Cobalt-Catalyzed Aminocarbonylation of Alkyl Tosylates: Stereospecific Synthesis of Amides

Article abstract of DOI:10.1002/anie.201905173

Metal-catalyzed aminocarbonylation is a standard approach for installing amide functionality in chemical synthesis. Despite broad application of this transformation using aryl or vinyl electrophiles, there are few examples involving unactivated aliphatic substrates. Furthermore, there are no stereocontrolled aminocarbonylations of alkyl electrophiles known. Herein, we report a stereospecific aminocarbonylation of unactivated alkyl tosylates for the synthesis of enantioenriched amides. This cobalt-catalyzed transformation uses a remarkably broad range of amines and proceeds with excellent stereospecificity and chemoselectivity.

Full text of DOI:10.1002/anie.201905173

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Accepted Article
Title: Cobalt-Catalyzed Aminocarbonylation of Alkyl Tosylates:
Stereospecific Synthesis of Amides
Authors: Brendon Sargent and Erik John Alexanian
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905173
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10.1002/anie.201905173
Angewandte Chemie International Edition
COMMUNICATION
Cobalt-Catalyzed Aminocarbonylation of Alkyl Tosylates:
Stereospecific Synthesis of Amides
Brendon T. Sargent and Erik J. Alexanian*
Abstract: Metal-catalyzed aminocarbonylation is
a
standard
stereoablative transformations. Recently, we reported a new
strategy for stereospecific C–C bond construction of unactivated
alkyl electrophiles using nucleophilic cobaltate catalysis.[6,7] We
hypothesize that this transformation involved a diene insertion of
an enantioenriched acylcobalt intermediate. We proposed that an
alternative catalytic mechanism involving nucleophilic substitution
of this intermediate could unlock a range of new, stereospecific
transformations. Herein, we report our initial studies towards this
approach for installing amide functionality in chemical synthesis.
Despite broad application of this transformation using aryl or vinyl
electrophiles, few examples involve unactivated aliphatic substrates.
Furthermore, there are no stereocontrolled aminocarbonylations of
alkyl electrophiles known. Herein, we report
a stereospecific
aminocarbonylation of unactivated alkyl tosylates for the synthesis of
enantioenriched amides. This cobalt-catalyzed transformation uses a
remarkably broad range of amines in a convergent manner, and
proceeds with excellent stereospecificity and chemoselectivity.
goal via
unactivated alkyl electrophiles using a broad range of amines and
commercially available cobalt catalyst. This highly
a catalytic, stereospecific aminocarbonylation of
a
chemoselective, catalytic method facilitates the stereospecific
synthesis of diverse amides from easily accessed chiral, non-
racemic alkyl tosylate building blocks.
The amide functional group is ubiquitous in organic
compounds, and is typically synthesized via the coupling of
carboxylic acids and amines.[1] An alternative concise, catalytic
approach to amide synthesis is the aminocarbonylation of
activated halides or pseudohalides using amines and CO, first
reported by Heck.[2] While this transformation has seen
widespread use in applications up to industrial scale,[3]
aminocarbonylation of widely available, unactivated aliphatic
electrophiles remains a major challenge. The few reported
processes require the use of alkyl iodides and either high energy
irradiation or organotin initiators in radical-mediated processes
(Figure 1).[4] In addition, these reactions often provide byproducts
involving multiple CO insertions.[4d,5] The lack of a practical,
chemoselective aminocarbonylation of unactivated alkyl
electrophiles is a major limitation of this attractive approach to
amide synthesis.
Our studies commenced with the aminocarbonylation of
unactivated secondary alkyl tosylate (S)-1 with morpholine 2
(Table 1). A catalytic system comprised of 10 mol % of
commercially available Co2(CO)8 and 2 equivalents of TMP
(2,2,6,6-tetramethylpiperidine) provided amide 3 in good yield
with high stereocontrol (86% 1H NMR yield, 97% es, entry 1)
under 40 atm CO in t-amyl-OH.[8] Substituting 20 mol % of the
cobaltate K[Co(CO)4] led to a slightly lower yield but similar
stereospecificity (entry 2). Decreasing the loading of the catalyst
to 5 mol % also decreased the yield, which we attribute to
increased direct alkylation of morpholine (entry 3). Other metal
carbonyls (e.g., Mn2(CO)10) were inefficient in the
aminocarbonylation
(entry
4).
Substituting
4-
(trimethylsilyl)morpholine as the nitrogen nucleophile–previously
used to intercept acylcobalt intermediates[9]–provided a lower
yield of the desired amide (62%, entry 5). Alternative organic
bases (entry 6) or inorganic bases (entry 7) were inferior to TMP.
Removing TMP from the reaction also significantly lowered the
reaction efficiency (entry 8). The use of t-amyl-OH as solvent was
critical, as a polar aprotic solvent (e.g., THF) gave significantly
reduced yields of amide (entry 9). Lower pressures of CO (10 or
20 atm) could be used, however, the yield and enantiospecificity
of the reaction decreased (entry 10—11).[10] No reaction occurred
in the absence of the cobalt catalyst (entry 12).
Pd-catalyzed aminocarbonylation of alkyl iodides: Ryu (2007)
5 mol % Pd catalyst
75 atm CO
3 equiv piperidine
N
N
n-Bu
O
I
n-Pent
Ph3P Pd Cl
Cl
n-Pent
N
[bmim]NTf2
500 W Xe lamp, 16 h
Pd catalyst
44% yield
This work: Co-catalyzed, stereospecific aminocarbonylation of unactivated alkyl tosylates
O
First-row, commercially available
catalyst
10 mol % Co2(CO)8
40 atm CO
R1
R1
R3
OTs
N
High functional group tolerance
Stereospecific catalysis
1.3 equiv 1° or 2° amine
or ammonium carbamate
2 equiv TMP
t-amyl-OH, 70 °C
R2
unactivated
alkyl tosylates
chiral, non-racemic
amides
Efficiently transforms unactivated
alkyl tosylates
Figure 1. Aminocarbonylations of unactivated alkyl electrophiles.
Table 1. Stereospecific, cobalt-catalyzed aminocarbonylation of an unactivated
alkyl tosylate with morpholine.
O
10 mol % Co2(CO)8
Ph
Ph
OTs
HN
40 atm CO
The control of absolute stereochemistry in the
aminocarbonylation of alkyl electrophiles is another critical goal
which is unlikely to be attained via radical-mediated,
N
+
O
2 equiv TMP
t-amyl-OH
70 °C, 48 h
O
2
1
3
1.3 equiv
[*]
B. T. Sargent, Prof. E. J. Alexanian
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599 (USA)
E-mail: eja@email.unc.edu
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201905173
Angewandte Chemie International Edition
COMMUNICATION
PinB
yield
(%)[a]
es
(%)[b]
O
entry
variation from standard conditions above
O
1
2
none
20 mol % K[Co(CO)4] instead of Co2(CO)8
5 mol % instead of 10 mol % Co2(CO)8
Mn2(CO)10 instead of Co2(CO)8
4-(trimethylsilyl)morpholine instead of morpholine
TEA instead of TMP
85
70
68
<2
62
39
18
36
32
58
45
<2
97
98
96
N
O
O
3
8
71% yield[b]
93% es
4
5
96
87
99
95
95
93
94
6
7
Cs2CO3 instead of TMP
8
No TMP
9
THF instead of t-amyl-OH
10
11
12
20 atm CO instead of 40 atm CO
10 atm CO instead of 40 atm CO
no Co2(CO)8
O
N
O
Ph
N
Reactions were performed with [1]0 = 0.25 M. [a] Yields determined by 1H NMR
spectroscopy of crude reaction mixture using an internal standard. [b]
Enantiospecificity (es) = (eeproduct/eesubstrate) x 100%, determined by chiral HPLC
analysis.
O
O
Me
13
12
53% yield[b,c]
98% ee
43% yield[b]
97% es
We next applied the aminocarbonylation to a range of chiral,
non-racemic alkyl tosylates using morpholine as the nucleophile
(Table 2). Aliphatic substrate 2-octyl tosylate provided the desired
morpholine amide (4) in good yield and with near perfect
stereospecificity. Pendant alkenes and acetate functionality were
well tolerated, providing the respective aminocarbonylation
products 5 and 6 efficiently and with excellent stereospecificity.
The cobalt catalyst reacted with high chemoselectivity in the
presence of common electrophilic (7) and nucleophilic (8) aryl
cross-coupling partners. In addition, the reactions of heterocyclic
ester substrates proceeded with good yield and high stereocontrol
(9 and 10). A substrate with ketone functionality–which would be
problematic in typical sequences using organometallic reagents–
readily carbonylated to provide 11 in 62% yield and 95% es.
Importantly, the aminocarbonylation is not limited to methyl
branching, as an ethyl substituted alkyl tosylate provided amide
12 with excellent enantiospecificity (97%). Primary alkyl tosylates
also participate, even in the presence of α-substitution (13).
Finally, we found that the aminocarbonylation was not restricted
to acyclic substrates, as cycloalkyl amides 14 and 15 were
prepared in good yields.
[a] Isolated yields unless otherwise noted. Enantiospecificity (es)
=
(eeproduct/eesubstrate) x 100%, determined by chiral HPLC or SFC analysis. [b]
Reaction yield determined by 1H NMR spectroscopy of crude reaction mixtures
using an internal standard. [c] The reaction time was 72 h.
An exceptionally diverse array of amines participate in the
aminocarbonylation, highlighting the broad scope of the process
(Table 3). We found that a number of cyclic secondary amines
readily generated the desired amides in good yield and high
enantiospecificity, including piperidine, thiomorpholine, N-Boc
piperazine, 4-(N-Boc-amino)piperidine, pyrrolidine, and azepane
(16-21). Acyclic secondary amines are also useful nucleophiles,
as products 22 and 23 were isolated in good yield. Most
importantly, we found that a wealth of primary amines were viable
coupling partners. Cyclohexylamine and n-hexylamine gave high
yields of products 24 and 25, respectively, with good stereocontrol.
Pendant functionality on the primary amines was also tolerated,
including an alkene, heterocycles, and an unprotected indole (26-
28 and 31). Amino acid alkyl esters were also coupled in good
yield and stereospecificity (29-30). Furthermore, the
aminocarbonylation was amenable to primary amide synthesis,
using ammonium carbamate as an ammonia surrogate to
efficiently deliver amide 32 with excellent stereocontrol.
Table 2. Stereospecific, catalytic aminocarbonylation of alkyl tosylates with
morpholine.[a]
Table 3. Stereospecific, catalytic aminocarbonylation of (S)-1 with 1° and 2°
amines and ammonium carbamate.[a]
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10.1002/anie.201905173
Angewandte Chemie International Edition
COMMUNICATION
A
mechanistic
proposal
for
the
stereospecific
aminocarbonylation of alkyl tosylates is shown in Scheme 1.
Octacarbonyldicobalt first disproportionates to the cobaltate anion
by addition of the amine or TMP.[13] Following SN2 displacement
of the tosylate by the anionic cobaltate carbonyl, the alkylcobalt
intermediate undergoes CO migratory insertion with retention of
configuration.[8] Nucleophilic displacement of the acylcobalt
species with the amine nucleophile delivers the chiral, non-
racemic amide product and regenerates the catalyst.
Scheme 1. Plausible catalytic cycle for the catalytic stereospecific
aminocarbonylation.
O
Co2(CO)8
Ph
[a] Isolated yields. Enantiospecificity (es)
determined by chiral HPLC analysis.
= (eeproduct/eesubstrate) x 100%,
N
amine
O
3
X
[Co(CO)4]
Ph
OTs
The aminocarbonylation also facilitates access to carboxylic
acids or ketones in stereospecific fashion. For example, simple
1
HN
+ base + CO
O
substitution
of
the
amine
nucleophile
for
1-
2
(trimethylsilyl)imidazole
enables
direct
stereospecific
O
Ph
Co(CO)4
carboxylation following acylimidazole hydrolysis during the acidic
aqueous workup (eq 1). Furthermore, addition of MeMgCl to
morpholine amide 3 efficiently delivers chiral, non-racemic ketone
35 with excellent stereospecificity (eq 2).[11] The asymmetric
synthesis of such a non-symmetrical ketone containing an a-
chiral center remains a synthetic challenge, usually requiring
multistep sequences and the use of chiral auxiliaries.[12] These
transformations further highlight the value of the catalytic
aminocarbonylation in the asymmetric synthesis of important
carbonyl compounds from easily accessed chiral building blocks.
Ph
Co(CO)3
In conclusion, we have developed
a
stereospecific,
aminocarbonylation of alkyl tosylates with amines utilizing a
commercially available, first-row transition metal catalyst. This
transformation readily provides valuable chiral, non-racemic
amides–as well as carboxylic acids and ketones–from readily
available enantioenriched alcohols. The broad scope of the
reaction is highlighted by the use of a diverse range of nitrogen
nucleophiles, including the challenging use of primary amines.
Ongoing efforts continue to develop unique, stereospecific
transformations using first-row metal catalysis and to apply this
methodology in complex synthesis.
Acknowledgements
Financial support was provided by Award R01 GM107204 from
the National Institute of General Medical Sciences.
Considering the excellent chemoselectivity of the
transformation, applications involving more complex substrates
are easily envisioned. For example, the use of pharmaceutically
relevant amine amoxapine as a nucleophile provided concise
access to coupling product 37 (eq 3). It is worth noting that the
aminocarbonylation outcompetes undesired alkylation of the
amine. As shown in equation 4, in the absence of the cobalt
catalyst, facile direct alkylation of the amine is observed.
Keywords: alkyl tosylate • aminocarbonylation • cobalt •
stereospecific • synthetic methods
[1]
V. R. Pattabiraman, J.W. Bode, Nature 2011, 480, 471.
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COMMUNICATION
[2]
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[3]
[4]
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2344.
[5]
[6]
[7]
[8]
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879.
[10] Under lower pressures of CO, isomerization to the primary amide was
observed. See the Supporting Information for reaction details.
[11] R. Martín, P. Romea, C. Tey, F. Urpí, J. Vilarrasa, Synlett 1997, 12, 1414.
[12] a) M. C. Kohler, S. E. Wengryniuk, D. M. Coltart, In Stereoselective
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10.1002/anie.201905173
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Brendon T. Sargent, Erik J. Alexanian*
Page No. – Page No.
Cobalt-Catalyzed Aminocarbonylation
of Alkyl Tosylates: Stereospecific
Synthesis of Amides
Metal-catalyzed aminocarbonylation is a standard approach for installing amide
functionality in chemical synthesis. Despite broad application of this transformation
using aryl or vinyl electrophiles, few examples involve unactivated aliphatic
substrates. Furthermore, there are no stereocontrolled aminocarbonylations of alkyl
electrophiles known. Herein, we report a stereospecific aminocarbonylation of
unactivated alkyl tosylates for the synthesis of enantioenriched amides. This cobalt-
catalyzed transformation uses a remarkably broad range of amines in a convergent
manner, and proceeds with excellent stereospecificity and chemoselectivity.
This article is protected by copyright. All rights reserved.