Highly Selective Manganese(I)/Lewis Acid Cocatalyzed Direct C?H Propargylation Using Bromoallenes

Article abstract of DOI:10.1002/anie.201710835

A manganese(I)/Lewis acid cocatalyzed direct C?H propargylation with high selectivity has been developed. BPh₃ was discovered to not only promote the reactivity, but also enhance the selectivity. Secondary, tertiary, and even quaternary carbon centers at the propargylic position could be directly constructed. Both internal and terminal alkynes are easily accessible. The chirality was successfully transferred from an axially chiral allene to central chirality. The reactivity of the manganese catalyst in this reaction was found to be unique among transition metal catalysts.

Full text of DOI:10.1002/anie.201710835

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Highly Selective Manganese(I)/Lewis Acid Cocatalyzed Direct C
−H Propargylation using Bromoallenes
Authors: Can Zhu, Luca Jonas Schwarz, Sara Cembellin, Steffen
Greßies, and Frank Glorius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710835
Angew. Chem. 10.1002/ange.201710835
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10.1002/anie.201710835
Angewandte Chemie International Edition
COMMUNICATION
Highly Selective Manganese(I)/Lewis Acid Cocatalyzed Direct
C−H Propargylation Using Bromoallenes
Can Zhu, Jonas Luca Schwarz, Sara Cembellín, Steffen Greßies, and Frank Glorius*
Direct C–H allylation (well established by Pd, Rh, Ru, Ir, Co, Cu etc.)
Abstract:
A manganese(I)/Lewis acid cocatalyzed direct C−H
LG
propargylation with high selectivity has been developed. BPh3 was
discovered to not only promote the reactivity, but also enhance the
selectivity to afford the propargylation. Secondary, tertiary or even
quaternary carbon centers at the propargylic position could be
directly constructed. Both internal and terminal alkynes are easily
accessible. The chirality was successfully transferred from an axially
chiral allene to the central chirality. The reactivity of the manganese
catalyst in this reaction was found to be unique comparing other
transition metal catalysts.
DG
DG
TM catalysis
(a)
+
or
Ar
Ar
C(sp2)-C(sp3) bond formation
Direct unactivated C–H propargylation (undeveloped)
coupling site
R
DG
DG
R
TM catalysis
A
LG
Ar
(b)
Ar
+
or
R
LG
B
[TM]
possible candidate
[TM]
challenging
he efficient construction of carbon-carbon (C−C) bonds is
Ma et al. 2016: Pd-catalyzed acidic C–H propargylation using propargylic carbonates
at the core of organic synthesis.[1] One elegant solution is
T
[Pd]/dppf
Nuc
R1
R2
LG
R1
R2
LG = OCO2Me
the utilization of transition metal-catalyzed C−H activation
(c)
+
Nuc-H
R
R
ligand control
reactions, which have emerged as an effective tool for the
functionalization and assembly of organic molecules for
pharmaceutical and material sciences.[2] Recently, the selective
construction of C(sp2)−C(sp3) bonds has attracted more and
more attention.[3] On the other hand, acetylene is a fundamental
and crucial group in organic chemistry, which can be easily
transferred to many other functional groups,[4] and also has
broad applications in click chemistry.[5] Therefore, the direct C−H
propargylation would definitely be an efficient and powerful
strategy to realize both the construction of a C(sp2)−C(sp3) bond
between two molecule fragments, and the introduction of an
acetylene moiety in an one-step manner.[6]
malononitrile
malonate
Selective propargylation
bearing quaternary center
This work
: Mn(I)-catalyzed selective unacidic C–H propargylation using bromoallenes
DG
R1
R2
DG
R1
R2
C(1)=C(2)
insertion
Ar
Ar
(d)
(e)
Br
[Mn]
DG R1
R
1
2 3
[Mn]
R
Int-1
+
Ar
+ - +
base
R
Br
R2
DG
DG
LG = Br
Ar
Ar
Br
R
R
C(3)=C(2)
R1
insertion
[Mn]
R2
R1
So far, many catalysts, such as Pd, Rh, Ru, Ir, Co, Cu
complexes could realize the direct C−H allylation, although with
an issue of regioselectivity, forming a C(sp2)−C(sp3) bond
(Scheme 1a).[7] In contrast, the direct C−H propargylation is
much less investigated, especially those starting from
unactivated C−H bonds (Scheme 1b). The coupling partner in
the direct C−H propargylation could be an alkyne with a leaving
group (LG) at the propargylic position (A), or an allene directly
connected to a LG (B). However, the control of the selectivity
during the reaction is greatly challenging, given the fact that the
formation of an allenyl metal complex is more favorable in
comparison with a propargylic intermediate. Therefore, in most
cases, these reactions of either A[8] or B[9] give rise to the
corresponding allenes rather than the propargylic products. Only
in rare cases,[10] such as Friedel−Crafts type reactions,[11] the
direct C−H propargylation could be observed as the major
Int-2 R2
LG = leaving group. TM = transition metal. DG = directing group. Nuc = nucleophile. dppf =
1,1'-bis(diphenylphosphino)ferrocene.
Scheme 1. Previous studies and this work.
pathway, however, limited to electron-rich aromatic systems
and/or acidic C−H bonds only.[12] In 2016, Ma et al. described a
highly efficient Pd-catalyzed acidic C−H propargylation using
propargylic carbonates (Scheme 1c).[12a] The ligand controls the
selectivity leading to propargylic compounds rather than allenes.
To the best of our knowledge, the direct C−H activation/
propargylation is still undeveloped, thus highly desirable.
In the past decade, great progress on C−H activation
chemistry has been achieved based on complexes of 4d or 5d
noble metals. In contrast, the utility of manganese complexes is
unfortunately scarce, although manganese is earth-abundant,
inexpensive, and of low toxicity.[13] In this field, recent years have
witnessed the significant progress, achieved by the groups of
Kuninobu and Takai,[14] Wang,[15] Ackermann,[16] our group[17]
and others.[18] Herein, we disclose our recent observations on
the highly selective manganese(I)/Lewis acid cocatalyzed direct
C−H propargylation using bromoallenes. Bromoallenes are a
class of easily accessible, mostly stable compounds.[19] More
than 30 natural products have been discovered bearing this
[*]
Dr. C. Zhu, J. L. Schwarz, Dr. S. Cembellín, S. Greßies, Prof. Dr. F.
Glorius
Westfälische Wilhelms-Universität Münster, Organisch-Chemisches
Institut, Corrensstraße 40, 48149 Münster, Germany
E-mail: glorius@uni-muenster.de
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.201710835
Angewandte Chemie International Edition
COMMUNICATION
R
structural motif, while the chemistry of bromoallenes is highly
undeveloped.[20] The utility of bromoallenes as the coupling
partner in the direct C‒H propargylation shows their unique
character as potential building blocks in organic synthesis.
However, two big challenges still exist: 1) The selective C=C
insertion [C(1)=C(2) vs. C(3)=C(2)] into the C−Mn bond would
lead to a propargylic compound (Scheme 1d) or an allene
product (Scheme 1e); 2) This newly formed acetylene would
probably be even more reactive towards insertion into the C‒Mn
bond, compared with bromoallenes.[15a-b,18a]
10 mol% Mn(CO)5Br
2.5-10 mol% BPh3
2 equiv K3PO4
DG
R1
R
DG
+
Ar
Ar
R2
1.5 equiv
Br
R1
10-50 mol% H2O
Et2O, 60-80 oC, time
R2
1
2
3
indole derivatives
CO2Et
MeO
CO2Et
O2N
CO2Et
CO2Et
MeO2C
N
N
N
N
2-py
2-py
2-py
2-py
3a
3b
3c[a]
(5 h): 68%, >40:1
(5 h): 80%, >40:1
(5 h): 75%, >40:1
3d (2.5 h): 61%, >40:1
CO2Et
CO2Et
CO2Et
CO2Et
Our initial attempt began with the coupling reaction of N-(2-
pyridyl)indole 1a and bromoallene 2a under the catalysis of
Mn(I). Inspiringly, the indole-C(2) propargylated product 3a,
bearing an all-carbon quaternary center, was observed in 36%
yield as the major product (Scheme 2). However, allene 4a
could also be detected in 12% yield. Base screening suggested
that K3PO4 was the best (see Table S1 in the Supporting
Information). To our delight, the addition of BPh3 (2.5 mol%) not
only promoted the conversion of the starting material, but also
enhanced the selectivity of 3a/4a further to 14:1. It is noteworthy
that the addition of H2O (10 mol%) lead to almost full conversion
affording 3a in 76% yield, with much higher selectivity (38:1).
Finally, by using BPh3 (5 mol%) as the cocatalyst, the formation
of 3a was further increased to 83% yield, with excellent
selectivity (>40:1).
Me
Br
N
N
N
N
Br
F
2-py
2-py
2-py
2-py
3e
3f[a]
3g
3h[a]
(5 h): 51%, 3:1
(5 h): 54%, 25:1
(5 h): 60%, >40:1
(5 h): 68%, >40:1
tertiary carbon center
CO2Et
CO2Et
CO2Et
CO2Et
N
N
N
Me
N
2-py
2-py
2-py
2-py
3j
(5 h): 82%, 30:1
3i (5 h): 80%, >40:1
3k (5 h): 81%, >40:1
3l (5 h): 71%, >40:1
OAc
O
OTs
OBn
N
N
nPr
nPr
N
nPr
N
nPr
2-py
2-py
2-py
2-py
3m (7 h): 91%, >40:1
3n (6 h): 94%, >40:1
3o (9 h): 93%, >40:1
3p (7 h): 90%, >40:1
92% yield for 1.087 g (7 h), >40:1
secondary carbon center
other DGs
CO2Et
CO2Et
CO2Et
CO2Et
O
CO2Et
10 mol% Mn(CO)5Br
2 equiv base
+
+
N
nPr
N
N
N
N
Br
1.5 equiv
2a
N
N
CO2Et
Me
2-py
DCE, 80 oC, 5 h
2-py
2-pym
CONMe2
2-py
2-py
4a
2-py
3a
3q (7 h): <5%[b]
3i' (5 h): 65%, >40:1
3i'' (5 h): -[c]
3r (5 h): 84%, >40:1
1a
base
BPh3
H2O
3a
4a
3a 4a
ratio of /
other heteroaromatic rings
(2.5 mol%)
(10 mol%)
CO2Et
CO2Et
2-py
CO2Et
CO2Et
K2CO3
K3PO4
36%
42%
12%
6%
3:1
7:1




O
2-py
S
[a]
56%
4%
14:1
K3PO4


N
S
N
[a]
2-py
76%
2%
38:1
2-py
K3PO4




[a,b]
K3PO4
3u[d] (5 h): 35%, >40:1
3v[d] (5 h): 41%, >40:1
3s
3t
83%
2%
>40:1
(5 h): 67%, >40:1
(5 h): 55%, 7:1
Late-stage Diversification
O
Scheme 2. Optimization of the reaction conditions. [a] Et2O was used as the
solvent. [b] BPh3 (5 mol%) was used. DCE = 1,2-Dichloroethane.
O
steroid
derivative
O
O
O
N
O
N
nPr
2-py
HN
O
H
N
nPr
N
nPr
H
H
2-py
2-py
from
lithocholic acid
With the optimal reaction conditions in hand, we turned to
studying the substrate scope (Scheme 3). Functional groups,
such as 5-OMe, 5-NO2, 5-CO2Me, 5-Br, 6-Br, and 6-F on the
benzene ring were well tolerated to afford the corresponding
products 3b-g in 54-75% yields, with good selectivities (25:1
to >40:1). The introduction of a substituent onto the C(3)-position
of the indole decreased both the yield and selectivity. Moreover,
a tertiary carbon center could also be constructed from tri-
substituted allenes, affording 3i-l in good yields (71-82%) with
excellent selectivities (30:1 to >40:1). The scope of
bromoallenes was also investigated, and found to be broad in
this approach as shown by the formation of 3m-p. Furthermore,
it is noteworthy that the propargylation could also occur to build
AcO
amino acid derivative
H
3y[e]
3w (5 h): 60%, 30:1
3x (5 h): 90%, >40:1
(12 h): 94%, >40:1
Scheme 3. Substrate scope. Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol),
Mn(CO)5Br (10 mol%), BPh3 (2.5-10 mol%), H2O (10-50 mol%), and K3PO4 (2
equiv) in Et2O (1 mL) at 60-80 oC. The ratio of 3/4 was determined from the
crude 1H NMR. [a] The reaction was run without H2O. [b] 1a was recovered in
95% yield. [c] 1i’’ was recovered in 95% yield. [d] The reaction was conducted
at 90 oC using the corresponding chloroallene instead of bromoallene. [e]
Mixed solvent (Et2O/DCE = 1:1) was used.
could be extended to other heteroaromatic systems, including
pyrrole, thiophene, and benzothiophene, with good selectivity
(up to >40:1). The propargylation reaction afforded 3w, bearing
an imide group, in 60% yield. The employment of α-amino acid
and lithocholic acid[22] derivatives afforded 3x and 3y in 90 and
94% yield, respectively, with >40:1 selectivity, implying the
potential application on late-stage diversification in biomolecular
and medicinal chemistry.
a
secondary carbon center in 3r, without any further
isomerization to the allene under basic conditions.[21] A survey of
the directing group showed that reaction worked equally well
with 2-pyrimidinyl as the directing group, while carbamoyl group
failed to promote such propargylation. Finally, this approach
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10.1002/anie.201710835
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COMMUNICATION
Terminal-alkyne formation is one of the crucial topics in
organic chemistry, but greatly challenging especially in C−H
activation reactions, due to the fact that they perform as active
coupling partners under many C−H activation catalysts,
including the Mn(I) catalyst.[15b,18a] However, to our great
surprise, the employment of a tri-substituted allene 2q in this
approach directly afforded the terminal alkyne 3z in 64% yield,
with satisfying selectivity (16:1; Scheme 4). This chemistry will
provide a direct and novel strategy to introduce terminal-alkyne
groups into molecules, implying broad applications in click
chemistry.
electron richness at C(2). This inductive effect has important
mechanistic implications for the reaction of the thiophene or
benzothiophene system (see Scheme 3).[23] However, the
selective insertion occurring at C(1) rather than C(3) is due to
the nature of the Mn(I) catalyst. In order to show the unique
catalytic activity of the manganese catalyst,
a series of
traditional C−H activation catalysts, including Pd, Rh, Ir, Co, Cu,
and Re complexes were tested under the standard reaction
conditions (see the Supporting Information). The results
indicated that none of these catalysts could promote this
transformation. Finally, a robustness screen was applied to
exhibit the functional group and heterocycle tolerance of this
approach (see the Supporting Information).[24]
10 mol% Mn(CO)5Br
2.5 mol% BPh3
+
Enzymatic kinetic resolution (EKR) is an efficient and
scalable approach to produce chiral secondary alcohols.[25]
Based on it, chiral propargylic alcohol (R)-6 was easily obtained
in 42% yield (Scheme 6). Subsequent transformations afforded
76% yield of chiral bromoallene (S)-2e with 97% ee on 5-gram
scale.[19] The employment of chiral bromoallene ((S)-2e, 97% ee)
in this approach afforded 81% yield of 3k with 91% ee. The axial
chirality in the bromoallene could be successfully transferred to
the central chirality at the propargylic position, which is difficult to
construct with other methodologies. The slight loss of
enantiomeric purity in chirality transfer was probably due to
reaction mechanism, rather than racemization process during
the reaction, since the same level of enantioselectivity was
detected after 3 h.
2 equiv Cs2CO3
N
N
Br
3Å M.S.
DCE, 80 oC, 5.5 h
2-py
2-py
1.5 equiv
3z: 64%, 16:1
1a
2q
Scheme 4. Synthesis of Terminal Alkyne.
To gain a deeper insight into the reaction mechanism, the
deuterium kinetic isotope effect (KIE) was determined from two
parallel kinetic experiments with a value of 1.10 (Scheme 5a).
These results indicate that the C−H bond cleavage is unlikely
involved in the rate-determining step. Moreover, intermolecular
competition experiments indicated that electron-rich indoles are
more reactive in this reaction (Scheme 5b). The reaction using a
simple allene (4) in place of bromoallene 2a could not realize the
subsequent insertion of allenyl C−C double bond into C−Mn
bond, leading to hydroarylated product 5 (Scheme 5c).[18d] These
observations show that the bromine atom on allene performs not
only as a leaving group, but also as a crucial element controlling
electronic distribution in the allene moiety. The presence of
bromine results in the electron deficiency of C(1) and C(3), while
enzymatic kinetic resolution
OH
OAc
n-C5H11
OH
n-C5H11
CALB
isopropenyl acetate
+
n-C5H11
toluene, rt, 18 h
6
rac-
6
(R)- : 42% yield
7
(S)- : 50% yield
i) Bromination
ii) Allene formation
76% for 2 steps
5 g scale
CO2Et
10 mol% Mn(CO)5Br
5 mol% BPh3
2 equiv K3PO4
H
CO2Et
(a) Parallel experiments (kinetic isotopic effect)
CO2Et
+
N
Br
1.5 equiv
2e
10 mol% Mn(CO)5Br
CO2Et
N
n-C5H11
20 mol% H2O
Et2O, 60 oC, time
5 mol% BPh3
2 equiv K3PO4
2-py
3k
2-py
H/D
+
N
Br
1.5 equiv
2a
1a
(S)- : 97% ee
N
5 h, 81% yield, 91% ee, >40:1
10 mol% H2O
DCE, 70 oC
KIE = 1.10
2-py
2-py
3a
3 h, 70% yield, 91% ee, >40:1
1a: recovered in 15% yield
1a or [D]-1a
CO2Et
Intermolecular competition experiments
(b)
MeO
Scheme 6. Chirality Transfer Experiments.
R
CO2Et 10 mol% Mn(CO)5Br
5 mol% BPh3
N
+
2-py
3b: 56%
CO2Et
2 equiv K3PO4
N
Br
0.3 mmol
2a
2-py
10 mol% H2O
+
Et2O, 80 oC, 1 h
In conclusion, we have developed a novel manganese(I)/
Lewis acid cocatalyzed direct C−H propargylation reaction with
high efficiency and selectivity. The propargylation reaction is
based on the manganese catalyst, which is earth abundant, and
an inexpensive metal. Lewis acid (BPh3) was introduced as the
cocatalyst to enhance the electrophilicity of bromoallene,
promoting not only the reactivity, but also the selectivity.
Catalytic amount of H2O was found to accelerate the reaction by
increasing the solubility of the base (K3PO4) in the solvent.
Furthermore, the substrate scope shows good functional-group
tolerance and potential applications on late-stage diversification.
Secondary, tertiary and even quaternary carbon centers could
be constructed at the propargylic position. Moreover, it is
noteworthy that the direct C−H propargylation is not only working
1b
R = OMe (
)
MeO2C
CO2Me (1d)
0.1 mmol for each
N
2-py
3d: 33%
The inductive effect of bromine
(c)
CO2Et
1
2 3
2a
+ - +
Br
H
CO2Et
vs.
CO2Et
+
N
H
N
standard conditions
2-py
2-py
1a
4
5
1a
1.5 equiv
was recovered in 83% yield
Scheme 5. Mechanistic Studies.
This article is protected by copyright. All rights reserved.

10.1002/anie.201710835
Angewandte Chemie International Edition
COMMUNICATION
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Acknowledgements
We acknowledge generous financial support from the Alexander
von Humboldt Foundation (C.Z.) and Alfried Krupp von Bohlen
and Halbach Foundation (J.L.S.). We are grateful to Philipp
Gerdt for experimental assistance. We also thank Andreas
Lerchen, Dr. Michael J. James, and Santanu Singha for fruitful
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DOI:10.1002/anie.201708271.
Keywords: Manganese • Lewis acid • C−H activation •
propargylation • bromoallene
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10.1002/anie.201710835
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Can Zhu, Jonas Luca Schwarz, Sara
Cembellín, Steffen Greßies, and Frank
Glorius*
Page No. – Page No.
Highly Selective Manganese(I)/Lewis
Acid Cocatalyzed Direct C−H
Propargylation Using Bromoallenes
A manganese(I)/Lewis acid cocatalyzed direct C−H propargylation with high selectivity
has been developed. BPh3 was discovered to not only promote the reactivity, but also
enhance the selectivity to afford the propargylation. Secondary, tertiary or even
quaternary carbon centers at the propargylic position could be directly constructed. Both
internal and terminal alkynes are easily accessible. The chirality was successfully
transferred from an axially chiral allene to the central chirality. The reactivity of the
manganese catalyst in this reaction was found to be unique comparing other transition
metal catalysts.
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