Rhodium catalyzed C-C bond cleavage/coupling of 2-(azetidin-3-ylidene)acetates and analogs

Article abstract of DOI:10.1039/c9cc06446j

The C-C bond cleavage/coupling of 2-(azetidin-3-ylidene)acetates with aryl boronic acids catalyzed by a rhodium complex was studied with a "conjugate addition/β-C cleavage/protonation" strategy.

Full text of DOI:10.1039/c9cc06446j

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Rhodium catalyzed C–C bond cleavage/coupling
of 2-(azetidin-3-ylidene)acetates and analogs†
Cite this: Chem. Commun., 2019,
55, 12707
a
Xuan Yang,
Wei-Yu Kong,a Jia-Ni Gao,a Li Cheng,b Nan-Nan Li,a Meng Li,a
a
ab
Hui-Ting Li,a Jun Fan,a Jin-Ming Gao,
Qin Ouyang *c and Jian-Bo Xie
*
Received 20th August 2019,
Accepted 26th September 2019
DOI: 10.1039/c9cc06446j
rsc.li/chemcomm
The C–C bond cleavage/coupling of 2-(azetidin-3-ylidene)acetates However, there are a lot of restrictions for the b-C cleavage process
with aryl boronic acids catalyzed by a rhodium complex was studied due to competitive transformations, such as b-H cleavage, proto-
with a ‘‘conjugate addition/b-C cleavage/protonation’’ strategy.
nation, etc. Thus, the successful examples of C–C bond activation
with b-C cleavage mode have been mainly focused on ligand
Functionalization of inactivated bonds is an intriguing target exchange with alcohol substrates,5b,6 1,2-addition to a ketone,7
for synthetic chemists. The development of transition metal cycloaddition,8a–g etc.,8h–k most of which resulted in a heteroatom-
catalysts and understanding of the catalytic process has helped linked transition metal intermediate lacking a b-H.
very fast developments during the last several decades for
The Rh(I) catalyzed conjugate addition of aryl boronic acids
directly activating extensive inactive C–H bonds;1 however, to electron deficient unsaturated compounds9 (Scheme 1a)
inactive C–C single bonds haven’t been included.2 By intuitive inspired us as it could produce an a-Rh intermediate (the
explanation, this could be attributed to the fact that C–C bonds assumed potential precursor for b-C cleavage) by isomerization
are usually surrounded by C–H bonds and thus the transition of the enolate Rh. In 2012, Matsuda et al. reported the first and
metal catalyst might not be able to ‘‘bypass’’ the C–H bonds. so far the sole example for tandem conjugate addition/C–C
Therefore, direct oxidative addition of C–C single bonds by a activation of a,b-unsaturated compounds in a proton free
low valence transition metal represents a big challenge condition, producing ketones possessing a 1,10-spirobiindane
and there are many restrictions. Successful direct activation skeleton (Scheme 1b).10 However, the controllable conjugate
of C–C bonds via oxidative addition3 used to require special addition/C–C activation process under competitive protonation
coordination-directing groups (such as pyridyl, phosphine circumstances remained unknown and challenging. Herein we
and oxazolynyl, etc.),4 highly strained small cyclic molecules report the ‘‘conjugate addition/b-C cleavage/protonation’’ (CCP)
(such as biphenylene, functionalized cyclobutanone, vinyl and strategy for 2-(azetidin-3-ylidene)acetates and their analogs, owing
alkenyl cyclopropane, etc.),5a–g or good leaving groups (such as to the convenience of synthesis of unsaturated g-aminobutyric
-CN, allyl, etc.),4e,5h or be driven by aromatization.5i An alter-
native mode for C–C bond activation is b-C cleavage of transi-
tion metal intermediates, which we preferred in this work.
A variety of transition metal intermediates could be potential
substrates for b-C cleavage because they provide a chance to
combine b-C cleavage with other organic transition metal
transformations by a tandem process and thus greatly enrich
the practicability of C–C bond activation in a one-pot reaction.6i,7,8
a Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of
Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China.
E-mail: jianbo_xie@nwafu.edu.cn
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, China
c College of Pharmacy, Third Military Medical University, Chongqing 400038,
China. E-mail: ouyangq@tmmu.edu.cn
Scheme 1 Evolution of the reactions between an a,b-unsaturated
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
compound and aryl boronic reagent.
c9cc06446j
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acid with this strategy and our research interest in precise control produced the CA product 4aa exclusively, while ferrocene
of transition metal intermediates (Scheme 1c). It should be noted diphosphine L3 and 1,2-bis(diphenylphosphanyl)benzene L8
that b-C cleavage occurred in the presence of a protic agent and so gave 4aa and the CCP product 3aa as a mixture. Diphosphine
represents a quite different difficulty from Matsuda’s work.10
ligands bearing the flexible linear chain skeleton could also
We initiated our research with tert-butyl 3-(2-methoxy-2- provide the CCP product 3aa, and the number of carbon atoms
oxoethylidene)azetidine-1-carboxylate 1a and phenylboronic on the skeleton determined the selectivity while dppp that
acid 2a in the presence of Rh(I) catalyst and various ligands contains three carbons on the skeleton (L5) is optimal
in dioxane, especially, with water as the protic agent (Table 1, (Table 1, entries 4–7). The bidentate aminophosphine ligand
entries 1–15). Screening of the ligands showed that the skeleton L13, as well as the monodentate ligands including phosphine,
of the ligand was crucial to selectivity between the CCP product phosphite and NHC, showed inferior reactivity and entirely CA
3aa and conjugate addition (CA) product 4aa. Binaphthyl selectivity (Table 1, entries 9–14). After screening the bases with
diphosphine L1 and 9,9-dimethylxanthenyl diphosphine L2 L5, we found that a different inorganic base did not affect the
reactivity and selectivity much while sodium tert-butoxide
slightly improved the selectivity (Table 1, entry 15). We then
compared various alcohols as protic agents (Table 1, entries 16–19).
Table 1 Optimization of the reaction conditionsa
The bulky alcohol with a large pKa value, tAmyl-OH, was superior to
the others and the content of CCP product in the crude product
reached 83%. After decreasing the loading of tAmyl-OH to
1.0 equivalent, the ratio of CCP/CA was further improved to
93/7 (Table 1, entries 20-22). Solvents also influenced the
reactivity and selectivity, and the selectivity increased to 95/5
in cyclopentyl methyl ether (CPME) with full conversion
(Table 1, entries 23–26). Next, we carefully screened other
analogues of L5 as the ligand, and the 4-CF3 substituted one
L18 was found to be the best with 96/4 selectivity. Finally, we
found the optimum amount of phenylboronic acid 2a to be
1.8 equivalents, while the content of 3aa was 97%.
With the optimal conditions in hand, we sought to define
the scope of aryl boronic acids (Table 2). First, an array of
substituted phenylboronic acids with ortho-, meta- and para-
substituents was tested. We found it was sensitive to the ortho-
substituent, and only the ortho-fluoro phenylboronic acid could
produce the desired product 3ab in 32% yield while other ortho-
substituted phenylboronic acids gave only a trace of the desired
product or 1a wasn’t consumed at all. Substituents on meta- or
para-positions did not affect the yield and selectivity, and both
electron-rich (2c, 2d, 2j and 2k) and electron-deficient (2e–2g,
2i, 2l-2n and 2p) phenyl boronic acids were suitable for this
reaction. In most of the cases, the CCP products could be
obtained in good to excellent yields (66–92%), except for the
para-bromo substituted 3an. The para-vinyl substituted product
3aq could also be obtained in 71% yield. Heteroaromatic
substrates, such as those containing an indole ring (2r),
dibenzo[b,d]furan (2s), or benzo[d][1,3]dioxole (2t) in place
of the phenyl ring, could produce the CCP products with
acceptable yields. We examined (pinacolboryl)benzene 2a0 in
place of 2a as well. In this case, tripotassium phosphate should
be used instead of sodium tert-butoxide while the catalyst
loading was increased to 5 mol%, for the sake of full conver-
sion. To our delight, the ratio of CCP/CA could be further
increased to 98/2, and 3aa was obtained in 94% yield. With
this method, we synthesized the furyl product 3au and thio-
phenyl product 3av in 46% and 39% yield, respectively.
Entry
Ligand Solvent
Protic agent Conv.b (%) 3aa/4aab
1c
L1
L2
L3
L4
L5
L6
L7
L8
Dioxane H2O
499
25
82
Trace/499
Trace/499
17/83
2c
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane H2O
Dioxane MeOH
Dioxane iPrOH
Dioxane tBuOH
Dioxane tAmyl-OH
Dioxane tAmyl-OH
Dioxane tAmyl-OH
Dioxane tAmyl-OH
3c
4c
5
Trace/499
44/56
30/70
5c
499
499
56
6c
7c
2/98
8c
44
17
13
74
11
6
15
499
499
499
499
499
499
499
499
20
40/60
9c
L9
Trace/499
Trace/499
Trace/499
Trace/499
Trace/499
Trace/499
51/49
53/47
63/37
71/29
77/23
10c
11c
12c
13c
14c
15d
16d
17d
18d
19d
20d,e
21d, f
22d,g
23d,g
24d,g
25d,g
26d,g
27d,g
28d,g
29d,g
30d,g
31d,g
L10
L11
L12
L13
L14
L5
L5
L5
L5
L5
L5
L5
L5
83/17
90/10
93/7
80/20
L5
L5
L5
DME
tAmyl-OH
tAmyl-OH
MeTHF
Trace
Trace
499
70
499
499
499
53
—
—
95/5
19/81
93/7
91/9
96/4
52/48
tBuOMe tAmyl-OH
L5
CPME
CPME
CPME
CPME
CPME
CPME
CPME
tAmyl-OH
tAmyl-OH
tAmyl-OH
tAmyl-OH
tAmyl-OH
tAmyl-OH
tAmyl-OH
L15
L16
L17
L18
L19
32d,g,h L18
499
97/3
a
The reaction was performed on a 0.22 mmol scale in 1.6 mL of solvent
with 0.2 equivalent of base and 56 equivalents of protic agent was used
b
unless otherwise indicated. Conversion and selectivity were determined
We then turned to define the scope of 2-(azetidin-3-
ylidene)acetate esters and their analogs (Table 3). For esters
with different alcohol partners (1b–1f), the CCP products were
by analysis of crude product with 1H NMR. K2CO3 as the base. NaOtBu
c
d
as the base. 7 equivalents of tAmyl-OH. 2 equivalents of tAmyl-OH.
e
f
g
h
1 equivalent of tAmyl-OH. 1.8 equivalents of phenylboronic acid.
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Table 2 Substrate scope of aryl boronic acida,b
Table 3 Substrate scope of unsaturated compoundsa,b
a
Reaction conditions: 1 (0.22 mmol), 2a (0.40 mmol), CPME (1.6 mL),
NaOtBu (0.044 mmol), tAmyl-OH (0.22 mmol). ND, not detected; NR, no
reaction. Yield of isolated product. Only conjugate addition product
was obtained. 10 mol% Rh catalyst was used. Only hydrolysis of the
ester group in the starting material was identified as the main product.
b
c
d
e
a
Reaction conditions: 1a (0.22 mmol), 2 (0.40 mmol), CPME (1.6 mL),
NaOtBu (0.044 mmol), tAmyl-OH (0.22 mmol). Yield of isolated product.
b
furnished in high to excellent yields. However, only CA product
was obtained when a ketone substrate was used (1g). To our
delight, the substrates with other electron-withdrawing groups,
including unsaturated amide (1h) and unsaturated nitrile (1i),
also furnished the CCP products smoothly in good yields, while
the unsaturated phosphonate substrate (1j) was less reactive.
We also changed the functional groups on the nitrogen atom
from tert-butoxycarbonyl to (benzyloxy)carbonyl (1k), benzoyl (1l),
tosyl (1m), and the CCP products also were obtained in
good yields in these cases. However, alkyl protected amines
(1n and 1o) and the substrates possessing a cyclobutane (1p)
unit or oxetane one (1q) in place of an azetidine ring were less
reactive and none of the desired CCP product was obtained.
Scheme 2 Synthetic transformations.
g-aminobutyric acid (6), or asymmetric reduction of the double
Typically,
a
CCP product contains the unsaturated bond11 to give the chiral g-aminobutyric acid ester (7) which could
g-aminobutyric acid (GABA) unit and could be transformed to be further transformed to the chiral g-lactam (9, 92% ee) via a
various structures based on the functional groups (Scheme 2). deprotection (8) and cyclization process. To further demonstrate the
For example, it could undergo cyclization to form the unsaturated usefulness of the CCP process, we started from Ezetimibe 10, a
g-lactam (5) in quantitative yield (this indicates the (Z)-configuration medication used to treat high blood cholesterol and certain other
of the double bond), or hydrolysis to give the unsaturated lipid abnormalities and got the Ezetimibe boronic acid 11 after
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Scheme 3 Proposed catalytic cycle.13
several transformations.12 The boronic acid 11 reacted with 1c
smoothly to furnish the desired CCP product 12 in 48% yield. It
could also be transformed to the unsaturated g-lactam modified
Ezetimibe 13 and 14 after simple deprotection and cyclization
processes (Scheme 2d).
We assume that the reaction starts with a ligand exchange
between Rh(I)(L18)(coe)Cl and sodium tert-butoxide, that produces
the reactive Rh(I)(OR) species I (Scheme 3). Via the trans-metalation
process of I and aryl boronic acid 2, an organo transition metal
intermediate II is formed. II could react with the a,b-unsaturated
ester 1 to give enolate Rh(I) III-A or be quenched by the protic agent
to regenerate I, which could be certified by separation of the
deboration byproduct Ar–H because it has high boiling point.
The extra consumption also explains why 2 should be used in
1.8 equivalents for full conversion of 1. The enolate Rh(I) III-A
could either be quenched to furnish the undesired CA product 4
and regenerate I, or undergo isomerization to form the a-Rh ester
intermediate III-B. The configuration of the double bond could be
explained by the four-member-square-plane transition state, as the
anti-configuration in III-B is favorable because of the repulsion
between the aryl group and the ester group in III-B0. The alkyl Rh(I)
intermediate IV is formed after the b-C cleavage and it undergoes a
fast protonation to furnish the CCP product 3 and regenerate I.
The protonation rate of IV is faster than that of III-A or III-B since
IV is more basic, and that makes the postponed protonation
feasible (Scheme 3).
In summary, we showed how b-C cleavage, other than the
well-known protonation, could occur for an intermediate of
conjugate addition in the presence of a protic agent. A wide
range of aryl boronic acids as well as their pinacol esters, and
a,b-unsaturated compounds possessing a 2-(azetidin-3-ylidene)
unit reacted smoothly to furnish the CCP products.
The authors gratefully acknowledge the Financial support
from the NSFC (21702164), National Key R&D program of China
(2018YFA0507900), Northwest A&F University and State Key
Laboratory of Elemento-Organic.
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Conflicts of interest
There are no conflicts to declare.
13 See the ESI† for the detailed experiments for mechanistic studies.
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