Reductive Decarboxylative Alkynylation of N-Hydroxyphthalimide Esters with Bromoalkynes

Article abstract of DOI:10.1002/anie.201706781

A new method for the synthesis of terminal and internal alkynes from the nickel-catalyzed decarboxylative coupling of N-hydroxyphthalimide esters and bromoalkynes is presented. This reductive cross-electrophile coupling is the first to use a C(sp)?X electrophile, and appears to proceed via an alkynylnickel intermediate. The internal alkyne products are obtained in yields of 41–95 % without the need for a photocatalyst, light, or a strong oxidant. The reaction displays a broad scope of carboxylic acid and alkyne coupling partners, and can tolerate an array of functional groups, including carbamate NH, halogen, nitrile, olefin, ketone, and ester moieties. Mechanistic studies suggest that this process does not involve an alkynylmanganese reagent and instead proceeds through nickel-mediated bond formation.

Full text of DOI:10.1002/anie.201706781

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Accepted Article
Title: Reductive Decarboxylative Alkynylation of N-Hydroxyphthalimide
Esters with Bromoalkynes
Authors: Liangbin Huang, Astrid M. Olivares, and Daniel John Weix
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706781
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10.1002/anie.201706781
Angewandte Chemie International Edition
COMMUNICATION
Reductive Decarboxylative Alkynylation of N-Hydroxyphthalimide
Esters with Bromoalkynes
Liangbin Huang,[a] Astrid M. Olivares,[a] and Daniel J. Weix*[a]
Abstract: A new method for the synthesis of terminal and internal
alkynes from the nickel-catalyzed decarboxylative coupling of N-
hydroxyphthalimide esters (NHP esters) and bromoalkynes is
presented. This reductive cross-electrophile coupling is the first to use
a C(sp)-X electrophile, and appears to proceed via an alkynylnickel
intermediate. The internal alkyne products are obtained in 41-95%
yield without the need for a photocatalyst, light, or strong oxidant. The
reaction displays a broad scope of carboxylic acid and alkyne coupling
partners and can tolerate an array of functional groups including a
carbamate N-H, halogen, nitrile, olefin, ketone, and ester. Mechanistic
studies suggest that this process does not involve an
alkynylmanganese reagent and involves nickel-mediated bond
formation.
this transformation is through the Corey-Fuchs reaction[10] or the
Seyferth-Gilbert homologation[11] of aldehydes to terminal alkynes.
While this approach has proven useful, it often requires the
synthesis of the aldehyde from the more abundant carboxylic acid,
strong base to effect the rearrangement, and additional steps if
an internal alkyne is desired.
Typical conversion of an alkanoic acid to an internal alkyne
O
O
H
R’
R
OH
R
H
R
R
This work: reductive alkynylation of NHP-ester
O
O
O
N
R
OH
esterification
R
O
(dtbbpy)NiBr2
Mn, LiBr, r.t.
R’
O
R
Cross-electrophile coupling[1] has recently been shown to be a
general approach to the formation of C-C bonds and the number
and type of electrophiles that can be cross-coupled has grown
rapidly in the past decade. The formation of C(sp3)-C(sp2) bonds
has been the most studied,[2],[3] but the selective formation of
C(sp2)-C(sp2)[4] and C(sp3)-C(sp3)[5] bonds has also been
demonstrated (Scheme 1). In particular, the coupling of aryl[2] and
vinyl halides[3] with alkyl halides has proven to be a useful
alternative to other cross-coupling approaches.[6] In contrast,
cross-electrophile coupling to form C(sp)-C(spx) bonds has not
been demonstrated (Scheme 1), even though bromoalkynes are
easily generated from terminal alkynes.[7] [8]
R’
R’
halogenation
H
Br
Scheme 2. Comparison of alkynylation strategies.
We envisioned
a
more convergent approach, the
decarboxylative coupling of an N-hydroxyphthalimide (NHP) ester
with an alkynyl bromide (Scheme 2).[12],[13] Strategically, this
approach differs from the above strategy because it avoids the
aldehyde intermediate. Additionally, the alkyne component can be
substituted, allowing for direct synthesis of functionalized internal
alkynes. While this exact transformation is unknown, related
strategies have been investigated recently. For example, the
oxidative decarboxylation of aliphatic acids to form alkyl radicals
with subsequent capture by alkynyl electrophiles.[14] Concurrent
with these studies, Fu reported on the coupling of terminal alkynes
with a-amino NHP esters[15] and Baran reported on the coupling
of N-hydroxytetrachlorophthalimide (TCNHPI) esters with
alkynylzinc or magnesium reagents.[16] Our proposed approach
would avoid the need for organometallic reagents and the more
expensive TCNHPI[17] without being limited to a-amino acid
derivatives.[15] Although this approach would use alkyne
electrophiles, bromoalkynes[7] are more easily prepared than
ethynylbenziodoxolones[18] or alkynyl sulfones.[14a-c]
C(sp3)
C(sp2)
C(sp2)
C(sp3)
C(sp2)
C(sp3)
Alkyl
X
Alkyl NHP
X
Many
Reports
Allyl
Ni, Co, or Pd
reductant
Acyl
X
Ar
X
C(spx)
Alkynyl-X
C(sp)
Unknown
Scheme 1. Types of bonds formed by reductive cross-electrophile coupling.
This absence in the literature could be related to a number of
potential problems. First, the high reactivity of bromoalkynes
could pose a selectivity problem.[9] Second, the low steric bulk of
the alkyne could lead to rapid transmetalation and homocoupling
to form diynes. Finally, alkynes can act as radical acceptors and
strong ligands, potentially leading to catalyst inhibition and side
reactions.
Initial results using conditions we reported for the coupling of
iodoarenes to NHP esters[13a] resulted in a low yield of the cross-
product (Table 1, entry 1, 3a) and a large amount of the
homodimer (diyne). Two changes solved this selectivity problem
(entries 1-3): changing the reductant from Zn to Mn (from 11 to
43% yield) and adding in LiBr as an additive (43% to 78% yield).[4c,
We were motivated to explore the reactivity of alkynyl
electrophiles in order to develop a new synthesis of alkylated
alkynes from carboxylic acids. The most often used solution for
19]
Examination of several other salts showed that both LiCl and
LiBr improve the yield of cross-product at the expense of diyne
formation. Stoichiometric amounts of LiBr were required to
observe a beneficial effect (entries 8 and 9). Small improvements
in yield were obtained when using an excess of either coupling
partner (entries 10 and 11).
[a]
Dr. L. Huang, A. M. Olivares, Prof. Dr. D. J. Weix
Department of Chemistry
University of Rochester
Rochester, New York 14627-0216, USA
E-mail: daniel.weix@rochester.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706781
Angewandte Chemie International Edition
COMMUNICATION
Control experiments showed that both nickel and ligand were
essential for this transformation (entries 12 and 13). A redox
active ester appears to be required because 1b was not
consumed under these reaction conditions (entry 14). Other
redox-active esters (HOBt or HOAt esters 1c and 1d) were also
not consumed under these conditions (entry 14).
successfully transformed into the alkynylation products in
moderate to good yields (3j, 3k and 3m).
Next, the scope of the bromoalkynes was tested in our
reductive coupling method. Both the alkyl substituted and the
phenyl substituted bromoalkynes were coupled with 3,3-
dimethylbutanoic acid NHP ester in good yields (3o and 3p).
Several functional groups can be appended onto the alkyl chain
of the bromoalkynes including malonate (3q), OTBS (3r), cyanide
(3s), phthalimide (3t), and alkene (3u), without preventing product
formation.
Table 1. Optimization of the decarboxylative alkynylation.
TIPS 10 mol% NiBr2(dme)
10 mol% dtbbpy
TIPS
TIPS
O
+
+
Mn (3 equiv)
NMP (0.6 mL)
LiBr (1 equiv)
OR
Br
1a
2a
3a
diyne
TIPS
(0.25 mmol)
(0.25 mmol)
r.t., overnight
Not all substrates tested coupled in high yield under these
conditions. An NHP ester with a free carboxylic acid and a
bromoalkyne with a free hydroxyl group resulted in low yields.
Finally, NHP esters that would generate an allylic or benzylic
radical failed to give alkynylation products.
O
O
N
t-Bu
t-Bu
N
N
N
N
N
R =
N
N
N
N
N
O
O
dtbbpy
1a
1b
1c
1d
Table 2. Substrate scope of NHP-ester and bromoalkyne.
Yield of
Yield of
Entry
Change from Conditions in Scheme
3a[a]
diyne[a]
R2
R1
O
O
O
10 mol% NiBr2(dme)
10 mol% dtbbpy
1
2
3
4
5
6
7
8
Zn instead of Mn, omit LiBr
omit LiBr
none
11
43
78
67
42
43
46
78
53
89 (86)
84
n.d.
n.d.
n.d.
40
23
11
9
21
16
19
14
13
8
R3
R2
R1
R3
N
Mn (3 equiv)
NMP (1.2 mL)
LiBr (1 equiv)
r.t., overnight
+
Br
2 (0.5 mmol)
LiCl instead of LiBr
KF instead of LiBr
KBr instead of LiBr
NaI instead of LiBr
LiBr (2 equiv)
LiBr (0.5 equiv)
1.5 equiv of 1a
1.5 equiv 2a
O
1 (1.5 equiv)
3
O
TIPS
TIPS
n = 1; 3b 42%
n = 2; 3c 65%
EtO
9
n
TIPS
10
11
12
13
14
O
3d 91%
3a 86%
18
6
n.d
>40
omit dtbbpy
omit NiBr2(dme)
1b-d instead of 1a
Me
Me
Me
TIPS
TIPS
O
O
CbzHN
3e 55%
Br
TIPS
[a] Corrected GC yield using n-dodecane as the internal standard; isolated
yield in parentheses.
BocHN
3f 49%
3g 52%
Under the optimized conditions, various alkyl NHP esters and
bromoalkynes were cross-coupled successfully in 41-95% yield
(Table 2). Functional group compatibility is promising, and the
reaction tolerates ketones (3b and 3c), esters (3d) and the N-H of
secondary carbamates (3e). The high reactivity of the NHP esters
compared to other alkyl electrophiles was demonstrated in
product 3f, where an alkyl bromide was tolerated, albeit in
moderate yield. Another advantage of the NHP esters is that
readily available amino acids can be easily converted into useful
alkynyl amino acids (3g) and alkynyl amines (3k and 3m).
Propargylglycine, obtainable from 3g by routine deprotection, has
been made on large scale to support pharmaceutical synthesis.[20]
Our route, from aspartic acid, is an attractive alternative to the
chiral auxiliary approach that was recently reported.[21] Linoleic
acid was coupled to form 3i in high yield without isomerization of
the Z-olefins. Although these reactions were set up in a glovebox
for convenience, the chemistry could be run on preparative scale
(5 mmol NHP ester) on the benchtop without the need for strict
exclusion of moisture and air. Subsequent removal of the TIPS
protecting group with nBu4NF (1 M in THF) gave the terminal
alkyne in 84% yield over the two steps.
Me
n = 3
TIPS
R
R = TIPS, 3i 95%
R = H, 4i 84%[a]
3h 92%
Ph
O
N
Boc
3k 47%[b]
HN
Boc
TIPS
TIPS
TIPS
TIPS
3j 73%[b]
3m 41%[b]
3l 64%[b]
Me
R
3q 71%[c]
R = n-C6H14, 3o 71%[c]
R = Ph, 3p 62%[c]
TIPS
3n 70%
MeO2C
CO2Me
3
FG
FG = CN, 3s 62%[c]
FG = phthalimide, 3t 49%[c]
OTBS
3u 67%[c]
3r 76%[c]
[a] This reaction was run on 3.3 mmol scale and the crude product was
deprotected with TBAF before isolation. Yield is over two steps. [b] Reaction run
at 50°C. [c] Reaction run at lower concentration (1.8 mL of NMP).
Three potential mechanisms were proposed: 1) in-situ
formation of an alkynyl manganese reagent and subsequent
a-Branched redox-active esters were suitable substrates for
the alkynylation reaction (3j-n), but reactions with dibranched
substrates did not form product. The value of using an aliphatic
acid as a source for the alkyl moiety was demonstrated with these
compounds, as the corresponding alkyl halides are not
commercially available or fail to couple.[22] For example, 3-
halotetrahydrofurans, 2-halopyrrolidines, and 2-amido alkyl
halides are not easily accessible starting materials, whereas the
corresponding aliphatic acids are relatively affordable and can be
nickel-catalyzed cross-coupling,[16] 2) nickel-catalyzed radical
23],[13a]
generation[13b,
and outer-sphere addition of the free
radical to the bromoalkyne;[14a-c] 3) sequential reaction of two
electrophiles with the nickel catalyst and bond-formation at
nickel.[24] At this time, we can rule out the first two mechanistic
possibilities (vide infra).
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10.1002/anie.201706781
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COMMUNICATION
Given the high reactivity of alkynyl bromides and the
positive effect of LiBr on the reaction outcome, an additive
known to increase the rate of insertion of Mn or Zn,[25] we
suspected an alkynylmanganese reagent might be an
intermediate. However, when silylated bromoalkyne 2a was
subjected to standard conditions without adding nickel or
ligand (Scheme 3a), the bromoalkyne was not consumed and
only a trace of hydrodebrominated alkyne was observed. This
shows that direct insertion of Mn into the C-Br bond is slow and
suggests that Mn serves to reduce a nickel intermediate.
Although we are unsure of the role of LiBr in minimizing
formation of diyne, our own work and that of Osakada and
a process that requires an alkynylnickel intermediate (Table 1 and
Scheme 3d).
Finally, we briefly studied the reactivity of two possible nickel
intermediates to shed light on the mechanism (Scheme 3d). The
nickel(0) complex (dtbbpy)Ni0(cod) reacted rapidly with both
electrophiles at rt, in each case forming an as-yet unidentified
organonickel intermediate (5 and 6).[29] Both of these
intermediates, either after isolation and washing to remove
excess electrophile or without isolation, react with the
complementary electrophile to form cross-product.[22e],[30] While
these studies demonstrate that an inner-sphere, nickel-mediated
mechanism is possible, further studies will be required before a
complete catalytic cycle can be proposed.[24]
Yamamoto[26]
suggests
that
diyne
arises
from
dialkynylnickel(II) intermediates. Added LiBr could slow ligand
exchange between alkynylnickel(II) intermediates, inhibiting
diyne formation.
In conclusion, the reductive alkynylation to form a C(sp)-C(sp3)
bond has been achieved, opening a new class of reactions to
cross-electrophile coupling and demonstrating that even highly
reactive electrophiles can be coupled selectively. The resulting
method provides a convenient and direct synthesis of a wide
variety of internal alkynes from convenient precursors and useful
alternative to methods that proceed via olefination or use alkyl
halides.
(a)
Mn (3 equiv)
with or without LiBr (1 equiv)
Br
H
NMP (1.2 mL), r.t., 16 h
TIPS
TIPS
< 1% conversion
after reaction, quenched with H+
2a
(b)
O
O
via
2a
O
N
Acknowledgements
conditions as
in Table 2
TIPS
O
1.5 equiv
3v, 65%
The authors gratefully acknowledge funding from the NIH NIGMS
(R01 GM097243 to DJW) and the NSF (NSF DGE-1419118 to
AMO). DJW is a Camille Dreyfus Teacher-Scholar. Additional
funding from Novartis, Pfizer, and Boehringer Ingelheim is also
gratefully acknowledged. Matthew Goldfogel, Amanda Spiewak,
and Keywan Johnson (Univ. of Rochester) are acknowledged for
assistance with substrate synthesis. Theresa Iannuzzi is thanked
for assistance with EPR spectroscopy experiments.
(c)
O
O
O
2a
O
3a
+
N
N
conditions as
in Table 2
+ TEMPO
O
1.5 equiv
7a, 39%
23%
(d)
[NiII]
2a
1a
(dtbbpy)Ni0(cod)
diyne
3a
+
LiBr
5
17%
TIPS
Keywords: Cross-electrophile coupling • Homogeneous
catalysis • Alkynes • Alkylation • Cross-coupling
1a
[Nin]
2a
(dtbbpy)Ni0(cod)
18%
3a
LiBr
6
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COMMUNICATION
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10.1002/anie.201706781
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Liangbin Huang, Astrid M. Olivares, and
Daniel J. Weix*
Page No. – Page No.
Reductive Decarboxylative Alkynylation
of N-Hydroxyphthalimide Esters with
Bromoalkynes
A new method for the synthesis of terminal and internal alkynes from the nickel-catalyzed
decarboxylative coupling of N-hydroxyphthalimide esters (NHP esters) and bromoalkynes is
presented. This reductive cross-electrophile coupling is the first to use a Csp-X electrophile,
and appears to proceed via an alkynylnickel intermediate. The internal alkyne products are
obtained in 41-95% yield without the need for a photocatalyst, light, or strong oxidant. The
reaction displays a broad scope of carboxylic acid and alkyne coupling partners and can
tolerate an array of functional groups including a carbamate N-H, halogen, nitrile, olefin,
ketone, and ester. Mechanistic studies suggest that this process does not involve an
alkynylmanganese reagent and involves nickel-mediated bond formation.
This article is protected by copyright. All rights reserved.