Decarboxylative Alkynylation

Article abstract of DOI:10.1002/anie.201705107

The development of a new decarboxylative cross-coupling method that affords terminal and substituted alkynes from various carboxylic acids is described using both nickel- and iron-based catalysts. The use of N-hydroxytetrachlorophthalimide (TCNHPI) esters is crucial to the success of the transformation, and the reaction is amenable to in situ carboxylic acid activation. Additionally, an inexpensive, commercially available alkyne source is employed in this formal homologation process that serves as a surrogate for other well-established alkyne syntheses. The reaction is operationally simple and broad in scope while providing succinct and scalable avenues to previously reported synthetic intermediates.

Full text of DOI:10.1002/anie.201705107

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Decarboxylative Alkynylation
Authors: Joel M. Smith, Tian Qin, Rohan R. Merchant, Jacob T.
Edwards, Lara R. Malins, Zhiqing Liu, Guanda Che, Zichao
Shen, Scott A. Shaw, Martin D. Eastgate, and Phil S. Baran
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705107
Angew. Chem. 10.1002/ange.201705107
Link to VoR: http://dx.doi.org/10.1002/anie.201705107
http://dx.doi.org/10.1002/ange.201705107

10.1002/anie.201705107
Angewandte Chemie International Edition
COMMUNICATION
Decarboxylative Alkynylation
Joel M. Smith†[a], Tian Qin†[a], Rohan R. Merchant[a], Jacob T. Edwards[a], Lara R. Malins[a], Zhiqing Liu[b],
Guanda Che[b], Zichao Shen[b], Scott A. Shaw[c], Martin D. Eastgate[d] and Phil S. Baran*[a]
wherein an alkynyl amino acid derivative (3) was accessed from
a parent amino acid (1) in 4 steps.8 This type of unnatural amino
acid has proven to be of critical value to practitioners in chemical
biology and drug discovery.2d In contrast, a mild decarboxylative
alkynylation strategy could dramatically simplify the pathway to 3
because the native carboxylate of a glutamic acid (2) could be
viewed as a progenitor of the alkyne unit without redox-
manipulations. Whereas other decarboxylative alkynylation
strategies require the use of engineered alkynyl coupling
partners (e.g. sulfonyl, iodine (III) reagents),9a–k strong
oxidants,9a or photo-induced electron transfer (PET) reagents,9g–
Abstract: The development of a new decarboxylative cross-coupling
protocol that affords terminal and substituted alkynes from various
carboxylic acids is described using both nickel- and iron-based
catalysts. The use of N-hydroxytetrachlorophthalimide (TCNHPI)
esters is crucial to the success of the transformation, and the
reaction is amenable to in situ carboxylic acid activation. Additionally,
an inexpensive, commercially-available alkyne source is employed in
this formal homologation process that serves as a surrogate for
other well-established alkyne syntheses. The reaction can be
conducted on
a mole scale, and the conditions are mild,
k
this design would provide convenient access to terminal
alkynes with little to no need for subsequent manipulation or
removal of protecting groups (Figure 1C).
operationally simple, and broad in scope while providing succinct
avenues to previously reported synthetic intermediates.
Alkynes are amongst the most versatile functionalities in
organic chemistry.1 In addition to an array of utility in the fossil
fuel industry,2a materials science,2b chemical biology,2c and drug
discovery,2d alkynes have a privileged role in organic synthesis,
serving as both nucleophiles and electrophiles. The relatively
limited range of methods available for their construction is
therefore puzzling. This has been particularly true of terminal
alkynes, which often have to be accessed from aldehyde
synthetic precursors.3 Homologation reactions of this variety
have largely been limited to classic reactions including the
Corey-Fuchs alkynylation,4 the Seyferth-Gilbert homologation,
and their respective modifications (e.g. Bestmann-Ohira
protocol).5 While these methods have been widely adopted, they
have considerable limitations, including the use of strongly basic
conditions and/or costly reagents that are not easily commutable
to complex systems or to those where an economically prudent
production process is needed. Additionally, it is commonplace
that one or more concession steps are required to access the
aldehyde substrates employed in these procedures.3 In this
Communication, a simple protocol for alkynylation is disclosed
wherein native carboxylic acids6 are swiftly transformed into both
substituted and terminal alkynes in a practical, straightforward
fashion.
Our investigation of the title transformation commenced with an
evaluation of various metal salts, ligands, solvents, and
activated esters. After considerable optimization (see Supporting
Information), it was found that the piperidine derived TCNHPI
ester
4 smoothly underwent the desired decarboxylative
alkynylation forming 6 in 82% isolated yield10 (Figure 1C) utili-
zing an alkynyl zinc reagent (5) derived from ethynylmagnesium
bromide and ZnCl2. The optimal catalyst was derived from a
A. Inspiration
BocHN
CO2Bn
BocHN
[cross-coupling]
CO2Bn
[Traditional
Approach]
BocHN
CO2Bn
CO2H
4 steps (2014)
1 step?
CO2H
1
3
2
H
B. Traditional synthesis of terminal alkynes
[Corey-Fuchs]
two step sequence
strong base required
O
O
H
R1
R2
R1
R2
steps
R1
R2
H
OH
[Bestmann-Ohira]
expensive reagent
R3
R3
R3
[alkyl acid]
ClZn
H
activation;
[organometallic]
[This work]
C. Optimization: Coupling of redox-active esters with alkynylzinc reagentsa
Recently, research efforts in this laboratory have explored the
utility of carboxylic acids and their redox-active ester (RAE)
derivatives as electrophiles in
a
variety of cross-coupling
Cl
Cl
protocols including arylation,7a,c,d,f alkylation,7b,e decarboxyla-
tion,7e borylation,7g and alkenylation.7h The success of these
decarboxylative processes prompted the investigation of alkynyl
nucleophiles as suitable cross-coupling partners towards forging
sp–sp3 C–C linkages. Inspiration to achieve such a reaction was
motivated by several useful alkynes that are extremely laborious
to access. An illustrative example is depicted in Figure 1A,
ZnCl•LiCl
H
O
Cl
O
H
(5, 2.5 equiv)
N
TsN
NiCl2•6H2O (20 mol%)
L1 (20 mol%)
THF/DMF, rt, 12 h
O
Cl
O
TsN
entry
4
6 82%
yield (%)b
deviation from above
1
2
3
4
5
6
7
8
9
in situ activationc
A* from NHPI
73
16
A* = At, in situ from HATU
NiCl2 glyme, L1
THF/MeCN
0
72d
53
•
[a]
Dr. J. M. Smith, Dr. T. Qin, R. R. Merchant, J. T. Edwards, Dr. L. R.
Malins and Prof. Phil S. Baran.
28d
62d
40e
NiCl2
NiCl2
•
•
glyme, L2
glyme, L3
[x-ray]
R
R
The Scripps Research Institute (TSRI)
North Torrey Pines Road, La Jolla, California, 92037, United States
E-mail: pbaran@scripps.edu
FeBr2•H2O, Grignard reagent
No added Ni cat. or ligand
< 1
N
N
a
b
[b]
[c]
[d]
[†]
Dr. Z. Liu, G. Che, Z. Shen
Asymchem Laboratories, (Tianjin) Co., Ltd.,TEDA
Tianjin, 300457, P. R. China
0.1 mmol.
Yield by 1H NMR with 1,3,5-
trimethoxybenzene as an internal standard.
c TCNHPI (1.1 equiv), DIC (1.1 equiv), CH2Cl2 (0.2
M). d 20 mol% [Ni] and L, alkynylzinc (2.5 equiv). e
2 0 m o l % [ F e ] , N M P / T H F, – 1 5 ° C ,
ethynylmagnesium bromide (1.5 equiv). See
Supporting Information for additional details.
R = OMe, L1
R = H, L2
R = tBu, L3
Dr. Scott A. Shaw
Discovery Chemistry, Bristol-Myers Squibb,
350 Carter Road, Hopewell, New Jersey, 08540, United States
Dr. Martin D. Eastgate
Chemical Development, Bristol-Myers Squibb
One Squibb Drive, New Brunswick, New Jersey 08903, United States
These authors contributed equally.
Figure 1. (A) Synthesis of an unnatural alkynyl amino acid derivative. B)
Traditional synthetic routes from carboxylic acids to terminal alkynes and
design of a new terminal alkyne cross-coupling synthetic strategy. (C)
Optimization of reaction conditions. TCNHPI
phthalimide, DIC = N,N’-diisopropylcarbodiimide.
= N-hydroxytetrachloro-
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10.1002/anie.201705107
Angewandte Chemie International Edition
COMMUNICATION
Cl
O
R3
ZnCl•LiCl(5)
[alkyl acid]
Cl
[redox-active ester]
NiCl2•6H2O (20 mol %)
L1 (20 mol %)
• > 30 examples
Cl
Cl
[alkynylation]a
R1
HO
N
• primary, secondary acids
• terminal/substituted alkynes
• in situ activation
DMF/THF, rt,
12 h, R3 = H
Cl
Cl
O
O
8
R1
O
O
Cl
• broad functional group tolerance
• mild, scalable
• isotope labeling
• natural products
• peptides
OH
R2
R3
11
DCC or DIC, CH2Cl2
Cl
R1
N
9
R3
R2
(10)
BrMg
O
[activation]
O
7
R2
FeBr2•H2O (20 mol %)
NMP/THF, –15 °C
15 min, R3 ≠ H
[isolated] or [in situ]
A Terminal alkynes
H
H
H
H
H
H
H
BocHN
TsN
TsN
N
Ts
CO2Me
CbzHN
H
CO2Bn
Ph
N
6: [Ni] 82%, 75%b
[Fe] 40%c
12: [Ni] 82%
13: [Ni] 48%
14: [Ni] 83%
15: [Ni] 65%d
16: [Ni] 52%
17: [Ni] 63%g
H
O
H
iPr
O
H
Me
H
H
Me
Me
O
O
O
O
H
AcO
O
Cl
Cl
O
Ar
Me
Me
H
22: [Ni] 59%, dr > 20:1g
Ar = biphenyl
from Corey lactone acid
[x-ray]
18: [Ni] 47%
19: [Ni] 42%
Me
20: [Ni] 45%
21: [Ni] 50%
H
Me
H
O
H
Me
Me
Me
H
Me
O
O
H
AcHN
Et
N
N
H
H
H
H
O
N
H
NH2
AcO
O
O
O
Me
23: [Ni] 57%g
from cholenic acid
24: [Ni] 72%
from dehydrocholic acid
[x-ray]
25: [Ni] 43%f
OH
Me
B Substituted Alkynes
Ph, 26: [Ni] 42%, [Fe] 72%
R=
Me
nBu, 27: [Fe] 60%
TMS
13C
13C
tBu, 28: [Ni] 26%c, [Fe] 45%
Me
N
TMS, 29: [Ni] 29%c [Fe] 65%, 61%d, 60%e
R
Ph
Et
(CH2)3Cl, 30: [Ni] 41% [Fe] 52%
cyclopropyl, 31: [Fe] 67%
Me, 32: [Ni] 19%c [Fe] 57%
CH2OBn, 33: [Fe] 74%
TsN
Me
Me
Ts
TsN
35: [Fe] 54%
Limitations:
O
36: [Fe] 43%
37: [Fe] 57%
4-MeOPh, 34: [Fe] 81%
(R = TMS)
[x-ray]
H
Me
TMS
H
Ph
H
O
O
Me
Me
BocHN
Boc
N
MeO2C
O
CO2Et
CO2Bn
O
O
38: [Fe] 41%, dr > 20:1g
40:
39: [Fe] 51%
[Fe] 45%, > 99% ee
41: [Fe] 40%
42: [Ni] 10%
43: [Ni] 0% yield
44: [Ni] 0% yield
Scheme 1. Scope of the Ni and Fe-catalyzed decarboxylative alkynylation with TCNHPI redox-active esters. a) Reaction conditions with [Ni]: RAE (1.0 equiv),
NiCl2•6H2O (20 mol %), L1 (20 mol%), ethynylzinc chloride (2.5 equiv), THF/DMF, rt, 12 h. Reaction conditions with [Fe]: RAE (1.0 equiv), FeBr2•H2O (20 mol%),
alkynyl Grignard (1.5 equiv), NMP/THF, 15 min, –15 °C. b) 4.0 mmol scale. c) NMR yield using internal standard. d) in situ reaction with TCNHPI (1.1 equiv) and
DIC (1.1 equiv). e) 2.0 mmol scale. f) For details, see Supporting Information. g) in situ reaction with TCNHPI (1.1 equiv) and DCC (1.1 equiv).
catalytic system provided superior yields for the cross-coupling
of substituted alkynes (vide infra).
1:1 ratio of NiCl2•6H2O and L1. Other ligands gave inferior yields,
and changing the solvent from DMF to other polar solvents had
With the optimized conditions in hand for terminal alkyne
synthesis, the scope of the alkynylation reaction was evaluated
(Scheme 1). Under the standard conditions, ethynylzinc chloride
(5) was smoothly coupled with a variety of secondary and
primary RAE substrates (9). Simple cyclic (6, 12, 13, 20) and
acyclic (14–15) alkynes were easily generated, and amino acid
substrates with sensitive functionality were also easily converted
to their requisite alkynes (16–17). Alkynes with a-heteroatom
substitution were also products of homologation, albeit with
a
deleterious effect on reaction efficiency (entries 5-7).
Additionally, control experiments without catalyst or ligand
resulted in little product formation (Entry 9). In situ activation of
the carboxylic acid with DIC and TCNHPI resulted in only a
slightly reduced yield (73%), allowing for the transformation to
be simplified into a one-pot process (Figure 1C, entry 1). Simple
iron salts such as FeBr2•H2O (entry 8) with Grignard reagents
also delivered workable yields, a fortuitous finding as this
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10.1002/anie.201705107
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COMMUNICATION
lower yield (18–19). Furthermore, heterocyclic moieties were
tolerated under the mild reaction conditions, with the 3-pyridyl
product (15) formed in good yield following an in situ activation
protocol. Complex steroidal derivatives (23–24) proved to be
exceptional coupling products with notably sensitive acetate and
ketone functionalities left unperturbed in the coupling. Perhaps
most impressively, the tetrapeptide 25 was successfully
synthesized with this methodology, demonstrating the potential
application of this reaction to late-stage diversification of peptidyl
side-chain carboxylic acids. The synthesis of alkynes with
benzylic substitution (10%, 42), proline (0%, 43) and tertiary
substitution (0%, 44) represent current limitations of this
coupling.
demonstrating the chemoselectivity of the cross-coupling
reaction.11 12 Currently, the reactivity difference remains unclear
when comparing the reactions catalyzed by either Ni or Fe.
Following the evaluation of the scope, both a mechanistic
inquiry and simple product diversification were investigated. As
with prior research on RAEs in cross-coupling, it was postulated
that this transformation proceeded via a radical pathway.6d,13 In
order to probe this hypothesis, the activation and cross-coupling
of cyclopropane substrate 45 under Fe catalysis was examined,
resulting in the isolation of the ring-opened product 46 in 56%
yield (Scheme 2A). As a further indication of the decarboxylative
nature of this reaction, 3,4,5,6-tetrachlorophthalimide was also
isolated in 52% yield. If desired, TCNHPI can be regenerated
While Ni catalysis proved successful with ethynylzinc chloride
(5), expanding the transformation to include substituted alkynes
proved more challenging. Additional optimization (see
Supporting Information), revealed that using FeBr2•H2O with an
NMP/THF solvent mixture and 1.5 equivalents of alkynyl
Grignard proved fruitful for coupling a variety of substituted
alkynes (26–34).11 As shown in Scheme 1, substituted alkynes
bearing silyl (29), alkyl (27, 28, 30-33), and aryl (26, 34) groups
from this byproduct using
a
known protocol.14 Further
mechanistic studies are currently ongoing.
Decarboxylative alkynylation opens up many interesting
opportunities for synthesis. For instance, the simple exchange of
a carboxylate with a TMS-substituted alkyne enables a formal
Arndt-Eistert homologation after simple hydroboration/oxidation
of 29 to carboxylic acid 47 (Scheme 2B).15 Next, the
difunctionalization of acetylene could be achieved in a simple
way. Thus, terminal alkyne 14 was succesfully employed in a
hydrozirconation/RAE cross-coupling protocol to access
difunctionalized alkene 48 in 58% yield (Scheme 2C).6h
Alternatively, alkyne 14 could be directly cross-coupled under Fe
catalysis to afford the disubstituted alkyne 49. This example
showcases a new tactic for the construction of C–C bonds
starting with commodity chemicals (simple acids and acetylene)
and sustainable coinage metal catalysts. Lastly, a Click reaction
with benzyl azide was carried out on peptidyl alkyne 25 to form
triazole 50, illustrating a direct application of peptide alkynes
relevant to peptide-labeling and bioconjugation.16
were
efficiently
generated.
Additionally,
a
bis-13C
trimethylsilylacetylene nucleophile was successfully coupled (35),
A
Mechanistic Probe
CO2A*
Ar MgBr
FeBr2•H2O (20 mol %)
NMP/THF, –15 °C
45 (A* from TCNHPI)
46: (56%)
OMe
B
Arndt-Eistert Transformation
TMS
Chx2BH; H2O2, NaHCO3
CO2H
Most importantly, known synthesis pathways can be
dramatically improved by employing the decarboxylative
alkynylation technology. For example, alkyne 53 was a late-
(60%)
TsN
TsN
47
29
stage intermediate in
a recent (2011) synthesis of (+)-
C
(Hydro)Alkylation
sapinofuranone B (Scheme 3A).17 While this key intermediate
was prepared in 11 steps (25% overall yield), it was envisioned
that an iterative bis-functionalization of a tartaric acid derivative
could provide faster access. First, in situ activation of mono-acid
51 and reaction with TIPS-protected ethynyl Grignard under Fe
catalysis proceeded in 43% yield with complete diastereocontrol.
This silylalkyne intermediate was saponified, and the resulting
carboxylic acid was subjected to a decarboxylative Giese
reaction and in situ TIPS removal delivering 53 in 47% yield (7:1
dr).18
H
Ph
14
Cp2ZrClH
ZnCl2;
Ni/L
CO2A*
EtMgBr;
FeBr2•H2O
(81%)
(58%)
TsN
(4) RAE (A* from TCNHPI)
Ph
Ph
4
4
TsN
TsN
48
49
D
Click Reaction on Peptidyl Alkyne
Secondly, decarboxylative alkynylation provided a mild and
efficient route to various unnatural amino acids. The reaction of
protected glutamic acid 2 was successful via isolation of the
RAE (72% yield) and in situ activation (69% yield). This simple
protocol provides for a significant improvement to the state of
the art in preparing this valuable intermediate.7 Furthermore, this
reaction was conducted on 1 mol scale and the product was
isolated in 73% yield with no erosion of enantiopurity. The
alkyne (3) was then saponified to afford amino acid 58 in
quantitative yield, providing facile access to this expensive
unnatural amino acid (ca. $1000/g).19
[Cu]
O
O
BnN3
Ac
Ac
I
I
E
Y
E
Y
P
P
NH2
NH2
(74%)
N
25
50
N
N
H
Bn
Scheme 2. (A) Radical ring opening of a cyclopropyl methylene RAE (45). (B)
Formal Arndt-Eistert transformation. (C) Functionalization of terminal alkyne
26. (D) Copper-assisted azide-alkyne cycloaddition on peptide 44.
demonstrating that this reaction can potentially provide access
to valuable isotopically labeled intermediates. The Fe-catalyzed
alkynylation reaction was also successful in producing acyclic
alkynes (36–37, 41) and more challenging coupling products
including a tartrate derived alkyne (38, accessed via in situ
activation), a spirocyclobutanone (39), and a glutamic acid
derivative (40). It is noteworthy that, in the latter three examples,
As a demonstration of the utility of alkynyl amino ester 3, it was
subjected to various post-alkynylation functionalizations. For
example, indole 54 and benzofuran 55 were synthesized in good
yield via
a Sonagashira reaction and Larock annulation,
respectively, using Pd catalysis.20 Both symmetrical (56) and
unsymmetrical diynes (57) were synthesized under Cu catalysis
using a Glaser coupling protocol.20 In particular diyne 57 could
the carbonyl
presence of
functionalities remained intact even in the
slight excess of Grignard nucleophile,
a
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10.1002/anie.201705107
Angewandte Chemie International Edition
COMMUNICATION
be a useful unnatural amino acid for bioimaging using Raman
spectroscopy (ATRI).22
Keywords: nickel catalysis • iron catalysis • redox-active esters
• alkynylation • homologation
A
Tartaric Acid
[1]
(a) Chemistry and Biology of Naturally-Occurring Acetylenes and
Related Compounds (Eds: J. Lam, H. Breteler, T. Arnason, L. Hansen),
Elsevier, Amsterdam, 1988; (b) Chemistry of Triple-Bonded Functional
Groups (Ed.: S. Patai), Wiley-VCH, New York, 1994; (c) Modern
Acetylene Chemistry (Eds.: P. J. Stang, F. Diederich), Wiley-VCH,
Weinheim, Germany, 1995.
Me
O
Me
O
Me Me
[Ni]
[Fe]
(52)
BrMg
TIPS
CO2Me
O
O
(47%
7:1 dr)
(43%
> 20:1 dr)
LiOH
(>99%)
HO2C
CO2Et
51
2 steps from
(+)-diethyltartrate
53
H
CO2Me
[2]
(a) P. Pässler et al. “Acetylene,” Ullman’s Encyclopedia of Industrial
Chemistry, Wiley-VCH, Weinheim, Germany, 2002; (b) Y. Liu, J. W. Y.
Lam, B. Z. Tang, Natl. Sci. Rev. 2015, 2, 493; (c) J. C. Jewett, C.
Bertozzi, Chem. Soc. Rev. 2010, 39, 1272; (d) P. Thirumurugan, D.
Matasiuk, K. Jozwiak, Chem. Rev. 2013, 113, 4905.
previously 11–16 steps
2010/2011 (ref. 17)
B
Alkyne Amino Acid
[lit: 2014; 4 steps
34 % yield, n = 0]
BnO2C
BocHN
R
BnO2C
CO2H
n
[69%, from acid
72 %, from RAE
73%, 1 mol (RAE), n = 1]
[3]
For a review, see: D. Habrant, V. Rauhala, A. M. P. Koskinen, Chem.
Soc. Rev. 2010, 39, 2007.
2
BocHN
$ 1.3/gram
(n = 1)
3: R =
H
[4]
[5]
E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769.
[Cu]
[Pd]
[Cu]
[Pd], [Cu]
LiOH
(a) D. Seyferth, R. S. Marmor, P. Hilbert, J. Org. Chem. 1971, 36, 1379;
(b) J. C. Gilbert, U. Weerasooriya, J. Org. Chem. 1982, 47, 1837; (c) S.
Ohira, Synth. Commun. 1989, 19, 561; (d) S. Müller, B. Liepold, G.
Roth, H. J. Bestmann Synlett 1996, 521; (d) Roth, G. J.; Liepold, B.;
Muller, S. G.; Bestmann, H. J. Synthesis 2004, 59.
R =
BnO2C
2
NHBoc
N
O
H
[Sonogashira]
54: (99%)
[Glaser]
56: (93%)
[Larock]
55: (93%)
Ph
[6]
[7]
For reviews on decarboxylative cross-coupling, see: (a) W. I. Dzik, P. P.
Lange, L. J. Gooßen, Chem. Sci. 2012, 3, 2671; (b) J. Cornella, I.
Larrosa, Synthesis 2012, 44, 653; (c) N. Rodríguez, L. J. Gooßen,
Chem. Soc. Rev. 2011, 40, 5030; (d) J. D. Weaver, A. Recio, A. J.
Grenning, J. A. Tunge, Chem. Rev. 2011, 111, 1846; (e) L. J. Gooßen,
N. Rodríguez, K. Gooßen, Angew. Chem., Int. Ed. 2008, 47, 3100.
HO2C
H
2
58: (>99%)
BocHN
[Cross-Glaser]
57: (40%)
Scheme 3. (A) Brief synthesis of intermediate 53 en route to the synthesis of
(+)-sapinofuranone B. (C) Scalable synthesis of alkynyl amino acid derivative
and subsequent diversification (See SI for experimental details).
(a) J. Cornella, J. T. Edwards, T. Qin, S. Kawamura, J. Wang, C.-M.
Pan, R. Gianatassio, M. Schmidt, M. D. Eastgate, P. S. Baran, J. Am.
Chem. Soc. 2016, 138, 2174; (b) T. Qin, J. Cornella, C. Li, L. R. Malins,
J. T. Edwards, S. Kawamura, B. D. Maxwell, M. D. Eastgate, P. S.
Baran, Science 2016, 352, 801; (c) J. Wang, T. Qin, T.-G. Chen, L.
Wimmer, J. T. Edwards, J. Cornella, B. Vokits, S. A. Shaw, P. S. Baran,
Angew. Chem. Int. Ed. 2016, 55, 9676; (d) F. Toriyama, J. Cornella, L.
Wimmer, T.-G. Chen, D. D. Dixon, G. Creech, P. S. Baran, J. Am.
Chem. Soc. 2016, 138, 11132; (e) T. Qin, L. R. Malins, J. T. Edwards,
R. R. Merchant, A. J. E. Novak, J. Z. Zhong, R. B. Mills, M. Yan, C.
Yuan, M. D. Eastgate, P. S. Baran, Angew. Chem. Int. Ed. 2017, 56,
260; (f) F. Sandfort, M. J. O’Neill, J. Cornella, L. Wimmer, P. S. Baran,
Angew. Chem. Int. Ed. 2017, 56, 3319; (g) C. Li, J. Wang, L. M.
Barton, S. Yu, M. Tian, D. S. Peters, M. Kumar, A. W. Yu, K. A.
Johnson, A. K. Chatterjee, M. Yan, P. S. Baran, Science, 2017, DOI:
10.1126/science.aam7355; (h) J. T. Edwards, R. R. Merchant, K. S.
McClymont, K. W. Knouse, T. Qin, L. R. Malins, B. Vokits, S. A. Shaw,
D.-H. Bao, F.-L. Wei, T. Zhou, M. D. Eastgate, P. S. Baran, Nature,
2017, 545, 213; (i) For other example of using RAE cross-coupling,
see: K. M. M. Huihui, J. A. Caputo, Z. Melchor, A. M. Olivares, A. M.
Spiewak, K. A. Johnson, T. A. DiBenedetto, S. Kim, L. K. G. Ackerman,
D. J. Weix, J. Am. Chem. Soc. 2016, 138, 5016; (j) L. Candish, M.
In summary, a decarboxylative alkynylation protocol has been
developed using both Ni and Fe catalysis. The reaction employs
an economical catalyst system coupled with the use of readily
available cross-coupling partners. The title transformation stands
as an expedient alternative to age-old methods for the
homologation of carbonyl compounds and benefits from
employing ubiquitous carboxylic acid starting materials as
electrophilic coupling partners. Substituted alkynyl Grignards
can also be coupled under functional group tolerant conditions
providing access to a variety of synthetically useful alkyne
products. The utility of the products was demonstrated through
various post-alkynylation transformations and synthetic
applications. From a strategic standpoint, we anticipate that the
use of alkynyl organometallics, commodity acids, and cheap
Earth-abundant catalysts to make C–C bonds should find
widespread practical use in various disciplines of chemical
science.
Teders,
F.
Glorius,
J.
Am.
Chem.
Soc.
2017,
DOI:
10.1021/jacs.7b03127. (k) D. Hu, L. Wang, P. Li, Org. Lett. 2017, 19,
2770; For a seminal use of RAEs of the phthalimide-type, see: (l) K.
Okada, K. Okamoto, M. Oda, J. Am. Chem. Soc. 1988, 110, 8736.
Acknowledgements
Financial support for this work was provided by NIH (grant
number GM-118176), Bristol-Myers Squibb, NIH (F32GM117816
postdoctoral fellowship to L. R. M), Department of Defense
(NDSEG fellowship to J. T. E.), and the Arnold and Mabel
Beckman Foundation (Postdoctoral Fellowship to J. M. S.) We
are grateful to D.-H. Huang and L. Pasternack (The Scripps
Research Institute) for assistance with nuclear magnetic
resonance spectroscopy. We are also grateful to Dr. Arnold
Rheingold, Milan Gembicky, and Curtis Moore for x-ray
crystallographic analysis.
[8]
[9]
Y. Murakami, R. Suzuki, H. Yanuma, J. He, S. Ma, G. Turino, Y. Y. Lin,
T. Usuki, Org. Biomol. Chem. 2014, 48, 9887.
For examples of decarboxylative alkynylation of alkyl carboxylic acids,
see: (a) H.-P. Bi, L. Zhao, Y.-M. Liang, C. Li, Angew. Chem. Int. Ed.
2009, 48, 792; (b) C. Zhang, D. Seidel, J. Am. Chem. Soc. 2010, 132,
1792; (c) H.-P. Bi, Q. Teng, M. Guen, W.-W. Chen, Y.-M. Liang, X. Yao,
C. Li, J. Org. Chem. 2010, 75, 783; (d) X. Liu, Z. Wang, X. Cheng, C.
Li, J. Am. Chem. Soc. 2012, 134, 14330; (e) Y.-S.Feng, Z.-Q.Xu, L.
Mao, F.-F.Zhang, H.-J. Xu, Org. Lett. 2013, 15,1472; (f) Q.-Q. Zhou, W.
Guo, W. Ding, X. Wu, X. Chen, L.-Q. Lu, W.-J. Xiao, Angew. Chem. Int.
Ed. 2015, 54, 11196; (g) J. Yang, J. Zhang, L. Qi, C. Hu, Y. Chen,
Chem. Comm. 2015, 51, 5275; (h) F. Le Vaillant, T. Cournat, J. Waser,
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Angewandte Chemie International Edition
COMMUNICATION
Angew. Chem. Int. Ed. 2015, 54, 11200; (i) C. Yang, J.-D. Yang, Y.-H.
Li, X. Li, J.-P. Cheng, J. Org. Chem.2016, 81, 12357; (j) J. Schwarz, B.
König, ChemPhotoChem DOI: 10.1002/cptc.201700034. (k) M. Jiang,
Y. Jin, H. Yang, H. Fu, Sci. Rep. 2016, 6, 26161; For a recent example
with arenes, see: (l) T. Okita, K. Kumazawa, R. Takise, K. Muto, K.
Itami, J. Yamaguchi, Chem. Lett. 2017, 46, 218.
[18] As this reaction proceeds via radical intermediates, the selectivity
reflects the inherent selectivity of the substrate. For similar results, see:
(a) Reference 7e; (b) D. H. R. Barton, A. Gateau-Olesker, S. D. Géro, B.
Lacher, C. Tachdjian, S. Z. Zard, Tetrahedron 1993, 49, 4589.
[19] (a) Price = $1096/g on 05/16/2017 from ChemPep, Inc.; (b) Price =
$3280/5g on 05/16/2017 from Affinity Research Chemicals Inc.
[10] For a recent example of Ni-catalyzed alkynylation, see: O. Vechorkin,
A. Godiniat, R. Scopelliti, X. Hu, Angew. Chem. Int. Ed. 2011, 50,
11777.
[20] (a) B. C. J. van Esseveldt, P. W. H. Vervoort, F. L. van Delft, F. P. J. T.
Rutjes, J. Org. Chem. 2005, 70, 1791; (b) B. C. J. van Esseveldt, F. L.
van Delft, J. M. M. Smits, R. de Gelder, H. E. Schoemaker, F. P. J. T.
Rutjes, Adv. Synth. Catal. 2004, 346, 823.
[11] For recent examples of Fe-catalyzed alkynylation, see: (a) T.
Hatakeyama, Y. Okada, Y. Yoshimoto, M. Nakamura, Angew. Chem.
Int. Ed. 2011, 50, 10973; (b) C. W. Cheung, P. Ren, X. Hu, Org. Lett.
2014, 16, 2566.
[21] K. Balaraman, V. Kesavan Synthesis, 2010, 3461.
[22] (a) H. Yamakoshi, K. Dodo, M. Okada, J. Ando, A. Palonpon, K. Fujita,
S. Kawata, M. Sodeoka, J. Am. Chem. Soc. 2011, 133, 6102; (b) H.
Yamakoshi, K. Dodo, A. Palonpon, J. Ando, K. Fujita, S. Kawata, M.
Sodeoka, J. Am. Chem. Soc. 2012, 134, 20681.
[12] For other examples of alkynyl Grignard cross-coupling with alkyl
halides, see: (a) L.-M. Yang, L.-F. Huang, T.-Y. Luh, Org. Lett. 2004, 6,
1461; (b) H. Ohmiya, H. Yorimitsu, K. Oshima, Org. Lett. 2006, 8, 3093;
(c) J. M. Hammann, D. Hass, C.-P. Tullman, K. Karaghiosoff, P.
Knochel, Org. Lett. 2016, 18, 4778.
[23] Crystallographic data (excluding structure factors) for structures 6, 20,
23 and 29 reported in this paper have been deposited in the Cambridge
Crystallographic Data Centre as supplementary publication nos. CCDC-
1549218, CCDC-1549219, CCDC-1549220 and CCDC-1549221.
[13] (a) J. K. Kochi, Acc. Chem. Res. 1974, 7, 351 (and references therein);
(b) M. Yan, J. C. Lo, J. T. Edwards, P. S. Baran, J. Am. Chem. Soc.
2016, 138, 12692.
[14] C. Einhorn, J. Einhorn, C. Marcadal-Abbadi, Synth. Commun. 2001, 5,
741.
[15] C. Alemany, J. Bach, J. Garcia, M. López, A. B. Rodriguez,
Tetrahedron 2000, 56, 9305.
[16] F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B.
Sharpless, V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 210.
[17] (a) J. S. Yadav, J. S. S. Reddy, S. S. Mandal, P. Srihari, Synlett 2010,
2636; (b) J. S. Yadav, J. S. S. Reddy, S. S. Mandal, P. Srihari,
Tetrahedron 2011, 67, 4620.
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Joel M. Smith†, Tian Qin†, Rohan R.
Merchant, Jacob T. Edwards, Lara R.
Malins, Zhiqing Liu, Guanda Che,
Zichao Shen, Scott A. Shaw, Martin D.
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Eastgate and Phil S. Baran*
Author(s), Corresponding Author(s)*
Decarboxylative Alkynylation
Page No. – Page No.
Title
All kinds of Alkynes:
A convenient method for the decarboxylative
alkynylation of redox active esters has been developed. The reaction is broad,
functional group tolerant, and provides access to alkynes that are both terminal
and substituted using either Ni or Fe catalysis. The method is used to swiftly
synthesize a variety of alkynyl intermediates that were previously difficult to
access using conventional alkynylation strategies.
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