Lewis Base-Catalyzed Amino-Acylation of Arylallenes via C-N Bond Cleavage: Reaction Development and Mechanistic Studies

Article abstract of DOI:10.1021/acscatal.0c01000

Lewis base-catalyzed transformations of allenes have received much attention over the last decades. However, this type of reaction has so far been limited to activated allenes bearing an electron-withdrawing group. On the other hand, cleavage of an amide C-N bond to forge other chemical bonds has been widely reported but restricted to low atom economy due to the waste of the amine moiety of amides. We initiated a project of metal-catalyzed amino-acylation of allenes via cleavage of amide C-N bonds. Surprisingly, an amino-acylation of weakly activated aryl allenes was discovered via Lewis base catalysis, providing 2-methyl-3-aroylindole products, "privileged structures"in drug discovery. This is a unique example of Lewis base catalysis of weakly activated allenes, which was not reported yet. Extensive experimental and computational studies have been conducted to provide insight into the reaction mechanism. The nucleophilic addition of Lewis base catalyst to aryl allene is the rate-limiting step. A challenging [1,3]-proton transfer is realized by nitrogen anion intermediate assisted sequential [1,4]- and [1,6]-proton transfer in the reaction pathway.

Full text of DOI:10.1021/acscatal.0c01000

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Article
Lewis Base-Catalyzed Amino-Acylation of Arylallenes via C-N
Bond Cleavage: Reaction Development and Mechanistic Studies
Zheng-Bing Zhang, Yusheng Yang, Zhi-Xiang Yu, and Ji-Bao Xia
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01000 • Publication Date (Web): 13 Apr 2020
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ACS Catalysis
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Lewis Base-Catalyzed Amino-Acylation of Arylallenes via C−N Bond
Cleavage: Reaction Development and Mechanistic Studies
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Zheng-Bing Zhang,†,§ Yusheng Yang, ‡ Zhi-Xiang Yu,*,‡ and Ji-Bao Xia*,†,§
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis, Suzhou
Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), University of Chinese Academy of Sciences,
Chinese Academy of Sciences, Lanzhou 730000, China
‡Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
§University of Chinese Academy of Sciences, Beijing 100049, China
ABSTRACT: Lewis base-catalyzed transformations of allenes have received great attention over the last decades. However, this
type of reactions has so far been limited to activated allenes bearing an electron-withdrawing group. On the other hand, cleavage of
amide C−N bond to forge other chemical bonds have been widely reported, but restricted to low atom economy due to the wastage
of the amine moiety of amides. We initiated a project of metal-catalyzed amino-acylation of allenes via cleavage of amide C−N
bond. Surprisingly, an amino-acylation of weakly activated aryl allenes was discovered via Lewis base catalysis, providing 2-
methyl-3-aroylindole products, a “privileged structures” in drug discovery. This is a unique example of Lewis base catalysis of
weakly activated allenes which was not reported yet. Extensive experimental and computational studies have been conducted to
provide insight into the reaction mechanism. The nucleophilic addition of Lewis base catalyst to aryl allene is the rate-limiting step.
And a challenging [1,3]-proton transfer is realized by nitrogen anion intermediate assisted sequential [1,4]- and [1,6]-proton transfer
in the reaction pathway.
KEYWORDS: Lewis base catalysis, C−N bond cleavage, proton transfer, weakly activated allenes, 3-aroylindoles
catalyst, which kinetically disfavors the formation of a
Introduction
zwitterionic intermediate.8 To the best of our knowledge, only
The allenes are three-carbon functional groups possessing a
one stoichiometric addition reaction of weakly activated
1,2-diene moiety and serve as valuable synthetic precursors
phenylallene with tributylphosphine was reported in 1984
for the construction of highly complex target molecules of
furnishing a phosphacyclopropane product.9
biological and industrial importance.1 Coordinative activation
of the cumulated double bonds with metal catalyst is one of
the most popular reaction modes for transformation of allenes,
which facilitate the attack of nucleophiles to form a new C−C
Scheme 1. Two General Activation Modes for the
Transformation of Allenes
Mode A: Metal catalysis
or C−heteroatom bond in an inter- or intramolecular fashion
M
(Scheme 1, Mode A).2 Transiton-metal-catalyst, such as Pd,
Metal cat.
reactant
•
Rh, Ir, Ru, have been widely used in the conversion of allenes
by coordinative activation, mostly via π-allyl metal
intermediate.3 Because of their soft and carbophilic character,
the gold or platinum catalysts have also been widely used for
the selective activation of allenes in the cyclization reactions.4
Another important mode for allene activation is Lewis base
catalysis, also named nucleophilic catalysis (Scheme 1, Mode
B).5 This type of reaction starts from a nucleophilic addition of
allene with Lewis base catalyst, such as phosphine, to generate
Coordinative activation
various products
•
allene
Lewis base cat.
reactant
[LB]
Zwitterionic intermediate
Activated allenes (Previous work)
: electron-withdrawing group (CO2R, CN...)
Mode B: Lewis Base catalysis (Nucleophilic catalysis)
a
zwitterionic
intermediate.6,7
Countless
catalytic
transformations of allenes have been reported affording useful
products via Lewis base catalysis. However, all of these
reactions are limited to activated allenes bearing an electron-
withdrawing group, for example, allenyl esters. To date, there
is no example of catalytic transformations of non-activated or
weakly activated allenes via Lewis base catalysis, such as aryl
allenes or alkyl allenes. This may owe to the high activation
barrier of nucleophilic addition of the central carbon atom of
non-activated or weakly activated allene with Lewis base
The amide is a ubiquitous functional group with
numerous methods for its synthesis. However, it is noteworthy
that the amides feature only limited use as synthetic
intermediate. It comes as no surprise that the C−N bonds of
amide have high stability and rigidity due to the strong
resonance effect between the nitrogen lone pair and the anti-
bonding orbital (π*) of the carbonyl group.10 The selective
breaking C−N bond in amides has been recognized a
longstanding challenge in synthetic chemistry. Recently,
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considerable progress has been achieved for transition-metal
Page 2 of 11
Scheme 3. Amino-acylation of Allenes via Selective
Cleavage of Amide C−N Bond
catalyzed cleavage of amide C−N bonds.11 In particular,
various ketones have been successfully synthesized via
catalytic cross-coupling of amides with the organometallic
reagents12 or the unsaturated chemical compounds.13 And
transition-metal-free transamidation via cleavage of the amide
C−N bonds has also been developed.14 This strategy has
become a powerful tool to construct C−C or C−heteroatom
bonds. Despite these elegant precedents in transformation of
amides via cleavage of C−N bonds, all these reactions are
inherently restricted to low atom economy due to the wastage
of the amine moiety of amides (Scheme 2, type 1). In contrast,
the amino-acylation of multiple chemical bonds will be highly
desirable, as it incorporates both moieties of the amide into the
product (Scheme 2, type 2). These reactions were usually
achieved via electrophilic activation of the alkyne, followed
by N-addition of the amide to form a zwitterionic intermediate
and subsequent [1,3]-acyl migration.15 Unfortunately, there are
only limited reports in this area, even though there are some
other progresses showing that the amino-acylation of highly
active arynes16 and ynones17 with amides can be realized. In
this regard, development of new catalytic amino-acylation
reactions of multiple chemical bonds via cleavage of the
amide C−N bond is highly desirable.
1
2
3
4
5
6
7
8
a. Proposed reaction pathway (Hypothesis): Metal catalysis
O
•
migratory
insertion
non-activated allene
Ar
Metal cat.
Ar
Ar
[M]
O
reductive
elimination
N
N
Ar
•
or other isomers
O
Ar
9
N
Ar
[LB]
O

acyl
migration
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Ar
O
Ar
Ar
cyclization
Lewis base cat.
(PR3, DMAP)
Me
N
Ar
N
: Boc
b. Unexpected reaction pathway (This work): Lewis base catalysis
Results and Discussion
We designed and synthesized an arylallene containing
amide 1a as the starting material. Transition-metal-catalyzed
alcoholysis or Suzuki coupling reaction have been achieved
recently via cleavage of the amide C−N bond in this type of
amides.19 With 1a as the substrate, intramolecular amino-
acylation of allene was investigated with various transition
metal catalyst. To our delight, Rh-catalyzed amino-acylation
of 1a afforded the desired product 2a in 12% yield with N-
Scheme 2. Two Reaction Types for the Cleavage of Amide
C−N Bonds to Construct New Chemical Bonds
o
heterocyclic carbene (NHC) ItBu as ligand at 80 C (Table 1,
entry 1). Screening other metal catalysts did not improve the
Type 1: amine moiety left as waste by-product
Table 1. Reaction Developmenta
cross-coupling
esterification or transamidation
O
O
O
H
N
H
N
[M]
H
R
X
•
Ph
Me
+
+
Ar
R
Ar
X
10-20 mol % catalyst
X = O or N
O
solvent, 100 °C, 20-48 h
C–C formation
C–X formation
by-products
by-products
N
N
Ph

Boc
Boc
1a
O
2a
Ar
N
MeO
OMe
Me
Me
N
N
P
N
amino-acylation
N
N
tBu
tBu
O
N
Ar
N
OMe
P(4-MeO-C6H4)3
ItBu
DMAP
t (h)
20
PPy
C–C and C–N formation
Type 2: both moieties incorporate into the product
entry
1c
catalyst
solvent
THF
yield (%)b
12
Rh(cod)2OTf/ItBu
ItBu
Originally we planned an intramolecular amino-acylation
of allene by using transition metal catalyst (Scheme 3). We
proposed that an acylmetal-amido species could be generated
by oxidative addition of low-valent metal catalyst into the
amide C−N bond.11 The subsequent amino-acylation would be
achieved by coordination of this acylmetal-amido intermediate
to multiple chemical bond, followed by migratory insertion
and reductive elimination (Scheme 3a). However, we found
that an unexpected metal-free amino-acylation occurred
(Scheme 3b). Herein, we would like to report a novel
intramolecular amino-acylation of arylallenes via Lewis base
catalysis and C−N bond cleavage, affording the 2-methyl-3-
aroylindoles that have been recognized as “privileged structure”
in pharmaceutical industry.18. Lewis base catalysis of weakly
activated allenes has been achieved for the first time in this
research. The detailed mechanism is elucidated by control
experiments and DFT calculations.
2c
THF
20
31
3c
ItBu
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
20
33
4
ItBu
20
35
5
PPh3
20
trace
trace
38
6
P(n-Bu)3
PCy3
20
7
20
8
P(4-MeO-C6H4)3
DMAP
PPy
20
46
9
20
51
10
11d
12d
13e
14e,g
15e,h
20
48
DMAP
DMAP
DMAP
DMAP
-
48
37
48
61
THF
48
66 (63)f
THF
48
50
THF
48
0
aReaction conditions: 1a (0.1 mmol), catalyst (20 mol %), solvent (0.5 mL),
100 °C. bThe yield was determined by GC with n-dodecane as an internal
standard. c80 °C. dSolvent (1 mL). eTHF (2 mL) fIsolated yield in the
parenthesis. gWith 10 mol % DMAP. hWithout catalyst.
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yield of the 2a (see Table S1 in Supporting Information). the hetero-aroyl group, such as furan-2-carbonyl and
1
2
3
4
5
6
7
8
Surprisingly, the control experiment showed that 2a was
obtained in 31% yield with ItBu as catalyst without transition-
metal-catalyst (Table 1, entry 2). The yield of 2a was
thiophene-2-carbonyl, could also be tolerated, leading to the
corresponding products 2w and 2x in 82% and 80% yield.
Synthetic Application. To demonstrate the synthetic utility of
this new methodology, 2-methyl-3-aroylindole product 2a was
converted into several useful synthetic intermediates via
common manipulations (Figure 1). The Boc protecting group
can be easily removed under mild conditions
(K2CO3/MeOH/H2O), subsequent bromination with N-
bromosuccinimide (NBS) afforded 3H-indole 3 in overall 74%
yield by two steps. Alternatively, a direct bromination of 2a
with NBS gave benzilic bromide 4 in 83% yield. Furthermore,
by sequential Wittig reaction and Boc deprotection, 3-alkenyl
indole 5 was obtained easily in 88% yield. In addition, routine
reduction of 2a with NaBH4 generated the corresponding
o
increased to 35% when the reaction was performed at 100 C
in 1,4-dioxane (Table 1, entry 4). Because transformations of
activated allenes bearing an electron-withdrawing group via
Lewis base catalysis have been broadly investigated, we
speculated that the ItBu might play a role of Lewis base
catalyst in this reaction due to its good σ-donor property and
the conjugated effect of arylallene. Phosphines were
subsequently tested because they are the most common Lewis
base catalysts in the transformation of activated allenes. The
trace amount of 2a was observed with triphenylphosphine or
tributylphosphine (Table 1, entries 5 and 6). However, the
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electron-rich
tricyclohexylphosphine
and
tri(4-
alcohol 6 in excellent yield.
O
methoxyphenyl)phosphine yielded 2a in 38% and 46% yield,
respectively (Table 1, entries 7 and 8). We then turned to
pyridine-based Lewis base catalyst and found that the yield of
2a was increased to 51% when the readily available and
bench-stable 4-dimethylaminopyridine (DMAP) was used
(Table 1, entry 9). Different solvents were then examined (see
Table S1 in Supporting Information). The moderate yields of
2a were obtained with THF, CH3CN, and toluene, but 2a was
not detected with the protonic solvent, such as MeOH. Further
evaluation of the reaction concentrations showed that the yield
of 2a could be improved to 66% in THF at lower
concentration (0.05 M) (Table 1, entry 13). The yield was
decreased to 50% when lowering the catalyst loading to 10
mol % (Table 1, entry 14). Finally, a control experiment
revealed the importance of the catalyst, and no reaction
occurred in the absence of Lewis base catalyst (Table 1, entry
15).
With the suitable reaction conditions in hand, we explored
the scope of different N-(ortho-allenylaryl)amides (Table 2).
The electronic effects of different aniline substituents were
first examined. Introduction of the electron donating groups,
such as p-Me, p-OMe, and p-Ph, to the aniline moiety of 1 led
to the corresponding products 2b, 2c and 2d in moderate to
good yields (58-74%). The substitutions of electron-
withdrawing group (p-CF3 or p-CN) on the aryl ring of the
aniline moiety provided 2e and 2f in 86% and 79% yield. The
halogen atoms were also well tolerated (2g and 2h). Notably,
the good functional group tolerance makes this method very
useful for the synthesis of highly functionalized 3-aroylindoles.
The substrate with meta-Me on the aryl ring of aniline gave 2i
in moderate yield. However, a trace amount of product 2j was
obtained with the substrate bearing methyl group at the ortho-
position of aniline moiety, presumably due to the steric effect.
Furthermore, the 2-ethyl-3-aroylindole 2k was obtained in
moderate yield with corresponding 1k (R = Me) as substrate.
Finally, the Boc group was found essential for the successful
C−N bond cleavage. When the substrate 1l without N-Boc
protection was used as substrate, no C−N bond cleavage was
detected and a direct addition product 2-methyl indole 2l was
obtained in good yield.
O
Ph
Br
a) K2CO3
MeOH/H2O, 70 o
b) NBS, DCM, rt
c) NBS, (PhCO)2O
CCl4, 80 o
Br
Ph
C
C
Me
N
N
Boc
3
O
4
, 83%
, 74%
Ph
Me
Boc
N
2a
HO
Ph
Me
Ph
d) (PPh3)3MeBr
f) NaBH4
MeOH/THF, rt
n-BuLi, THF, 0 °C
Me
e) K2CO3, 70 °C
N
N
H
Boc
5
6
, 95%
, 88%
Figure 1. Transformations of 2-methyl-3-aroylindole 2a
2-Methyl-3-aroylindole is one of the “privileged
structures” in drug discovery due to their excellent capability
of binding to many receptors with high affinity.18 For example,
Pravadoline (WIN 48098), an antiinflammatory and analgesic
drug, contains the core structure of 2-methyl-3-aroylindole.20
By Pd-catalyzed cross-coupling and the following acylation,
1n was easily prepared in two steps by one column separation.
from commercially available reagents. Then, DMAP-catalyzed
amino-acylation of 1n afforded 2n in good yield under the
standard conditions. With 2n as the substrate, the pravadoline
was easily obtained in 77% yield by two steps through Boc
deprotection and sequent substitution reaction with the
corresponding alkyl bromide (Scheme 4).
Scheme 4. Synthesis of Antiinflammatory and Analgesic Drug
Pravadoline
a. allenylSn(n-Bu)3 (1.5 equiv)
•
Pd2(dba)3 (2 mol %), P(2-furyl)3 (20 mol %)
CuI (10 mol %), DMF, rt, 2 h
I
O
Boc
N
H
b. 4-methoxybenzoyl chloride (3.1 equiv)
DMAP (25 mol %), Et3N (2.2 equiv)
DCM, 0 °C - rt, 12 h
N
Boc
OMe
OMe
1n
, 70%
DMAP (20 mol %)
THF, 100 °C, 48 h
O
a. K2CO3 (3 equiv)
MeOH/H2O, 70 °C, 2 h
O
Next, we investigated the scope of the acyl group of 1.
The aroyl moiety bearing electron-donating groups (Me, OMe)
and electron-withdrawing groups (CO2Me, NO2, CF3) are well
tolerated affording the corresponding 3-aroylindoles in
moderate to good yields (2m−2q, 44−72%). The reaction
tolerated halogen atoms (F, Cl, Br) at the para-, meta-, and
ortho- positions of phenyl in aryl group (2r−2u). Moreover,
b. NaH (1.1 equiv)
N
OMe
Me
Br
Me
N
N
O
N
Boc
2n
(1.2 equiv)
DMF, rt, 12 h
O
Pravadoline
, 77%
, 72%
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Table 2. Substrate Scope of Intramolecular Amino-acylation of Allenes via C−N Bond Cleavagea
1
2
R
Me
Me
O
N
N
3
4
5
6
•
Ar
DMAP (20 mol %)
Ar
R
O
THF, 50-120 °C, 24-48 h
Ar
N
N
Ar
: H or Me
Boc
R
DMAP
Boc
1
2
7
8
Aniline functional group
9
O
O
O
O
O
O
Me
MeO
Ph
F3C
NC
Ph
Ph
Me
Ph
Me
Ph
Ph
Ph
Me
Ph
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
N
Me
N
N
N
N
N
Boc
Boc
Boc
Boc
Boc
Boc
b
c
d
2a
, 63%, 52%
2b
2c
2d
2e
2f
, 79%
, 59%
O
, 58%
, 74%
O
, 86%
O
O
O
F
Cl
Ph
Ph
Ph
Me
Ph
Me
Me
Me
N
Me
Me
Me
N
N
N
N
N
Me
O
Ph
Boc
Boc
Boc
Boc
Boc
e
f
g
h
i
2g
2h
2i
2j
2k
2l
, 86%
, 92%
, 75%
, 47%
, trace
, 48%
Acyl functional group
O
O
O
O
O
Me
OMe
NO2
CF3
CO2Me
Me
N
Me
Me
Me
Me
N
N
N
Boc
N
Boc
Boc
Boc
Boc
2o
2m
2n
2p
2q
, 64%
, 72%
, 68%
, 59%
, 44%
Cl
Br
O
O
O
O
O
X
X
Me
Me
Me
Me
Me
N
N
N
N
N
Boc
Boc
Boc
Boc
Boc
2r
2t
2u
2v
2w
X = F
, 70%
, 57%
, 34%
, 36%
X = O
X = S
, 82%
2s
2x
X = Br
, 46%
, 80%
aAll reactions were conducted with 1 (0.1 mmol), DMAP (20 mol %) in THF (2 mL) at 100 °C for 48 h and isolated yield was provided unless otherwise noted. bWith
1 mmol 1a. cAt 70 °C, 36 h. dAt 50 °C, 24 h eAt 60 °C, 36 h. fAt 70 °C, 24 h. gAt 120 °C, 36 h. h30 mol % DMAP, THF (1 mL). iWith corresponding ArNH(COPh) 1l
Mechanistic Study. To gain the insight into the reaction
mechanism, several control experiments were performed. In
order to explore the possibility of a radical mechanism,21 the
radical inhibiting or trapping experiment was first conducted.
When the 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
used as an additive under the standard conditions, there is no
effect on the yield of 2a (Scheme 5a). This result indicates that
the reaction does not proceed through a radical pathway. Next,
the crossover reaction was carried out with 1b and 1n as the
substrates. The products 2b and 2n were obtained, and no
crossover product 2bn or 2nb was observed (Scheme 5b). This
result demonstrates that the amino-acylation of allene occurs
in an intramolecular fashion.
Then, the deuterium labeling experiments were
performed to understand the mechanism. The intramolecular
amino-acylation of α-deuterium labeled allene deuterio-1a (73%
2H) afforded deuterio-2a smoothly under the standard
conditions, which incorporates a single deuterium atom (60%
2H) at the 2-methyl group of the product (Scheme 6a). We
then performed the crossover deuterium scrambling
could exchange with active hydrogen in the proton transfer
process, such as the NH intermediate or the heteroatom anions.
Scheme 5. Control Experiments
a) Radical-trapping experiment
O
•
Ph
DMAP (20 mol %)
O
+
N
O
THF, 100 °C, 48 h
Me
N
N
Ph
Boc
Boc
(3 equiv)
2a
1a
, 64%
O
b) Crossover experiment
O
Me
Me
•
Ph
Ar
Me
O
Me
N
Me
N
N
Ph
Boc
Boc
Boc
1b
2b
2bn
, 54%
, 0%
DMAP (20 mol %)
THF, 100 °C, 48 h
+
•
+
O
O
Ar
Me
Ph
O
2
experiment with deuterio-1a (73% H) and 1n, leading to the
Me
N
N
N
Ar
2
2
products of deuterio-2a (40% H) and deuterio-2n (30% H)
under the standard conditions (Scheme 6b). The result
indicates that there may be a reaction intermediate which
Boc
2n
Boc
Boc
1n
Ar = 4-MeO-C6H4,
2nb
, 0%
, 62%
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Scheme 7. Proposed Mechanism
Furthermore,
a deuterium scrambling experiment with
2
O
DMAP
1
2
3
4
5
6
7
8
substrate 1n and deuterio-2a (40% H) was performed to rule
out the possible deuterium transfer from the relatively active
2-methyl group of 3-aroylindole product (Scheme 6c).22 As
expected, the amino-acylation product 2n was obtained
without deuterium incorporation and the deuterio-2a (40% 2H)
was recovered in 95% yield. Finally, the amino-acylation of
1a was carried out in the presence of 5 equivalent of
deuterium oxide (D2O), which afforded the D3-2n as the
•
Ph
Me
Me
Me
O
N
N
N
Ph
Boc
2a
Boc
1a
N
[DMAP]
DMAP
O
Ph
Me
O
2
[DMAP]
N
N
Ph
product incorporated three deuterium atom (71% H) at the 2-
9
Boc
INT6
Boc
INT1
methyl group of the product (Scheme 6d). This result indicates
that a trace amount of water as proton shuttle may assist the
proton transfers or an active reaction intermediate that could
exchange with active hydrogen exists in the reaction pathway.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
C-N bond
formation
C-C bond
formation
O
Ph
[DMAP]
[DMAP]
O
Scheme 6. Deuterium Labeling Experiments and Scrambling
Experiments
N
Ph
N
H
Boc
INT2
Boc
INT5
1a
a) Deuterium labeling experiment with deuterio-
C-N bond
cleavage
O
Ph
O
Ph
H
O
[1,6]-proton
transfer
•
Ph
D
73% 2
H
[DMAP]
[DMAP]
DMAP (20 mol %)
D
60% 2
H
Boc
THF, 100 °C, 48 h
N
N
NH
N
"standard conditions"
Boc
[1,4]-proton
transfer
Boc
INT4
Boc
INT3
Ph
O
1a
2a
deuterio-
deuterio- , 64%
1a 1n
b) Deuterium scrambling experiment with substrate deuterio- and
73% 2
0.6
0.5
0.4
0.3
0.2
0.1
0
H
O
O
•
•
F
"standard
Ph
D
Ar
D
conditions"
D
+
+
Boc
Boc
O
N
N
N
N
Boc
Boc
Ph
O
Ar
OMe
40% 2
H
30% 2
H
Me
Ar = 4-MeO-C6H4
2a
deuterio- , 54%
2n
deuterio- , 47%
1a
1n
deuterio-
H
1n
2a
c) Deuterium scrambling experiment with substrate
and product deuterio-
-0.1
-0.1
0
0.1
0.2
0.3
0.4
O
O
Ar
+
O
•
"standard
Ph
Substitution Constant σm
Ph
D
conditions"
O
+
D
Me
N
N
N
N
Ar
Boc
Boc
Boc
Figure 2. Hammett plot of kinetic competition experiments
40% 2
H
40% 2
H
Boc
Ar = 4-MeO-C6H4
2a
deuterio- , 95%
2n
, 50%
1n
2a
deuterio-
Finally, expulsion of DMAP produces the amino-acylation
product 2a and closes the Lewis base catalytic cycle. The
deuterium labeling and scrambling experiments corroborates a
sequential [1,4] and [1,6]-proton transfer in the proposed
catalytic cycle (Scheme 6). However, we are not sure whether
a trace amount of water assists the proton transfer process or
not. Furthermore, The hammett plot of kinetic competition
experiments showed a good positive linear effect when the
plot is derived from the meta-position of allenes σm values
(Figure 2. for details see Figure S1, S2, and S3 in Supporting
Information). This indicates that the rate-determine step of this
amino-acylation reaction may be the nucleophilic addition of
DMAP to allene.
1a
d) Deuterium scrambling experiment with
in the presence of D2O
O
•
DMAP (20 mol %)
D2O (5.0 equiv)
Ph
O
THF, 100 °C, 48 h
71% 2
H
CD3
N
N
Ph
Boc
Boc
1a
2a
D3- , 50%
Based on the mechanistic studies, the following reaction
pathway was proposed via Lewis base catalysis as depicted in
Scheme 7. The reaction starts with nucleophilic addition of
DMAP to aryl allene 1a, affording the pyridinium enamine
INT1.23 This zwitterionic intermediate then undergoes
nucleophilic addition to the amide’s carbonyl to give
intermediate INT2. Subsequent C−N bond cleavage of the
hemiaminal gives the intermediate INT3, which can be
regarded as a deprotonated amine. We have shown that a
direct allylic [1,3]-proton transfer is rather difficult due to the
high ring strain in the transition state.24 Thus, a successive [1,4]
and [1,6]-proton transfer generates the α,β-unsaturated ketone
INT5. The following nucleophilic addition of nitrogen anion
to β- position of α,β-unsaturated ketone results in INT6.
DFT Calculations
To further elucidate the reaction mechanism and the
proton transfer processes, we performed the density functional
theory (DFT) calculations (Figure 3). We choose 1a as the
substrate and DMAP as the catalyst to investigate the reaction
mechanism. Firstly, the nucleophilic addition of DMAP to 1a
generates the zwitterionic intermediate INT1 (the Gibbs
energy of activation for this step is 28.3 kcal/mol).
Subsequently, the intramolecular nucleophilic addition of the
zwitterionic species to the carbonyl carbon from different
sides occurred to give INT2 (via TS2) and INT2'
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O
[DMAP]
Ph
1
2
3
4
5
6
7
8
G
in kcal/mol.
H
[DMAP]
H
O
[DMAP]
Boc
TS-1,3
Boc
O
N
N
O
Ph
Ph
N
Ph
TS1
48.8
Boc
[DMAP]
[DMAP]
TS2'
28.3
H
O
NH
Boc
26.8
[DMAP]
O
N
Ph
N
Ph
H
O
Boc
[DMAP]
TS-L
22.2
O
O
Ph
H
TS2
21.7
Ph
Ph
N
[DMAP]
TS3'
20.1
[DMAP]
O
Boc
Boc
9
TS6
19.1
TS4
18.4
Me
Me
17.1
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
N
TS5
17.9
15.4
Boc
INT2'
Boc
INT1
Ph
[DMAP]
[DMAP]
8.5
6.9
H
[DMAP]
DMAP
INT2
O
INT3
N
[DMAP]
O
N
Ph
Boc
O
Boc
TS7
-6.4
5.1
INT5
N
Ph
•
H
Boc
0.0
1a
O
[DMAP]
-0.4
Ph
H
N
Ph
Boc
Me
Me
N
INT4
N
N
Boc
O
Ph
N
Boc
-12.2
INT6
O
Ph
[DMAP]
Ph
O
[DMAP]
O
Ph
N
H
DMAP
NH
Boc
O
Boc
Ph
[DMAP]
N
Me
N
-35.3
2a
Boc
Boc
Benzoyl Migration
Proton Transfer
Cyclization
Figure 3．Gibbs energy profile for the reaction of substrate 1a under the catalysis of DMAP. Computed at the SMD(THF)/M06-
2X/6-311+G(d,p)//M06-2X/6-31+G(d,p) level.
(via TS2'), respectively. The Gibbs energy of activation
involving TS2 is 6.3 kcal/mol, whereas this value for addition
reaction involving TS2' is 11.4 kcal/mol, indicating that
formation of INT2 is favored. After that, INT2 undergoes
fragmentation, by breaking a C−C bond to give INT3, in
which a NBoc anion is generated. This is a barrierless process
because scanning the potential energy surface of this C−C
bond breaking is a downhill process without involving a
transition state. It is easy for INT3 to undergo the
intramolecular [1,4]-proton transfer forming INT4 (the Gibbs
energy of activation for this step is 11.5 kcal/mol). Then, an
intramolecular [1,6]-proton transfer could form INT5 with a
NBoc anion (the Gibbs energy of activation for this step is
18.3 kcal/mol). INT4 might also expel DMAP catalyst to
generate the allene intermediate. However, the Gibbs energy
of activation for this step is 22.6 kcal/mol (via TS-L), which is
higher than that of the intramolecular [1,6]-proton transfer of
forming INT5. Comparing with the intramolecular [1,4]- and
[1,6]-proton transfers, assisted with NBoc anion, the direct
[1,3]-proton transfer is quite difficult (the Gibbs energy of
activation for this step is 41.9 kcal/mol, via TS-1,3). The
crossover deuterium labeling experiments could be explained
by the generation of INT4 that contains an acidic hydrogen
which can undergo hydrogen exchange intermolecularly in the
reaction process (Scheme 6b and 6c). The nucleophilic
addition of nitrogen anion in INT5 to β-position of α,β-
unsaturated ketone gives INT6 (the Gibbs energy of activation
for this step is 14.0 kcal/mol). Finally, elimination of the
DMAP via TS7 affords product 2a (the Gibbs energy of
activation for this step is 5.8 kcal/mol). The computations
suggest that the nucleophilic addition of DMAP to allene is the
rate-limiting step, which is consistent with the kinetic
competition experiments (Figure 2).
shown that if the proton transfers (for example, [1,2]- and [1,3]-
proton transfers) are very difficult, and water or other proton
sources are needed to catalyze these processes.24 If these
proton transfer processes are faster than diffusion controlled
process, there is no water assisted proton transfer. However, if
the proton transfer processes are slower than diffusion
controlled process, then there could be a competition between
direct proton transfer and water-assisted proton transfer. Thus,
to verify whether the proton shifts can also be assisted by a
trace amount of water, we considered the water-assisted
pathway (Figure 4). Both [1,4] and [1,6]-proton transfer
processes can be assisted by water in a concerted
O
O
[DMAP]
Ph
Ph
[DMAP]
G
H
H
in kcal/mol.
O
H
H
O
TS9
25.0
N
N
H
Boc
H
Boc
TS8
18.2
H2O
H2O
H2O
H2O
6.9
INT3
O
5.1
Ph
[DMAP]
-0.4
INT5
H
N
INT4
O
Ph
Boc
O
Ph
[DMAP]
[DMAP]
N
H
NH
Boc
Boc
Figure 4 Gibbs energy profile for the proton transfer assisted by
water. Computed at the SMD(THF)/M06-2X/6-311+G(d,p)//M06-
2X/6-31+G(d,p) level.
In the above discussion, we don’t consider the water
catalysis in the proton transfer processes. Previously, we have
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pathway.25 The reaction barrier of [1,4]-proton transfer is 11.3
To further understand the difference of weakly activated
1
2
3
4
5
6
7
8
kcal/mol (TS8), which is quite similar to that of the
intramolecular [1,4]-proton transfer pathway (11.5 kcal/mol,
TS4 in Figure 3). However, for the [1,6]-proton transfer
process assisted by water, the reaction barrier is 25.4 kcal/mol
(TS9), which is relatively higher than the intramolecular [1,6]-
proton transfer pathway (18.3 kcal/mol, TS5 in Figure 3).
These calculations indicate that the [1,4]-proton transfer might
be assisted by a trace amount of water in solvent, which can
explain the deuterium labeling experiments in Scheme 6 that
deuterium and hydrogen can exchange intermolecularly. Also,
we have to mention that direct protonations of INT4 and INT5
by water are energetically disfavored compared to the water-
assisted proton transfers in Figure 4 and these can be ruled out
(see Supporting Information).
allenes, parent allene, and activated allenes bearing an
electron-withdrawing group, we compared the reactivity of
different allenes with DMAP in the zwitterionic pyridinium
enamine intermediate formation step by the density functional
theory
(DFT)
calculations.
When
the
N-(ortho-
allenylphenyl)amide 1a is used as the substrate, the activation
barrier for nucleophilic additon of DMAP to the allene is as
high as 28.3 kcal/mol, which is almost the same as phenyl
allene 9 (Figure 5a and b). In comparision with the parent
allene 15, the activation barrier of 1a is 2.5 kcal/mol less,
which indicates phenyl group have limited capacity to activate
the allene (Figure 5c). However, when an ester group is
introduced into the parent allene, the corresponding allenyl
ester 16 has decressed activation barrier of nucleophilic
addition (about 22.1 kcal/mol), which demonstrates an
electron-withdrawing group on the allene kinetically favors
the formation of a zwitterionic intermediate (Figure 5d). These
theoretical results are consistent with the observed reactivities
of allenes in Scheme 8. These results suggest that only
increasing the reaction temperature is not responsible for
stepping over the inherent obstacle of nucleophilic catalysis of
the weakly activated allenes.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Further Study
To gain insight into the inherent distinction between
weakly activated allenes and activated allenes bearing an
electron-withdrawing group in Lewis base catalysis, we
performed experiments to compare the reactivity of different
allenes though γ-addition reaction with sulfonamide (TsNH2).
Phosphine-catalyzed γ-addition of activated allene 7 bearing
an electrion-withdrawing ester group afforded the desired
product 8 in excellent yield at room temperature (Scheme
8a).26 As expected, weakly activated allenes showed very low
reactivity in this Lewis base-catalyzed γ-addition reaction.
Addition of phenylallene 9 with TsNH2 afforded 10 in less
than 3% yield at 100 °C, leaving untouched starting material
in the reaction (Scheme 8b). When the arylallene 11 bearing
an electron-withdrawing nitro group at the para-position of
phenyl was used to test γ-addition of arylallene, the moderate
yield of 12 was obtained at 100 °C (Scheme 8c). However, a
trace amount of product 14 was observed when γ-addition of
the allene 13 with TsNH2 in the presence of Lewis base
catalyst under the standard amino-acylation conditions
(Scheme 8d). These results demonstrate that the reactivity of
aryl allenes is much lower than activated allenes and the Boc-
N-COPh group on the arene is not an electron-withdrawing
group for the activation of allenes.
[DMAP]
•
Me
Me
TS1
N
G = 28.3 kcal/mol
O
O
+
(a)
G = 15.4 kcal/mol
N
Ph
N
Ph
N
Boc
INT 1
Boc
1a
DMAP
Me
Me
[DMAP]
TS11
G = 28.2 kcal/mol
N
•
+
(b)
G = 17.1 kcal/mol
N
9
INT 7
DMAP
Me
Me
TS12
G = 30.8 kcal/mol
N
[DMAP]
+
+
(c)
(d)
•
G = 20.0 kcal/mol
N
15
INT 8
DMAP
Me
Me
Scheme 8. Lewis Base Catalyzed γ-Additions of Sulfonamide
to Allenes
TS13
G = 22.1 kcal/mol
[DMAP]
N
•
O
O
G = 3.9 kcal/mol
Me
OMe
OMe
N
O
O
PPh3 (20 mol %)
25 oC, Et2O, 12 h
•
Me
NHTs
16
INT 9
DMAP
TsNH
TsNH
+
+
(a)
(b)
2
2
OEt
OEt
Figure
5
Computed
at
the
SMD(THF)/M06-2X/6-
8
, 96%, E/Z = 3:7
7
311+G(d,p)//M06-2X/6-31+G(d,p) level.
LB Cat. (20 mol %)
100 oC, THF, 48 h
•
NHTs
Conclusion
9
DMAP
P(4-MeO-C6H4)3
10
10
, <3%
, <3%
In summary, we have developed a novel Lewis base-
catalyzed amino-acylation of weakly activated allenes to
produce 2-methyl-3-aroylindoles, one of the “privileged
structures” in pharmaceutical industry. Both acyl and amine
moieties are incorporated into the products via selective
cleavage of amide C−N bond, overcoming traditional amine
moiety as wastage after C(O)−N bond cleavage. The Lewis
base catalysis of weakly activated allenes is achieved for the
first time. The readily available simple DMAP was used as a
nucleophilic catalyst. This protocol provides a simple and
efficient strategy for the synthesis of biologically important 2-
methyl-3-aroylindoles with a range of substrates. Based on
experimental and computational studies, we have proposed a
reasonable mechanism for this amino-acylation reaction.
LB Cat. (20 mol %)
100 oC, THF, 48 h
•
NHTs
(c)
TsNH
+
+
2
O2N
O2N
11
DMAP
12
, 5%
12
P(4-MeO-C6H4)3
, 34%
•
NHTs
(d)
LB Cat. (20 mol %)
100 oC, THF, 48 h
Boc
Boc
Ph
TsNH
2
N
N
Ph
O
O
13
DMAP
P(4-MeO-C6H4)3
14
14
, trace
, trace
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Catalyzed Intramolecular Amination and Hydroamination Reactions
Several conclusions can be drawn from this study. (1) The
direct [1,3]-proton transfer is quite difficult. However, this
process could be facilitated by a successive [1,4]- and [1,6]-
proton transfer which are facile. Likes proton shuttles,
nitrogen anion intermediate assists the proton transfer
processes via the protonation/deprotonation mechanism. (2)
Although direct [1,3]-proton transfer process could be assisted
by a trace amount of water, the process is less favorable than
intramolecular successive [1,4]- and [1,6]-proton transfer (For
details, see Figures S4 and S5 in Supporting Information). (3)
The nucleophilic addition of Lewis base catalyst to weakly
activated allenes is the rate-limiting step. Due to the high
activation barrier of addition of Lewis base catalyst to allene,
nucleophilic catalysis of weakly activated allenes is
challenging. However, this hurdle may be got over though
generating thermodynamically stable intermediates or
of Allenes. Adv. Organomet. Chem. 2018, 69, 1−71; (d) Ye, J.; Ma, S.
Palladium-Catalyzed Cyclization Reactions of Allenes in the Presence
of Unsaturated Carbon-Carbon Bonds. Acc. Chem. Res. 2014, 47,
989−1000; (e) Han, X.-L.; Lin, P.-P.; Li, Q. Recent Advances of
Allenes in the First-Row Transition Metals Catalyzed C−H Activation
Reactions. Chin. Chem. Lett. 2019, 30, 1495−1502.
1
2
3
4
5
6
7
8
3.
(a) Schultz, R. G. π-Allylic Complexs from Allene.
Tetrahedron 1964, 20, 2809−2813; (b) Backvall, J.-E.; Jonasson, C.
Palladium-Catalyzed 1,2-Oxidation of Allenes. Tetrahedron Lett.
1997, 38, 291; (c) Parisotto, S.; Deagostino, A. π-Allylpalladium
Complexes in Synthesis: An Update. Synthesis 2019, 51, 1892−1912.
Also see ref 2a and 2d.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4.
Recent reviews: (a) Mascarenas, J. L.; Varela, I.; Lopez, F.
Allenes and Derivatives in Gold(I)- and Platinum(II)-Catalyzed
Formal Cycloadditions. Acc. Chem. Res. 2019, 52, 465−479; (b)
Marin-Luna, M.; O., N. F.; Silva Lopez, C. Gold-Catalyzed
Homogeneous (Cyclo)Isomerization Reactions. Front Chem. 2019, 7,
296−318; (c) Muratore, M. E.; Homs, A.; Obradors, C.; Echavarren,
A. M. Meeting the Challenge of Intermolecular Gold(I)-Catalyzed
Cycloadditions of Alkynes and Allenes. Chem. Asian. J. 2014, 9,
3066−3082; (d) Yang, W.; Hashmi, A. S. Mechanistic Insights into
the Gold Chemistry of Allenes. Chem. Soc. Rev. 2014, 43, 2941−2955;
(e) Munoz, M. P. Silver and Platinum-Catalysed Addition of O−H and
N−H Bonds to Allenes. Chem. Soc. Rev. 2014, 43, 3164−3183; (f)
Krause, N.; Winter, C. Gold-Catalyzed Nucleophilic Cyclization of
products. This may provide
a good strategy for the
transformation of non-activated or weakly activated allenes
via Lewis base catalysis in the future.
AUTHOR INFORMATION
Corresponding Author
Ji-Bao Xia: jibaoxia@licp.cas.cn
Zhi-Xiang Yu: yuzx@pku.edu.cn
Functionalized Allenes:
Heterocycles. Chem. Rev. 2011, 111, 1994−2009.
5. For selected reviews on nucleophilic phosphine catalysis:
a Powerful Access to Carbo- and
ORCID
(a) Lu, X.; Zhang, C.; Xu, Z. Reactions of Electron-Deficient Alkynes
and Allenes under Phosphine Catalysis. Acc. Chem. Res. 2001, 34,
535−544; (b) Methot, J. L.; Roush, W. R. Nucleophilic Phosphine
Organocatalysis. Adv. Synth. Catal. 2004, 346, 1035−1050; (c) Nair,
V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T.
Engaging Zwitterions in Carbon−Carbon and Carbon−Nitrogen Bond-
Forming Reactions: A Promising Synthetic Strategy. Acc. Chem. Res.
2006, 39, 520−530; (d) Cowen, B. J.; Miller, S. J. Enantioselective
Catalysis and Complexity Generation from Allenoates. Chem. Soc.
Rev. 2009, 38, 3102−3116; (e) Zhao, Q.-Y.; Lian, Z.; Wei, Y.; Shi, M.
Development of Asymmetric Phosphine-Promoted Annulations of
Allenes with Electron-Deficient Olefins and Imines. Chem. Commun.
2012, 48, 1724−1732; (f) Wang, Z.; Xu, X.; Kwon, O. Phosphine
Catalysis of Allenes with Electrophiles. Chem. Soc. Rev. 2014, 43,
2927−2940; (g) Ni, H.; Chan, W. L.; Lu, Y. Phosphine-Catalyzed
Asymmetric Organic Reactions. Chem. Rev. 2018, 118, 9344−9411;
(h) Guo, H.; Fan, Y. C.; Sun, Z.; Wu, Y.; Kwon, O. Phosphine
Organocatalysis. Chem. Rev. 2018, 118, 10049−10293.
Ji-Bao Xia: 0000-0002-2262-5488
Zhi-Xiang Yu: 0000-0003-0939-9727
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, DFT calculations, and characterization
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENT
We appreciate the funding for this work provided by the NSFC
(21772208, 21933003), Key Research Program of Frontier
Sciences of CAS (QYZDJSSW-SLH051), and Key Laboratory for
OSSO in LICP.
6.
Lu., X. Phosphine-Catalyzed Cycloaddition of 2,3-Butadienoates or
2-Butynoates with Electron-Deficient Olefins. Novel [3+2]
Selected examples on phosphine catalysis: (a) Zhang., C.;
A
Annulation Approach to Cyclopentenes. J. Org. Chem. 1995, 60,
2906−2908; (b) Zhu, X. F.; Lan, J.; Kwon, O. An Expedient
Phosphine-Catalyzed [4+2] Annulation: Synthesis of Highly
Functionalized Tetrahydropyridines. J. Am. Chem. Soc. 2003, 125,
4716−4717; (c) Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.;
Huang, F.; Liu, S.; Li, Y.; Yu, Z. -X. An Unexpected Role of a Trace
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Selected examples besides phosphine catalysis: (a) Zhao, G.-
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Mechanism, Regioselectivity, and the Kinetics of Phosphine-
Catalyzed [3+2] Cycloaddition Reactions of Allenoates and Electron-
Deficient Alkenes. Chem. Eur. J. 2008, 14, 4361−4373; (b) Cui, C.-X.;
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(a) Wiberg, K. B.; Breneman, C. M. Resonance
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For C(O)−N cross-coupling with alkyne, see: (a) Li, B.-J.;
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Acyl-tert-butyl-carbamates (Boc) and N-Acyl-tosylamides (Ts):
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Chem. 2016, 81, 8091−8094; (e) Szostak, R.; Meng, G.; Szostak, M.
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14.
(a) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Cui, Q.;
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Catalytic Transamidation Reactions Compatible with Tertiary Amide
Metathesis under Ambient Conditions. J. Am. Chem. Soc. 2009, 131,
10003−10008; (c) Cheung, C. W.; Ma, J. A.; Hu, X. Manganese-
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of Amides and Amidation of Esters at Room Temperature. Nat.
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Destabilization
in
N-Acylanilines
(Anilides):
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Twisted Rotationally Inverted Acyclic Amides. J. Am. Chem. Soc.
2018, 140, 727−734; (g) Szostak, R.; Szostak, M. N-Acyl-
glutarimides: Resonance and Proton Affinities of Rotationally-
Inverted Twisted Amides Relevant to N–C(O) Cross-Coupling. Org.
Lett. 2018, 20,1342−1345; (h) Liu, C.; Shi, S.; Liu, Y.; Liu, R,;
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Chang, C.-W.; Tseng, H.-Y.; Wang, C.-C.; Yang, Y.-N.; Chang, J.-Y.;
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G. Li, P. Lei, M. Szostak, Transition-Metal-Free Esterification of
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Lee, S.-J.; Hsieh, H.-P. Concise Synthesis and Structure−Activity
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Hsiao, C.-J.; Cheng, C.-C.; Yang, C.-R.; Liou, J.-P. 3-Aroylindoles
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Alkynylphenyl)lactams. Angew. Chem. Int. Ed. 2008, 47, 346−349.
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Yada, A.; Okajima, S.; Murakami, M. Palladium-Catalyzed
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(a) Lei, P.; Meng, G.; Shi, S.; Ling, Y.; An, J.; Szostak, R.;
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N and C-O Bonds. Chem. Sci 2017, 8, 6525−6530; (b) Bourne-
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Weakly activated allene
Lewis base catalysis
Valuable products
O
•
[LB]
acyl
Lewis base
Ar
migration
D
O
catalyst
Ar
Ar
O
Ar
DMAP

cyclization
CH2D
N
N
Ar
N
Ar
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Mechanism: sequential [1,4]- and [1,6]-proton transfer
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