Decarboxylative Elimination of N-Acyl Amino Acids via Photoredox/Cobalt Dual Catalysis

Article abstract of DOI:10.1021/acscatal.8b03282

A dual-catalytic strategy for the synthesis of enamides and enecarbamates directly from easily accessible and inexpensive amino acids has been realized. This mild and efficient protocol makes use of an organic photoredox catalyst and a cobaloxime catalyst to achieve decarboxylative elimination using hydrogen evolution to drive the oxidation. Thus, the reaction occurs without a stoichiometric oxidant or the forcing conditions previously employed in attempts to achieve similar eliminations.

Full text of DOI:10.1021/acscatal.8b03282

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Article
Decarboxylative Elimination of N-Acyl Amino
Acids via Photoredox/Cobalt Dual Catalysis
Kaitie C. Cartwright, and Jon A Tunge
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03282 • Publication Date (Web): 09 Nov 2018
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ACS Catalysis
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Decarboxylative Elimination of N-Acyl Amino Acids via
Photoredox/Cobalt Dual Catalysis
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Kaitie C. Cartwright, Jon A. Tunge*
Department of Chemistry, The University of Kansas, 2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045,
United States.
Supporting Information Placeholder
reaction scope because it is highly dependent on C–H bond strength
and thus, not very selective when many similar C–H bonds are
present. Sorensen recognized this limitation and has utilized
aldehydes as initiating groups that can be selectively activated due
to their low C–H bond strength.10 We envisioned that olefin
formation could be achieved using oxidative decarboxylation to
generate a radical intermediate followed by a HAT reaction. Such
use of photocatalytic decarboxylation would allow us to site-
specifically engage widely-available carboxylic acids in
elimination reactions without the need to rely on differential bond
strengths. Furthermore, crafting a cooperative catalytic system
utilizing a photoredox catalyst and cobaloxime catalyst would
allow for enamides and enecarbamates to be directly accessed from
N-acyl amino acids under mild conditions without stoichiometric
oxidants (Scheme 1C).
ABSTRACT: A dual catalytic strategy for the synthesis of
enamides and enecarbamates directly from easily accessible and
inexpensive amino acids has been realized. This mild and efficient
protocol makes use of an organic photoredox catalyst and a
cobaloxime catalyst to achieve decarboxylative elimination using
hydrogen evolution to drive the oxidation. Thus, the reaction occurs
without a stoichiometric oxidant or the forcing conditions
previously employed in attempts to achieve similar eliminations.
Enamides and enecarbamates possess synthetic utility as stable
nucleophilic building blocks in addition to the motif itself being
present in biologically active compounds.1 Methods toward their
synthesis include classical protocols such as the acylation of
imines, condensation of amines with aldehydes, and through the
Curtius rearrangement of acyl azides as well as more modern
transition metal catalyzed cross-coupling reactions with amides and
activated/stereo-defined olefins.2 Another appealing route is the
direct synthesis of functionally diverse enamides from readily
available and inexpensive amino acids.3 Herein, we describe a
noble metal-free procedure that accomplishes the direct conversion
of N-acyl amino acids to enamides via a sequential radical
decarboxylation and hydrogen evolution process facilitated by the
cooperation of an organophotoredox catalyst and cobaloxime
catalyst. This decarboxylative elimination strategy operates under
neutral conditions and bypasses the need for a stoichiometric
terminal oxidant and the pre-activation of the carboxylic acid
moiety.4 The marriage of the decarboxylation and hydrogen
evolution chemistry has allowed for a mild, operationally simple,
and economical route for enamide synthesis.5
Scheme 1:
A. Kochi’s Decarboxylative Elimination
Pb(OAc)4/
Cu(OAc)2
- produces a mix of products
- stoichiometric lead oxidant
- doesn't opperate with
amino acids
COOH
Benzene, HOAc
MeO
OMe
B. Sorensen’s Dehydrogenation of Alkanes
TBADT
COPC
- not site-selective
- dependent on bond strength
- deuterated solvents
- low yielding
hv, CD3CN
COPC = cobaloxime pyridine chloride
TBADT = tetra-n-butylammonium decatungstate
C. Decarboxylative Elimination via Dual Catalysis (This Work)
R2
R1
COOH
R2
R1
photoredox catalyst/
cobaloxime
MeOH, Blue LED, 38 o
Kochi pioneered the direct conversion of carboxylic acids into
olefins via decarboxylative elimination (Scheme 1A).6 However,
the utility of Kochi’s elimination is limited by the requirement of a
stoichiometric toxic lead oxidant, often forcing conditions, and
significant limitations in scope. Additionally, these reactions tend
to produce complex product mixtures.6,7 Most notably, this
elimination was not successful when applied to the α-amino acid
substrates of interest to us.8
NH
R3
NH
R3
C
- CO2 and H2 only byproducts
- mild conditions
- site-specific
- readily available reactants
- no stoiciometric oxidant
- no pre-activation of acid
The decarboxylative elimination was envisaged to be initiated
via protonation of a Co(I) species by an -amino acid (pKa ~ 2,
Scheme 2). It is well-documented that the basicity of Co(I) can be
exploited to generate a Co(III)-hydride species (pKa = 7.7) via
deprotonation of common acids.11 Thus, protonation of Co(I) will
provide an -amino carboxylate. Photo-oxidation of the
carboxylate, facilitated by a photoredox catalyst, followed by
decarboxylation will furnish an α-amino radical.12 The reduced
photoredox catalyst can in turn reduce Co(III) to Co(II), which is
In approaching the decarboxylative elimination of -amino
acids, we were inspired by Sorensen’s dehydrogenation of alkanes
(Scheme 1B).9 The dehydrogenation involves hydrogen atom
transfer (HAT) to generate an alkyl radical followed by a second
HAT reaction to generate the alkene. The need to initiate olefin
formation via a hydrogen atom transfer (HAT) reaction limits the
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an excellent HAT acceptor that targets the weak C–H bonds
Preliminary reactions suggested that the highest conversion
towards the desired olefin product was achieved with the
acridinium photocatalysts screened (>75% conversion), while poor
conversion was observed with 4CzIPN (32% conversion).19 Of the
acridinium catalysts that were investigated, Mes-2,7-Me2-Acr-Ph+
was found to perform the best (95% conversion) and thus was used
in further screenings.20
1
2
3
4
adjacent to the radical center (Scheme 2).13,14 This HAT would
provide the desired olefin and subsequent hydrogen evolution
(HER) would complete the cycle. Ultimately the transformation
would produce CO2 and H2 as the only stoichiometric byproducts
and would utilize visible light as an economical and
environmentally friendly energy input.15
5
6
7
Scheme 2: Hypothetical Mechanism
Next, the effect of catalyst loading on the decarboxylative
elimination was studied. Upon doing so, it became immediately
apparent that a slight excess of photocatalyst compared to
cobaloxime is vital to the reaction’s success (Table 1, entries 1-3).
Ultimately, a 3:5 ratio of cobalt to photocatalyst was determined to
be optimal. Isolated yields were further increased through a solvent
change from acetonitrile to methanol (Table 1, entry 7).
8
9
Co(III)
R
O
R
Co = cobaloxime
PC = photocatalyst
OH
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H2
HN
Co(I)
PC*
HER
Co(III)H2
R
R
O
R
R
N
Table 1: Optimization of Catalyst Loadings
SET
hv
H
O
HN
PC
HAT
Co(III)-H
Mes-2,7-Me2-Acr-Ph+BF4
H
-
COOH
N
PC
Co(dmgH)2ClPy
Boc
R
R
HN
N
Co(II)-H
32 W Blue LED
38 oC, 16 h, Ar
Boc
H
2a
H
1a
Co(III)-H
O
-
Entry Co(I)a Mes-2,7-Me2-Acr-Ph+BF4 Solvent
Yieldc
R
O
CO2
HN
(mol %)
(mol %)
R
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
Et2O
29%
57%d
28%
54%
30%
15%
68%
16%
0%
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9
3
3
5
6
1.5
0.75
3
3
3
3
5
3
10
3
1.5
5
5
To initiate studies, the elimination of N-Boc-phenylalanine (1a)
was investigated using several organic photoredox catalysts
combined
with
commercially
available
cobaloxime,
Co(dmgH)2ClPy (Figure 1). To generate the Co(I) nucleophile, the
starting Co(III) was reduced with one equivalent of zinc before
being subjected to the reaction mixture. The choice in photoredox
catalyst was narrowed down to the Fukuzumi family of
acridiniums16 and the fluorophore, 4CzIPN17 (Figure 1). These
photocatalysts appeared as the logical choices as a result of their
favorable oxidation potentials (E1/2 = > +2.0 V vs. SCE for
acridiniums and +1.35 V vs. SCE for 4CzIPN)18a,17 for the
oxidation of amino carboxylates (E1/2 = +0.95 V vs. SCE)12e and
their lower expense compared to commonly employed iridium
photocatalysts. Additionally, a favorable reduction potential for the
reduction of Co(III) to Co(II) (E1/2 = -0.68 V vs. SCE)18b must be
considered. In this regard, 4CzIPN has a much more negative
reduction potential (E1/2 = -1.21 V vs. SCE)15b while the common
acridinium catalyst (Mes-Acr-Me+) has a more closely matched
reduction potential (E1/2 = -0.57 V vs. SCE).18c
5
DMF
aCo(dmgH)2ClPy reduced with Zn (1 equiv.) and NaCl (3.3
equiv.) in 0.5 mL MeCN. b 0.2 mmol scale in MeCN (2 mL) under
argon. c Isolated yields; products isolated as a mix of E/Z-isomers.
dIsomer ratio (39:61 E:Z).
Having established the optimal catalyst loadings and solvent
choice, the initial reduction of Co(III) to Co(I) was explored.
Classically, this reduction had been performed with an excess of
sodium borohydride (NaBH4).11a,21 However, it was hypothesized
that any active reductant in the final reaction mixture would
interrupt the catalysts’ performance.
Table 2: Cobalt Catalyst Optimization
5 mol % photocatalyst
Co(dmgH)2ClPy/Zn
H
COOH
Boc
N
Boc
HN
32 W Blue LED
38 oC, 16 h, Ar
reductant
additive 1
2a
1a
Co(dmgH)2ClPy
Co(I)
reflux 50 min.
MeOH, Ar
Co(I) (3 mol%)
Mes-2,7-Me2-Acr-Ph+BF4- (5 mol%)
H
COOH
Boc
N
N
N
N
additive 2 (7.5 mol%)
Boc
BF4
ClO4
BF4
Ph
Ph
Me
HN
32 W Blue LED, 16 h
MeOH, Ar
Mes-2,7-Me2-Acr-Ph+
E1/2(P*/P-) = +2.09 V
Mes-Acr-Me+
E1/2(P*/P-) = +2.06 V
E1/2(P-/P) = -0.57 V
2a
Mes-Acr-Ph+
1a
E1/2(P*/P-) = +2.17 V
Entry Reductant
(amt.)
Additive 1
(amt.)
Additive 2 Yieldb
(7.5 mol%)
Cl
Cz
H
O
N
NC
Cz
CN
Cz
O
N
CoIII
Zn (3 mol%)
-
-
-
-
1
2c
3
4
5
6
7
NaCl (10 mol%)
68%
20%
38%
52%
70%
66%
82%
N
O
N
O
NaBH4 (2 mol%)
NaCNBH3 (7.5 mol%)
STAB (7.5 mol%)
STAB (7.5 mol%)
STAB (7.5 mol%)
STAB (7.5 mol%)
-
Cz
H
Co(dmgH)2ClPy
dmgH = dimethylglyoxime
Cz = carbazole
-
N
4CzIPN
E1/2 (Co(III)/Co(II)) = -0.68 V
-
E1/2(P*/P-) = +1.35 V
E1/2(P-/P) = -1.21 V
H2O
-
H2O
Na2CO3 (1 mol%)
Na2CO3 (1 mol%)
Figure 1: Potential Cooperative Catalysts Screened
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aGeneral conditions: Co(dmgH)2ClPy (3 mol%) and reductant
yields. dIsomer ratios were determined by 1H NMR. eMajor
isomer determined by NOESY.
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refluxed in methanol (0.5 mL) for 50 min. The reduced cobalt
catalyst solution was added to N-Boc-phenylalanine (0.2 mmol)
and Mes-2,7-Me2-Acr-Ph+ (5 mol%) then irradiated with blue
b
butyloxycarbonyl (Boc) and acetyl protecting groups provided
similar yields and E:Z selectivity (2a, 2b). This allows a simple
dipeptide to be utilized in the elimination chemistry (2c).
Additional functionalities on the aryl substituent in the para and
ortho positions were also tolerated and having an electron-
withdrawing substituent in the para-position provided a slight
increase in yield and E-selectivity. Conversely, an electron-
donating para substituent lead to a decrease in yield (2d-2g).
Amino acids other than phenylalanine derivatives provided
considerably higher yields when the nitrogen was acylated rather
than substituted with a carbamate protecting group (2i-2n), and
unprotected amino acids failed to undergo the reaction. Aside from
the protecting group influences, various aliphatic side chains,
including those with ester and amine functionalities, led to good to
excellent yields of enamides. Additionally, trisubstituted alkenes
(2o-2q) could also accessed through decarboxylative elimination.
LEDs for 16 h under argon. Isolated yields; isolated as a mix of
E/Z-isomers. cReduction performed in acetonitrile.
Thus, the choice in reductant and the amount used in the initial
catalyst reduction could impact the success of the elimination
reaction. In addition to zinc, NaBH4, sodium cyanoborohydride
(NaCNBH3), and sodium triacetoxyborohydride (STAB) were
screened (Table 2, entries 1-4). Apart from zinc, STAB provided
the highest isolated yield. The use of a catalytic amount of sodium
carbonate in the cobaloxime reduction with STAB as well as the
addition of water to the reaction solvent further increased the yield
(Table 2, entries 5-6). Upon utilizing these additives in conjunction,
an 82% isolated yield was achieved (Table 2, entry 7).
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In addition to optimization studies, control experiments were
also conducted. Only a trace amount of alkene was observed in the
absence of photocatalyst and no product was observed in the
absence of the cobalt catalyst. While the reaction could be carried
out under air, a decrease in yield to 60% was observed under
aerobic conditions. Finally, the reaction was found to reach
completion in 16 hours with no change in yield upon increasing the
irradiation time to 24 hours.
In addition to the success this protocol had with a variety of
amino acids, the decarboxylative elimination also proved to be
scalable. The scalability of this protocol is demonstrated by the 1
mmol reaction with amino acid (1a) (Scheme 3).22
Scheme 3: Scale-up Decarboxylative Elimination
With optimal conditions in hand, a variety of N-protected amino
acids were investigated for the direct synthesis of enamides and
enecarbamates (Table 3). Derivatives of phenylalanine were found
to be useful substrates for the elimination (2a-2i). Interchanging
tert-
Co(I) (3 mol%)
H
Mes-2,7-Me2-
N
COOH
Boc
Boc
Acr-Me+ ClO4- (5 mol%)
HN
(1a)
1 mmol
(2a)
83% yield, 54:46 E:Z
MeOH (10 mL), H2O (7.5 mol%)
32 W Blue LED, 16 h, Ar
Table 3: Scope of N-Acyl Amino Acids
To better understand the nature of the observed geometric ratios
of products, several additional experiments were conducted. It was
speculated that photo-isomerization of the alkenes could be a
factor, either through an electron transfer or energy transfer from
the photocatalyst to the alkene. Photoisomerizations of this nature
have been described by Weaver23 using iridium photoredox
catalysts but have not been previously reported with the
acridiniums. To explore this, the E- and Z- isomers of aspartic acid
derivative (2n) were independently subjected to the photocatalyst
and irradiated in acetonitrile. Indeed, isomerization was observed
in each case, producing a steady-state mixture of ca. 45:55 E:Z
(Scheme 4A).24,25 The same isomerization does not occur upon
irradiation in the absence of a photocatalyst or at elevated
temperature (50 oC). Taken together, these observations support a
hypothesis that the product E:Z ratios represent the photostationary
state of each product under the reaction conditions.
Mes-2,7-Me2-Acr-Ph+BF4- (5 mol%)
R3
R2
R2
R3
Co(dmgH)2ClPy (3 mol%)
MeOH, H2O (7.5 mol%), Ar
32 W Blue LED, 16 h
COOH
R1 HN R4
R1 HN R4
1a-x
2a-x
H
N
N
H
H
N
N
R
Boc
O
Boc
X
2a R = Boc; 82%, (65:35)
2b R = Ac; 85%, (65:35)
2c 77%, (66:34)
2d X = CN; 85%, (81:19)
2e X = F; 70%, (69:31)
2f X = Cl; 75%, (71:29)
2g X = OMe; 58%, (67:33)
Cl
H
H
N
N
Ac
Boc
2h 71%, (67:33)
2i 71%, (90:10)
H
Ac
N
H
N
R
N
R
H
2j R = Ac; 72%, (82:18)
2k R = Boc; 41%, (71:29)
2l R = Cbz; 52%, (71:29)
2m R = Ac; 90%, (85:15)
2n R = Boc; 34%, (80:20)
2o 90%
Further mechanistic information was provided by the reaction
of N-Boc phenylalanine in CD3OD in a sealed NMR tube (Scheme
4B). Analysis of the crude reaction mixture revealed the formation
of H-D and H2 in a 6:1 ratio. The H-D presumably results from
coupling of the exchangeable acid proton (Boc-NHCHBnCO2D)
with the H-atom abstracted in the HAT reaction. Since the
exchange of the N-H proton with deuterated solvent is slow under
the reaction conditions, the H-D hydrogen could originate from
either the N-H or C-H positions -to the radical. We favor the
pathway involving HAT from the C-H bond because we see no
evidence for imine formation. Moreover, subjecting a tertiary
amino acid, which lacks an N-H bond, to the standard reaction
conditions results in product formation (Scheme 4C). Interestingly,
the N-Me reactant exhibits a high selectivity for the E-olefin.
H
O
O
O
N
Boc
O
O
N
N
H
O
H
2p 66%
2q 73%, 64:36e
2r 45%, 67:33
O
R
H
N
H
N
N
H
Cbz
Ac
O
Ac
N
2s R = Ac; 80%, 75:25
2t R = Boc; 24%, >99:1
2u 77%, (76:24)
H
2v 51%, (10:90)e
aReactions were run on 0.2 mmol scale under argon. bCobalt
catalyst was reduced with STAB (7.5 mol%) and Na2CO3 (1
mol%) in MeOH (0.5 mL) at reflux for 50 min and added via
syringe to the reaction mixture. cAll yields reported are isolated
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conditions, all of which are seen in related attempts to achieve this
1
2
3
transformation. Further explorations into the reaction mechanism
and controlling the E/Z selectivity are currently under investigation
in our lab.
Scheme 4: Mechanistic Investigations
A. Photo-isomerization
4
5
6
7
8
9
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, 1H, 13C NMR spectra, and
characterization data for all new compounds. The Supporting
Information is available free of charge on the ACS Publications
website.
N
(5 mol%)
Ph
BF4
HN
HN
Boc
Boc
32 W Blue LED, 16 h
MeCN, Ar
2a (Z)
45:55 E:Z
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N
H
(5 mol%)
Ph
N
BF4
Boc
HN
32 W Blue LED, 16 h
MeCN, Ar
Boc
AUTHOR INFORMATION
2a (E)
43:57 E:Z
Corresponding Author
B. Reaction Monitored by 1H NMR Spectroscopy
tunge@ku.edu
H
Co(I)/Acr+
COOD
N
Boc
Notes
HN
CD3OD
Boc
2a
65% conversion
The authors declare no competing financial interests.
Blue LED
1a
ACKNOWLEDGMENT
C. Reaction with Tertiary Amino Acid
Me
N
We thank the National Science Foundation (CHE-1800147) and the
Kansas Bioscience Authority Rising Star program for financial
support. Support for the NMR instrumentation was provided by
NSF Academic Research Infrastructure Grant No. 9512331, NIH
Shared Instrumentation Grant No. S10RR024664, and NSF Major
Research Instrumentation Grant No. 0320648. X-ray analysis was
made possible through an NSF-MRI grant CHE-0923449.
Co(I)/Acr+
COOH
Boc
N
CH3OH
Blue LED
2w
52% E/Z > 95:5
Boc
Me
1w
The utility of enecarbamate scaffolds was also demonstrated
(Scheme 5). These scaffold are known to serve as nucleophiles
leading to additions β to the amine.1 This mode of nucleophilic
attack or in situ tautomerization results in imine formation which
allows (2a) to react as an electrophile thus providing the
opportunity for diversification α to the amine. Both nucleophilic
and electrophilic reactivities of (2a) are exemplified by the set of
reactions performed. As with many reactions with enamide and
enecarbamate substrates, these reactions are able to proceed with
both the E- and Z- isomers to provide one product derived from a
common intermediate. In cases where a single geometric isomer is
desired, the photo-isomerization reported by Weaver23a can be
exploited to enrich one geometric isomer. As such, the isomers of
2a were separated and the E- isomer was subjected to the
isomerization conditions to provide an the Z- olefin in good yield
with high selectivity (4:96 E:Z).
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H.; Nagai, K.; Setiawan, B.; Rantioamodjo, R.; Suzuki, K.; Nagano, N.
Structural Elucidation of YM-75518, A Novel Antifungal Antibiotic
Isolated from Pseudomonas sp. Q38009. Tetrahedron Lett. 1997, 38, 7573-
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35, 5934-5949.
Scheme 5: Reactions with Enecarbamate (2a)
H
(3a) 62% yield
(over 2 steps)
N
Boc
O
(3b) 81% yield
(over 2 steps)
26
h
1M HCl aq.
57 oC, ~16 h
,
4
4
Hydrolysis
Reduction
NaBH
2H,
iPrOH,
H
N
Pd/C,
CH3
CO
Boc
H
N
COOH
Boc
2. (a) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Late
Transition Metal-Catalyzed Hydroamination and Hydroamidation. Chem.
Rev. 2015, 115, 2596-2697. (b) Matsubara, R.; Kobayashi, S. Enamides and
Enecarbamates as Nucleophiles in Stereoselective C-C and C-N Bond-
Forming Reactions. Acct. Chem. Res. 2008, 41, 292-301.
Co(I)/Acr+
Friedel-Crafts1b
1-H-indo
Boc
2a
le,
horic
~16
Blue LED
HN
82% yield
(65:35 E:Z)
HN
phosp
50 oC,
acid
h
cat.
(3c) 69% yield
(over 2 steps)
Bromination
E-isomer,
NBS,
Isomerization23a
Ir(ppy)3
Blue LED, 30 o
1h
Br
H
NEt
30
o
C,
3
C
~16
N
3. Decarbonylative strategies towards enamide synthesis from amino acids:
(a) Garcίa-Reynaga, P.; Carrillo, A. K.; VanNieuwenhze, M. S.
Decarbonylative Approach to the Synthesis of Enamides from Amino
Acids: Stereoselective Synthesis of the (Z)-Aminovinyl-D-Cysteine Unit of
Mersacidin. Org. Lett. 2012, 14, 1030-1033. (b) Min, G. K.; Hernández, D.;
Lindhardt, A. T.; Skrydstruo, T. Enamides Accessed from Aminothioesters
via a Pd(0)-Catalyzed Decarbonylative/β-Hydride Elimination Sequence.
Org. Lett. 2010, 12, 4716-4719.
h
36 h
Boc
(3d) 29% yield
(over 2 steps)
82% yield (4:96 E:Z)
(over 2 steps)
HN
Boc
In conclusion, a mild and direct decarboxylative elimination of
readily available amino acids for the production of enamides and
enecarbamates has been realized. This protocol bypasses the use of
stoichiometric oxidants, toxic and expensive reagents, and harsh
4. Activation of acids for decarboxylation with redox-active groups: (a)
Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.; Wang, J.; Pan, C-M.;
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Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran, P. S. Practical Ni-
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