C-F bond cleavage enabled redox-neutral [4+1] annulation via C-H bond activation

Article abstract of DOI:10.1021/jacs.6b12142

Using α,α-difluoromethylene alkyne as a nontraditional one-carbon reaction partner, a synthetically novel method for the construction of isoindolin-1-one derivatives via Rh(III)-catalyzed [4+1] annulation reaction is reported. The 2-fold C-F bond cleavage not only enables the generation of desired product under an overall oxidant-free condition but also results in a net migration of carbon-carbon triple bond. In addition, the present reaction protocol exhibits a tolerance of a wide spectrum of functional groups due to the mild reaction conditions employed.

Full text of DOI:10.1021/jacs.6b12142

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Communication
C-F Bond Cleavage Enabled Redox-Neutral
[4+1] Annulation via C-H Bond Activation
Cheng-Qiang Wang, Lu Ye, Chao Feng, and Teck-Peng Loh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b12142 • Publication Date (Web): 18 Jan 2017
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Journal of the American Chemical Society
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C−F Bond Cleavage Enabled RedoxꢀNeutral [4+1] Annulation via
C−H Bond Activation
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Cheng-Qiang Wang,† Lu Ye,† Chao Feng†* and Teck-Peng Loh‡,§*
†College of Chemistry and Molecular Engineering, Institute of Advanced Synthesis, Jiangsu National Synergetic Innovation
Center for Advanced Materials, Nanjing Tech University, Nanjing, Jiangsu 210009, P.R. China.
‡Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P.R. China.
§Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University. Singapore 637616.
Supporting Information Placeholder
difluoromethylene alkyne could act as a one-carbon reaction
ABSTRACT: Using α,α-difluoromethylene alkyne as a nontradi-
component in an unprecedented Rh(III)-catalyzed [4+1] annula-
tion with N-methoxyl aroyl amide, enabling a straightforward
synthesis of multi-substituted isoindolin-1-one derivatives
(Scheme 1, b). Specifically, the whole transformation was charac-
terized by the following points: i) an oxidant-free process because
of two consecutive C-F bonds cleavage; ii) a regiospecific annula-
tion with both C-C and C-N bonds formation occurred on the
same distal sp hybridized carbon atom, which could be rational-
ized by electronic activation of alkyne group by gem-
difluoromethylene functionality; iii) a relocation of alkyne group
throughout the reaction, which resembles a two-fold SN2’ dis-
placement of fluorine atoms.9i,11 In addition, the introduction of an
alkyne motif would provide a great opportunity for the further
synthetic elaboration. It is also of synthetic importance, the un-
precedented integration of C-H bond activation, C-F bond cleav-
age and C-C triple bond migration provides a conceptually novel
strategy for the access of isoindolin-1-one derivatives.12
tional one-carbon reaction partner, a synthetically novel method
for the construction of isoindolin-1-one derivatives via Rh(III)-
catalyzed [4+1] annulation reaction is reported. The two folds C-F
bond cleavage not only enables the generation of desired product
under an overall oxidant-free condition but also results in a net
migration of carbon-carbon triple bond. In addition, the present
reaction protocol exhibits a tolerance of a wide spectrum of func-
tional groups due to the mild reaction conditions employed.
N-heterocyclic compounds are widely present in naturally oc-
curring compounds and find a broad application in pharmaceutical
research and materials science.1 For this reason, research investi-
gations targeting their efficient construction represent a blossom-
ing area in the synthetic organic chemistry.2 Among the methods
developed, transition-metal catalyzed intermolecular annulation in
its own right constitutes a powerful and privileged strategy.3 In
this context, direct annulation via C-H bond activation has spurred
great interest in the synthetic community as they enable a rapid
construction of diverse 5 or 6-membered N-heterocyclic com-
pounds from simple starting materials without resorting to sub-
strate pre-functionalization, leading to a more environmentally
benign and atom-economical process.4 Within this field, [n+2]
annulations using alkyne/alkene/allene as the two-carbon unit
have been well documented, however, regioselectivity issue with
respect to π system insertion is often of concern especially in the
case of sterically or electronically non-biased reaction partners.5
By contrast, [n+1] type annulations which integrate only one car-
bon atom essentially obviate such intrinsic issue. Nevertheless,
the reaction pattern is comparatively underdeveloped because of
the scarcity of readily available one-carbon reaction components.6
In this regard, the exploration of novel one carbon partner in [n+1]
annulation protocol is still highly desirable.
Scheme 1. CꢀF bond cleavage enabled redoxꢀneutral CꢀH
bond functionalization
Our study was commenced by examining the model reaction
between N-methoxyl benzamide 1a and gem-difluoromethylene
alkyne 2a using Rh(III) as the catalyst (Table 1). To our delight,
the desired product 3a was formed in 33% yield when the reaction
was carried out with [RhCp*Cl2]2, NaOAc as catalyst and additive
in methanol at 60 °C for 12 h (Table 1, entry 1). Notably, a
marked increase of reaction efficiency was observed when
molecular sieve was added, among which 3Å series was superior
(Table 1, entries 2-4). For basic additives, KOAc turned out to be
optimal (Table 1, entries 2, 5-6). Interestingly, when the reaction
temperature was decreased to 40 °C, product 3a was isolated in
With our continuing effort in the realm of C-H bond functional-
ization and the pursuit of new synthetic methodology for the as-
sembly of pharmaceutical relevant structural motifs,7 we have
quite recently developed an efficient protocol for monofluoroal-
kene synthesis via Rh(III)-catalyzed C-H/C-F bond activation
(Scheme 1, a).8 By harnessing heterolytic C-F bond cleavage,9
which allows a net removal of two electrons, a redox-neutral C-H
bond functionalization was thus attained.10 Keeping the merit of
C-F bond cleavage in mind, a continuing struggle in this arena
was pursued. Under this circumstance, it was found that gem-
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Page 2 of 6
Table 2. Scope of Nꢀmethoxyl benzamide derivativesa
82% yield (Table 1, entry 7). It is also noteworthy that using
1
2
3
4
5
6
7
8
AcOH instead of KOAc also led to the formation of 3a in 70%
yield (Table 1, entry 8). Furthermore, control experiments indict-
ed that the annulation hardly proceeded in the absence of either
[RhCp*Cl2]2 or KOAc (Table 1, entries 9-10). Intriguingly, the
use of a stoichiometric amount of KOAc was found to have a
severe impediment to the reaction outcome, implying that the in
situ generated HF may play a vital role in the C-F bond cleavage
step, presumably via hydrogen bond activation, which is con-
sistent with our previous work.8
O
O
F
F
R
N OMe
OMe
Ph
[RhCp*Cl2]2, KOAc
N
+
2
R
H
3Å MS, MeOH
40 °C, 12 h
Bu
Bu
Ph
2
1
2a
Me
3
O
O
O
N
OMe
N
OMe
N OMe
tBu
Bu
Bu
Bu
Table 1. Optimization studiesa
9
Ph
Ph
Ph
2
2
2
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3b, 85%
3c, 76%
3d, 70%
O
O
O
N
OMe
2
N
OMe
2
N
OMe
AcO
MeO
Bu
Bu
Bu
Ph
Ph
Ph
Ph
Ph
2
entry
1
additive 1
NaOAc
NaOAc
NaOAc
NaOAc
KOAc
K2CO3
KOAc
AcOH
KOAc
-
additive 2
-
yieldb
33
3e, 69%
3f, 63%
3g, 68%
O
O
O
MeO
N
OMe
N
OMe
N
OMe
2
2
3Å MS
4Å MS
5Å MS
3Å MS
3Å MS
3Å MS
3Å MS
3Å MS
3Å MS
3Å MS
80
MeS
O
Bu
Bu
Bu
O
MeO
3
70
Ph
Ph
2
2
b
4
78
3i
, 72%
3j
, 62%
3h
, 77%
O
O
O
5
84
6
7c
8c
9c,d
10c
11c,e
53
N
OMe
N
OMe
2
N
OMe
EtO2C
Ph
86(82)
70
Bu
Bu
Bu
Ph
Ph
2
2
b
b,d
3m
, 42%
O
3k
, 66%
3l
, 76%
ND
12
O
O
N
OMe
N
OMe
N
OMe
2
O
MeO2C
NC
KOAc
15
Bu
Bu
Bu
Me
Ph
Ph
2
Ph
aAll of the experiments were performed at relevant temperature
with 1a (0.1 mmol), 2a (0.12 mmol), additive 1 (0.03 mmol),
additive 2 (100 mg), [RhCp*Cl2]2 (0.002 mmol) in MeOH (0.5
2
b,d
b
b,c
3n
3o
3p
, 56%
, 44%
O
, 64%
O
O
b
N
OMe
N
OMe
2
N
OMe
mL) for 12 hours. NMR yield using tetrachloroethane as internal
O2N
F3C
X
standard; isolated yield was indicated in the parentheses. cThe
reaction was carried out at 40 °C. dIn the absence of [Rh] catalyst.
e2.0 equivalents of KOAc was added.
Bu
Bu
Bu
Ph
Ph
Ph
2
2
3s
X= F , 76%
3t
Cl , 72%
3q, 62%b,c
3r
, 56%
b
3u
Br , 70%
Having obtained the optimal reaction conditions, we next inves-
tigated the generality of this transformation with respect to the N-
methoxyl benzamide derivatives and the results were summarized
in Table 2. It is delightful to find that both electron-donating and
electron-withdrawing substituents were well accommodated, de-
livering the desired products in moderate to high yields. N-
Methoxyl benzamide 1b was converted into product 3b in 85%
yield, comparable to that of 1a. Substrates containing methyl, tert-
butyl or fused cycloalkyl groups all readily underwent the annula-
tion (3c-3e). Methoxyl, acetyloxyl functionalities were compatible
to the reaction conditions, furnishing the products in 63-77%
yields (3fꢀ3h). In the case of methlenedioxyl substituted N-
methoxyl benzamide 1i, the sterically more hindered C-H bond
was selectively cleaved in contrast to other meta-substituted sub-
strates wherein sterically more accessible cites are preferred (3c,
3e, 3l, 3v, 3y and 3z). Notably, methylthio group which is suscep-
tible to oxidative reaction conditions was well tolerated thanks to
the oxidant-free reaction conditions employed, giving rise to the
product 3j in 62% yield. Biphenyl and naphthyl derived amides
also worked well, providing products 3k, 3l in good yields. Inter-
estingly, amide with alkenyl substituent also proved to be the
viable substrate and when 1m was employed, product 3m was
isolated in synthetically useful yield, with the alkene residue re-
maining intact. The nice compatibility of this reaction was further
demonstrated by the fact that acetyl, ester, cyano, nitro, trifluoro-
methyl and silyl groups were all well tolerated, although slightly
O
O
N
O
N
I
N
OMe
OMe
OMe
2
HO
TMS
Bu
3v
Bu
Bu
Ph
Ph
Ph
2
2
b
3w
3x
, 63%
, 59%
, 61%
O
O
BocHN
Me
H
H
N OMe
N
OMe
H
Bu
Bu
3y, 70%
Ph
2
Ph
Me
O
2
3z, 60%
aAll experiments were performed with 1 (0.1 mmol), 2a (0.12
mmol), [RhCp*Cl2]2 (0.002 mmol), KOAc (0.03 mmol), 3Å mo-
o
lecular sieve (100 mg) in MeOH (0.5 mL) at 40 C for 12 hours.
bReactions were carried out at 80 C. Reaction time 24 hours.
o
c
dPivOH was used instead of KOAc.
tuning of the reaction conditions was occasionally required (3m-
3r, 3x). In addition, halogen atoms were all well tolerated, which
provide the opportunity for further derivatizations (3s-3v). It is
also worth mentioning that when substrates possessing additional
potential chelation functionalities such as alcohol, carbamate were
employed, the annulations occurred selectively on the ortho-
position of the amide directing group (3w, 3y). Moreover, es-
trone-derived substrate was amenable to this transformation and
furnished product 3z in 60% yield, indicating the potentiality of
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Journal of the American Chemical Society
the present protocol for the late-stage functionalization of com-
er product 3ap in 63% yield, only trace of desired product could
1
2
3
4
5
6
7
8
plex molecules.
be detected in the case of gem-dichlorine congener 2r. In addition,
essentially no desired products were observed when either mono-
fluorine or ketal counterparts were used in place of α,α-
difluoromethlene alkyne, thus implicating the key role of the gem-
difluorine group on this transformation (see supporting infor-
mation for detail). Interestingly, when α,α,α-trifluoromethyl al-
kyne 2s was reacted with amide 1d, no desired [4+1] but the tradi-
tional [4+2] annulation product 5 was obtained, for which the
exact reason was unclear at the present stage (eq 2). Furthermore,
the isoindolin-1-one derivatives obtained using this method are
also well suited for further synthetic elaborations because of their
enriched functionalities. For example, isoindolin-1-one 3d was
amenable to SmI2-mediated demethoxylation to afford 4a in mod-
erated yield, whereas isoindoline 4b could be obtained in 96%
yield with LiAlH4/AlCl3 reductive system. The embed alkynyl
substituent is also primed for further synthetic derivatization. For
example, triazole 4c could be generated in quantitative yield from
3ao via desilylation/Ru-catalyzed azide alkyne cycloaddition,
while for 3ak, Au-catalyzed intramolecular cyclization enabled
the formation of spirocyclic product 4d in 91% yield.
As depicted in Table 3, the reaction scope with respect to α,α-
difluoromethlene alkyne was further examined with amide 1d as
the model reaction partner. Alkyne substrates with different pri-
mary alkyl substituents engaged in this reaction uneventfully and
provided the desired products in moderate to good yields (3aa-
3ad). Substrate 2f, which bears a cyclohexyl group on the gem-
difluoromethylene carbon atom, reacted smoothly to afford 3ae in
67% yield. The smooth annulations with alkyne substrates con-
taining Bn, PMB, THP as well as Ac-protected hydroxyl group
also bore out the mildness of reaction conditions (3af-3ai). It is
noteworthy that free hydroxyl containing substrates 2k and 2l
participated in this annulation nicely without any deleterious ef-
fects on the reaction efficiency. Isoindolin-1-one product 3al with
a chlorine substituent on the alkyl chain was also readily obtained
when pivalic acid was used as the additive. Alkyne 2n bearing a
phthaloyl protected amino group was also examined, which gave
rise to the product 3am in 63% yield. Notably, the R1 of 2 was not
restricted to alkyl substituents. Specifically, phenylethynyl incor-
porated product 3an was obtained in 47% yield, whereas silyl-
derived α,α-difluoromethlene alkyne 2p uneventfully participated
in this reaction and produced 3ao in 64% yield. Additionally, the
practicality of this reaction was further proved by a gram-scale
reaction, which provided the desired product in comparable yield
as small-scale reaction (see supporting information for detail).
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Scheme 2. Control experiments and synthetic elaborations
O
N
OMe
X
X
1d
tBu
Ph
(1)
(2)
standard
conditions
R
Table 3. Scope of α,αꢀdifluoromethlene alkynesa
OMe
2q 2r
R
Ph
3ap 3aq
/
3ap
, 63%
X = F, R = Bu,
X = Cl, R = Pr,
/
MeO
3aq
, trace
O
O
O
F
F
F
OMe
[RhCp*Cl2]2, KOAc
F
F
OMe
CF3
N
OMe
R1
N
1d
R1
+
N
H
tBu
3Å MS, MeOH
40 °C, 12 h
Ph
2
tBu
R2
standard
conditions
R2
tBu
2s
1d
2
3
2
5
, 49%
Ph
O
O
O
O
N
OMe
i) SmI2, THF, 0 °C;
ii) LiAlH4, AlCl3, THF, 0 °C;
N
OMe
N
OMe
N
OMe
Bu
tBu
NH
tBu
tBu
tBu
tBu
Bu
R2
Bu
2
Bu
Ph
Ph
O
Ph
2
Me
4a
Ph
ii
2
, 45%
i
4b
, 96%
R2 = Me 3aa, 45%b,c
b,d
3ac
, 62%
3ad
, 68%
b
N
OMe
R1
3ab
, 69%
Ph(CH2)2
tBu
O
N
O
O
O
O
R2
iv
iii
3
OMe
N
N
OMe
N
OMe
N
OMe
N
OMe
Cy
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Bu
Bu
iii) 1) K2CO3, MeOH, rt; 2) RuCp*Cl(COD),
Ph(CH2)2N3, Toluene, 40 °C;
iv) Au(PPh3)Cl, AgOTf, Toluene, 3Å MS, 60 °C.
BnO
3
RO
Ph
4c, 98%
N
Ph
Ph
Ph
O
N
2
2
b,c
3ag
R= PMB
, 55%
3ae, 67%b
3af, 49%b,c
4d
, 91%
THP 3ah, 61%b
O
O
Although it is too arbitrary to draw a whole picture with respect
to the reaction mechanism based upon the present experimental
results, a simplified reaction pathway shown in Scheme 3 was
tentatively proposed for the interpretation of outcomes of this
novel transformation. At first, chelation assisted C-H bond cleav-
age of benzamide 1 occurs to afford the corresponding five-
membered rhodacycle I. Subsequently, a regioselectively migrato-
ry insertion, owing to the polarization of alkynyl motif by the
adjacent gem-difluorine substituent, via intermediate II would
occur to deliver the seven-membered rhodacycle III. With the
assistance of acid the following cleavage of one of these two C-F
bonds happens to selectively afford allene IV,13 which further
undergoes intramolecular aminorhodation of the proximal double
bond of allene tether to generate alkenyl rhodium intermediate
V.13c,14 At this stage, the following second β-F-elimination would
enable the generation of desired product 3 through a migratory
reconstruction of C-C triple bond accompanied by the catalyst
regeneration.15 It is worth noting, that it is the two-fold C-F bonds
heterolytic cleavage, which on one hand removes electrons from
reaction composite and on the other hand allows the relocation of
C-C triple bond, that a redox-neutral [4+1] annulation with skele-
ton rearrangement comes true.
O
N
N
OMe
N
OMe
OMe
tBu
tBu
Bu
3
3
Cl
3al
HO
OR
3
Ph
2
b
Ph
3ai
3aj,
R= Ac
H
, 57%
65%
2
c
3ak
, 77%
, 49%
O
O
N
O
OMe
N
OMe
Ph
N
OMe
tBu
tBu
Bu
3am
Bu
Bu
NPhth
TMS
b
3
b
b
3an
, 47%
3ao
, 64%
, 63%
aAll experiments were performed with 1d (0.1 mmol), 2 (0.12
mmol), [RhCp*Cl2]2 (0.002 mmol), KOAc (0.03 mmol), 3Å mo-
o
lecular sieve (100 mg) in MeOH (0.5 mL) at 40 C for 12 hours.
bReactions were carried out at 80 oC. cPivOH was used instead of
KOAc. dWithout the addition of 3Å molecular sieve.
To shed more light on the role of gem-difluorine group on this
reaction and reveal the synthetic potential of thus obtained struc-
tural motifs, several control experiments and synthetic elabora-
tions were attempted and the results were shown in Scheme 2. As
outlined in equation 1, while the reaction between 1d and α,α-
difluoromethlene alkyne substrate 2q worked effeciently to deliv-
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Su, S.-J.; Cao, Y. J. Mater. Chem. C. 2014, 2, 9565. (g) Shaikh, T. M.;
Hong, F.-E. J. Organomet. Chem. 2016, 139.
Scheme 3. Proposed reaction mechanism
1
2
3
4
5
6
7
8
(2) (a) Zhu, J. Eur. J. Org. Chem. 2003, 1133. (b) Chen, J.-R.; Hu, X.-
Q.; Lu, L.-Q.; Xiao, W.-J. Chem. Rev. 2015, 115, 5301. (c) Majumdar, K.
C.; Muhuri, S.; Islam, R. U.; Chattopadhyay, B. Heterocycles 2009, 78,
1109. (d) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243. (e) Larock, R. C.;
Zeni, G. Chem. Rev. 2004, 104, 2285.
(3) (a) Rubin, M.; Sromek, A. W.; Gevorgyan, V. Synlett 2003, 2265.
(b) Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625.
(4) (a) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (b) Satoh, T.;
Miura, M. Chem. Eur. J. 2010, 16, 11212. (c) Yamamoto, Y. Chem. Soc.
Rev. 2014, 43, 1575.
1
3
[RhCp*X2]
O
step 6
O
step 1
N
OMe
R
F
N
Rh
Cp*
OMe
R
Rh
R2
R1
Cp*
V
I
2
F
step 1: C-H activation
step 2&3: alkyne insertion
step 4&6: -F elimination
step 5: aminorhodation
step 5
step 2
O
O
9
OMe
Cp*
(5) For selected examples, see: (a) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X.
Angew. Chem. Int. Ed. 2013, 52, 6033. (b) Fukui, M.; Hoshino, Y.; Satoh,
T.; Miura, M.; Tanaka, K. Adv. Synth. Catal. 2014, 356, 1638. (c)
Hoshino, Y.; Shibata, Y.; Ken Tanaka, K. Adv. Synth. Catal. 2014, 356,
1577. (d) Prakash, R.; Shekarrao, K.; Gogoi, S. Org. Lett. 2015, 17, 5264.
(e) Noelia, C.; Del Rio, K. P.; Rebeca, G.-F.; Mascareñas, J. L.; Gulías,
M. ACS Catal. 2016, 6, 3349.
(6) For selected examples, see: (a) Burns, D. J.; Lam, H. W. Angew.
Chem. Int. Ed. 2014, 53, 9931. (b) Li, Y.; Qi, Z.; Wang, H.; Yang, X.; Li,
X. Angew. Chem. Int. Ed. 2016, 55, 11877. (c) Wrigglesworth, J. W.; Cox,
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N
OMe
R
R
Rh
•
R1
F
Rh
R2
Cp*
R1
R2
F
O
IV
OMe
II
F
N
F
step 4
step 3
Rh Cp*
R
R1
R2
III
F
F
In conclusion, we have reported a conceptually novel protocol
of C-H bond activation engaged defluorinative [4+1] annulation,
which allows the expedient construction of isoindolin-1-one de-
rivatives. The polarization of alkyne substrate by neighboring
gem-difluoromethylene group is deemed to be the key fact that
guarantee a regioselective insertion of π-system. Notably, this
reaction is featured by C-C triple bond relocation and oxidant-free
functionalization of C-H/N-H bonds thanks to the consecutive
two-fold β-F eliminations. Furthermore, this method provides a
redox-neutral, regio-specific and atom-economical pathway for
the assembly of structurally defined alkynyl-substituted isoin-
dolin-1-ones, which are not easily accessible using the known
methods. Last but not the least, this catalytic process represents a
rare example of utilizing sp carbon atom of alkyne as a one car-
bon reaction partner in the transition-metal-catalyzed [n+1] annu-
lation. We hope this methodology could find a broad application
in pharmaceutical research and organic synthetic chemistry and
further study to elucidate the detailed reaction mechanism is on-
going in our lab.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
iamcfeng@njtech.edu.cn
teckpeng@ntu.edu.sg
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the “1000-Youth Talents Plan”, a Start-up Grant
(39837110) from Nanjing Tech University and financial support
by SICAM Fellowship by Jiangsu National Synergetic Innovation
Center for Advanced Materials.
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