M. Kapur, Chem. – Asian J.,
2015, 10, 1505–1512; (e) R. Das and M. Kapur, Chem. – Eur.
J., 2016, 22, 16986–16990; (f) K. Kawai, Y. Bunno,
T. Yoshino and S. Matsunaga, Chem. – Eur. J., 2018, 24,
10231–10237.
15 The solvent was employed in order to perform the reaction
in a flask.
16 (a) X. Wu, B. P. Fors and S. L. Buchwald, Angew. Chem., Int.
Ed., 2011, 50, 9943–9947; (b) M. S. Mikus, C. Sanchez,
C. Fridrich and J. F. Larrow, Adv. Synth. Catal., 2020, 362,
430–436.
5 (a) J. L. Chiara, C. Destabel, P. Gallego and J. Marco-
Contelles, J. Org. Chem., 1996, 61, 359–360; (b) G. E. Keck,
Org. Biomol. Chem.
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