Enantioselective Oxidative Coupling of Carboxylic Acids to α-Branched Aldehydes

Article abstract of DOI:10.1021/jacs.8b07394

A new reactivity in organocatalysis is proposed to account for the coupling of carboxylic acids to α-branched aldehydes by combining primary amine catalysis and an oxidant. The developed methodology is an enantioselective α-coupling of aromatic and aliphatic carboxylic acids to α-branched aldehydes and proceeds in high yields (up to 97%) and for most examples good enantioselectivities (up to 92% ee). On the basis of experimental and mechanistic observations, the role of the primary amine catalyst is discussed.

Full text of DOI:10.1021/jacs.8b07394

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Communication
Enantioselective Oxidative Coupling of
Carboxylic Acids to alpha-Branched Aldehydes
Lars A. Leth, Line Næsborg, Gabriel J. Reyes-Rodríguez,
Henriette N. Tobiesen, Marc V. Iversen, and Karl Anker Jørgensen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07394 • Publication Date (Web): 24 Sep 2018
Downloaded from http://pubs.acs.org on September 24, 2018
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Enantioselective Oxidative Coupling of Carboxylic Acids to -
Branched Aldehydes
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Lars A. Leth, Line Næsborg, Gabriel J. Reyes-Rodríguez, Henriette N. Tobiesen, Marc V. Iversen, and
Karl Anker Jørgensen*
Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
enamine that is subsequently oxidized.8 We propose that the oxi-
dized enamine upon deprotonation might undergo further oxidation
generating a cationic intermediate that reacts with the carboxylic
acid.
ABSTRACT: A new reactivity in organocatalysis is proposed to
account for the coupling of carboxylic acids to -branched alde-
hydes by combining primary amine catalysis and an oxidant. The
developed methodology is an enantioselective -coupling of aro-
matic and aliphatic carboxylic acids to -branched aldehydes and
proceeds in high yields (up to 97%) and for most examples good
enantioselectivities (up to 92% ee). Based on experimental and
mechanistic observations the role of the primary amine catalyst is
discussed.
The direct addition of carboxylic acids to the -position of an alde-
hyde is challenging as it involves nucleophilic addition of the car-
boxylate to the nucleophilic enolate. To achieve such a reaction de-
sign one has to overcome the challenge of coupling two nucleo-
philic centers.1
During the last decades, the use of chiral amine catalysts has
become an important tool for functionalizing carbonyl compounds.
Secondary amines have been applied in enamine catalysis for in-
corporation of electrophiles in the -position of aldehydes (Figure
1a).2 This HOMO-raising strategy allows for incorporation of com-
mon functionalities, but the concept is limited to coupling of elec-
trophiles. A further development in organocatalytic activation of
Figure 1. (a) Organocatalytic electrophilic -functionalization of
aldehydes was disclosed by MacMillan through oxidative -
aldehydes. (b) -Allylation of aldehydes by SOMO-activation. (c)
coupling of aldehydes to allylsilanes by SOMO-activation of the
Inversion of reactivity by enamine oxidation allowing for -
coupling of nucleophiles, such as carboxylic acids, to aldehydes.
enamine (Figure 1b).3 In the following, we present a novel concept
in organocatalysis demonstrating the enantioselective oxidative
coupling of carboxylic acids to -branched aldehydes. To account
We initiated the investigation of the oxidative coupling by
treating -branched aldehyde 1a and 4-nitrobenzoic acid 2a with
for the reaction pathway, we propose it might proceed via an inter-
mediate other than a radical cation (Figure 1c).
Ag2CO3 in the presence of pyrrolidine-based aminocatalyst 3a (Ta-
ble 1, entry 1). These conditions afforded complete conversion into
the homo-coupled product 5 (7:1 d.r.; 92% ee).9 Switching to a pri-
mary amine catalyst was key for achieving the acid-coupling and
product 4a was formed in 39% product-selectivity applying cin-
chona-alkaloid derived aminocatalyst 3b (entry 2). Further im-
provement in product selectivity was obtained when aminocatalyst
3c was applied and 4a was isolated in 67% yield and 86% ee (entry
3). Next, different silver salts were tested as oxidants. Applying
AgNO3 decreased the conversion to 4a (entry 4), while employing
AgOAc afforded 4a in 52% yield and 79% ee (entry 5). Using
Ag2O favored the acid-coupling, however, 4a was isolated in only
38% yield (entry 6). Ag2CO3 was found to be the best oxidant and
a screening of solvents was initiated. In CHCl3 similar results com-
pared to CH2Cl2 were obtained (entry 7), whereas toluene and
CH3CN gave a decrease in yield and enantioselectivity (entries
8,9).
Despite the apparent simplicity of an ester bond, the construc-
tion of complex ester functionalities is a challenge in synthesis.4
The Mitsunobu reaction is a fundamental reaction for constructing
carboxylate esters allowing primary and secondary alcohols to re-
act with carboxylic acids.5 Additionally, stereospecific versions
have been reported starting from chiral secondary alcohols.6 The
preparation of chiral tert-alkyl carboxylates is challenging as the
reaction does not proceed with tertiary alcohols. In this context, a
variant of the Mitsunobu reaction was developed where chiral ter-
tiary alcohols react with alkoxydiphenylphosphines.7
Herein we disclose the organocatalytic enantioselective cou-
pling of carboxylic acids to the -position of -branched alde-
hydes, thereby inverting the reactivity compared to classic enamine
catalysis (Figure 1c). This strategy provides direct access to chiral
tert-alkyl carboxylates. The concept relies on condensation of a
chiral primary amine with an -branched aldehyde forming an
Table 1. Optimization of Reaction Conditions.
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ee (4a)
[%][d]
4a
[%][b,c]
5
entry[a]
oxidant
3
[%][b]
1
2
Ag2CO3
Ag2CO3
Ag2CO3
AgNO3
AgOAc
Ag2O
0
100
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2
-
3a
3b
3c
3c
3c
3c
3c
3c
3c
3c
3d
3e
-
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-
a Performed on 0.1 mmol scale. Product ratios measured by 1H NMR on the
crude reaction mixture. b For calculation of IPs see SI.
3
96 (67)
20
86
-
4[e]
5[e]
6
20
0
The calculated IP of enamine I derived from 1a and primary
amine catalyst 3f is 4.4 eV. The resulting radical cation II can be
deprotonated forming radical III leading to the cationic species IV
with a similar IP of 4.7 eV. Applying secondary amine catalyst 3g,
the enamine V has an IP of 4.4 eV, however in this case the radical
cation VI cannot be deprotonated and further oxidation affording
the double cationic species has an IP of 5.5 eV. For the primary-
amine catalyst, the two oxidations have similar IP, whereas for the
secondary amine catalyst, a second oxidation step leading to dica-
tionic species VII has a higher IP. In related studies on oxidative
cyclization of carboxylic acids via benzylic oxidation, formation of
a benzylic carbocation is supported by Hammett analysis.10 This
example might indicate the preference for carboxylates to react
with the carbocation rather than the transient radical intermediate.
We performed competition experiments and the results show that
aromatic aldehydes having electron-donating substituents react
faster than their more electron-poor counterparts (see SI). Further-
more, the product selectivity decreases, by favoring homo-cou-
pling, for electron-poor aldehydes, indicating two different reaction
pathways. Based on these results, it is not unlikely that the reactive
intermediate could be cationic species IV. However, coupling of
radical II or III11 with the carboxylic acid cannot be excluded.
Next, we turned attention towards exploring the substrate
scope. The reaction with 4-nitrobenzoic acid 2a on a 0.2 mmol
scale improved the yield of 4a to 97%, maintaining enantioselec-
tivity (Scheme 2). Nitro substituents in the 2- and 3-position of the
benzoic acid were tolerated providing the respective products in
91% yield, 86% ee (4b) and 68% yield, 72% ee (4c). Benzoic acid
derivatives bearing electron-withdrawing groups in the 4-position
reacted smoothly, providing the acid-coupled adducts 4d-f in good
yields and enantioselectivities. Despite the moderate yields, we
were satisfied that benzoic acid, as well as, the derivative bearing a
4-methyl substituent could be applied forming 4g and 4h, in 77%
and 74% ee, respectively. For more electron-rich benzoic acids, the
homo-coupling becomes a competing pathway. Halogen substitu-
ents were tolerated as 3-fluoro-, 3-bromo- and 3-chlorobenzoic ac-
ids provided 4i (87% yield, 90% ee), 4j (95% yield, 91% ee) and
4k (85% yield and 88% ee). The absolute configuration of 4k was
determined by X-ray crystallography (Figure 2).
68 (52)
100 (38)
82(70)
87 (47)
91 (50)
91 (59)
70 (53)
100 (78)
0
79
85
84
77
72
89
88
87
-
0
7[f]
8[g]
9[h]
10[i]
11
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
-
0
0
5
5
13
0
12
13[j]
14[j]
0
0
0
-
3e
a Performed on 0.1 mmol scale with 1.0 equiv. of 1a and 1.5 equiv. of 2a in
0.6 mL solvent. b Conversion measured by H NMR of the crude reaction
1
mixture by integration of all aldehyde peaks at full consumption of 3. c Iso-
lated yield in parenthesis. d ee determined by chiral stationary phase UPC2.
e 3 equiv. of oxidant. f CHCl3 as solvent. g Toluene as solvent. h CH3CN as
solvent. i Performed at 5 °C for 30 h. j No conversion observed after 7 h.
To increase enantioselectivity, the reaction was carried out at 5
°C. Although the enantioselectivity was improved to 89% ee, the
reaction time was prolonged leading to increased decomposition of
4a (entries 3,10). Finally, we examined the effect of the tertiary
amine moiety in the aminocatalyst. Moving from pyrrolidine to pi-
peridine resulted in more homo-coupling (entry 11). Interestingly,
the morpholino-based catalyst 3e provided selectively 4a in 78%
yield and 87% ee (entry 12). Finally, control experiments demon-
strated both aminocatalyst and Ag2CO3 to be essential for the reac-
tivity (entries 13,14).
To gain mechanistic insight and explore the influence of a pri-
mary vs. a secondary amine catalyst, we performed experimental
investigations and calculated ionization potentials (IPs) for relevant
intermediates (Scheme 1). For this purpose, 2-morpholinoethan-1-
amine 3f was tested in the reaction of 1a and 2a providing 4a in
74% selectivity. In contrast, applying the methylated version of the
catalyst (3g) under identical conditions, the homo-coupled product
5 was formed in 93% selectivity (Scheme 1a). This highlights the
importance of the aminocatalyst to be primary compared to second-
ary. Therefore, we decided to investigate the IPs for enamines de-
rived from primary and secondary amine catalysts (Scheme 1b).
Scheme 2. Enantioselective oxidative coupling of benzoic acid de-
rivatives to 1a.[a]
Scheme 1. Investigating the role of a primary vs. secondary amine
catalyst.
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AgOAc and CD3CO2D, this indicates that CD3CO2D is preferen-
tially incorporated compared to the acetate bound in AgOAc.
Scheme 4 shows the reaction of different -branched aldehydes
with 3-bromobenzoic acid 2j. Aldehydes having a methoxy-substi-
tuted phenyl provided 4q (96% yield, 87% ee) and 4r (93% yield,
83% ee). Similar results were obtained for a 3-chloro-substituted
aldehyde 4s (81% yield, 88% ee). A thioether functionality showed
compatibility to the oxidative reaction conditions as 4t was ob-
tained in 91% yield and 87% ee. Aldehydes bearing electro-neutral
aromatic substituents, such as 4-methyl and naphthyl, also afforded
the products 4u and 4v in high enantioselectivities (both 92% ee),
however in lower yields (38% and 40%, respectively). Subse-
quently, aldehydes with different aliphatic moieties in the -
position were tested. Aldehydes with -ethyl and -n-propyl pro-
vided 4w (87% yield, 80% ee) and 4x (95% yield, 76% ee), while
an -cyclopropyl aldehyde gave 4y in 86% yield and low enanti-
oselectivity. Perhaps, the decrease in enantioselectivity for alde-
hydes having bulky -substituents may be explained by the E/Z-
configuration of the enamine. Finally, a cyclic aldehyde was ap-
plied in the reaction and afforded 4z in 61% yield and 46% ee.
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Scheme 4. Enantioselective oxidative coupling of -branched al-
dehydes 1 with 3-bromobenzoic acid 2j.[a]
a Performed on 0.2 mmol scale with 1.0 equiv. of 1a and 1.5 equiv. of 2. ee
determined by chiral stationary phase UPC2. Absolute stereochemistry de-
termined by analogy to X-ray structure of 4k. b Reaction time 8 h. c 3 equiv.
of carboxylic acid and 0.5 equiv. of 4-hydroxybenzonitrile were added.
Next, the applicability of aliphatic carboxylic acids was ex-
plored. Beside the synthetic value, implementation of aliphatic car-
boxylic acids indicate that no oxidation of the acid occurs as these
can be prone to decarboxylation upon oxidation.12 Scheme 3 shows
that different carboxylic acids are converted smoothly into the cor-
responding chiral esters.
Scheme 3. Enantioselective oxidative coupling of aliphatic carbox-
ylic acids to 1a.[a]
a Performed on 0.2 mmol scale with 1.0 equiv. of 1 and 1.5 equiv. of 2j. ee
determined by chiral stationary phase UPC2. Absolute stereochemistry de-
termined by analogy to 4k. b 5 equiv. of 2j. c 3 equiv. of 2j. d Reaction time
was 6 h.
The absolute configuration of the acid-coupled adduct 4k was
determined to be R by X-ray analysis (Figure 2). Based on this, and
computed intermediate structures (see SI), we propose that the ter-
tiary amine may direct the oxidative coupling of enamine and car-
boxylic acid via N–H–O hydrogen bonding, which facilitates the
Re-face attack providing the observed adduct.
a Performed on 0.2 mmol scale with 1.0 equiv. of 1a and 3.0 equiv. of 2. ee
determined by chiral stationary phase UPC2. Absolute stereochemistry de-
termined by analogy to 4k. b5.0 equiv. of acetic acid and 3c as catalyst.
Chloroacetic acid and trifluoropropanoic acid afforded 4l (64%
yield, 87% ee) and 4m (83% yield, 90% ee). Ethoxyacetic acid pro-
vided 4n in moderate yield and enantioselectivity. Unactivated sub-
strates, such as hydrocinnamic acid and acetic acid, gave 4o and 4p
in moderate yields and 80% and 66% ee, respectively. In the cou-
pling of acetic acid, AgOAc was used as oxidant. To further inves-
tigate the origin of the incorporated acetic acid, we performed an
experiment with CD3CO2D (1.5 equiv.) in combination with non-
deuterated AgOAc (3.0 equiv.). The isolated product revealed a
69% integration of CD3CO2D and considering the 2:1 ratio between
Figure 2. Left: X-Ray crystal structure of 4k. Right: Proposed tran-
sition-state structure.
Encouraged by the results for coupling of carboxylic acids to
-branched aldehydes using a primary amine catalyst, we set out to
explore the possible extension of the reactivity to a more remote
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Lee, J.-F.; Lan, Y.; Lei, A. Sci. Adv. 2015, 1, e1500656. (d) Arceo,
E.; Jurberg, I. D.; Álvarez-Fernández, A.; Melchiorre, P. Nat. Chem
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position of an ,-unsaturated aldehyde. To our delight, subjecting
,-unsaturated aldehydes and carboxylic acid 2j to the standard
reaction conditions yielded the -acid-coupling products in moder-
ate yields and low enantioselectivities (see SI, page S14). It should
be noticed that similar conditions, but with a secondary amine cat-
alyst afforded the -homo-coupling.13 This result further highlights
the importance of the primary amine catalyst and supports the hy-
pothesis that homo-coupling and acid-coupling proceeds via differ-
ent reactive intermediates.
In summary, we have demonstrated that a chiral primary amine
catalyst in combination with -branched aldehydes and an oxidant
generates an intermediate that reacts with carboxylic acids afford-
ing a nucleophilic -coupling to the aldehydes. The methodology
proceeds for aromatic and aliphatic carboxylic acids giving access
to chiral tert-alkyl carboxylates in high yields and for most exam-
ples high enantioselectivities.
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(9) Næsborg, L; Leth, L. A.; Reyes-Rodríguez, G. J.; Palazzo, T.; Corti,
V.; Jørgensen, K. A. Chem. Eur. J., 10.1002/chem.201803506.
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Sci., 2017, 8, 7003. (b) Sathyamoorthi, S.; Bois, J. D. Org. Lett. 2016,
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(12) Griffin, J. D.; Zeller, M. A.; Nicewicz, D. A. J. Am. Chem. Soc. 2015,
137, 11340.
(13) Næsborg, L.; Corti, V.; Leth, L. A.; Poulsen, P. H.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2018, 57, 1606.
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Supporting Information
Experimental and computational details (PDF), and crystallo-
graphic data (CIF).
Corresponding Author
*kaj@chem.au.dk
ACKNOWLEDGMENT
This work was made possible by grants from Carlsberg Founda-
tion’s ‘Semper Ardens’ programme, FNU, Aarhus University and
DNRF. HNT thanks Novo Nordisk for a PhD grant.
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