Regiocontrolled Coupling of Aromatic and Vinylic Amides with α-Allenols to Form γ-Lactams via Rhodium(III)-Catalyzed C-H Activation

Article abstract of DOI:10.1021/acs.orglett.6b02903

A mild, regiocontrolled coupling of aromatic and vinylic amides with α-allenols to form γ-lactams via rhodium(III)-catalyzed C-H activation has been demonstrated. This [4 + 1] annulation reaction provides an efficient method for the synthesis of isoindolinones and 1,5-dihydro-pyrrol-2-ones bearing a tetrasubstituted carbon atom α to the nitrogen atom with good functional group tolerance. The hydroxyl group in the allene substrate is essential in controlling the chemo- and regioselectivity of the reaction probably by coordination interaction with the rhodium catalyst.

Full text of DOI:10.1021/acs.orglett.6b02903

Letter
pubs.acs.org/OrgLett
Regiocontrolled Coupling of Aromatic and Vinylic Amides with
α‑Allenols To Form γ‑Lactams via Rhodium(III)-Catalyzed C−H
Activation
Zhi Zhou, Guixia Liu,* and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, 200032, China
S
* Supporting Information
ABSTRACT: A mild, regiocontrolled coupling of aromatic and
vinylic amides with α-allenols to form γ-lactams via rhodium(III)-
catalyzed C−H activation has been demonstrated. This [4 + 1]
annulation reaction provides an efficient method for the synthesis of
isoindolinones and 1,5-dihydro-pyrrol-2-ones bearing a tetrasub-
stituted carbon atom α to the nitrogen atom with good functional group tolerance. The hydroxyl group in the allene substrate is
essential in controlling the chemo- and regioselectivity of the reaction probably by coordination interaction with the rhodium
catalyst.
Scheme 1. Diversified Reaction Modes of C−H
Functionalization Tuned by Different Substituted Allenes
he construction of heterocyclic scaffolds from simple and
readily available starting materials is important in view of
T
their prevalence in bioactive molecules.1 Among a broad range of
synthetic methods, the heteroannulation of allenes2 has proven
to be a versatile strategy.3 In recent years, allenes have been used
as the coupling partners in transition metal catalyzed C−H
functionalization,4 which provides a step- and atom-economical
route to various heterocycles from less functionalized sub-
strates.5,6 A variety of heterocycles can be accessed through this
protocol to furnish dihydroisoquinolinone,5a,d,i dihydro-
pyridone,5i indolo[2,3-c]pyrane-1-one,5b dihydrofuran,5c eight-
membered lactam,5e chromane,5f,h and phthalide.5g Despite
impressive progress, the development of new types of reactions
between C−H and allenes affording privileged heterocycles is
still in demand.
Compared with alkynes and alkenes,7 allenes are less explored
in C−H functionalization. A major challenge existed in the C−H
functionalization with allenes arises from the difficulty to achieve
high chemo- and regioselectivity, which is usually controlled by
electronic and steric effects of allenes. Normally, carbometalation
of allenes forms a new C−C bond at the central carbon atom of
the allene moiety to produces a π-allyl metal species I (Scheme
1a, eq 1), which potentially enables the subsequent reaction
occurring at either side of the allylic carbon.5a,d,f−h The
regioselectivity can be switched in some cases, in which
carbometalation takes place at the less substituted CC bond
giving vinyl metal species II (Scheme 1a, eq 2).6a,d,e,i Taking
advantage of different substitued allenes, diversified reaction
modes of C−H functionalization can be achieved. Herein, we
present a regiocontrolled [4 + 1] annulation5f−h of N-
methoxybenzamides or N-methoxyacrylamides with α-allenols
(Scheme 1b), in which the hydroxyl group in the allene is crucial
for the chemo- and regioselectivity probably by coordination
with rhodium catalyst to form a regioselective η1-allyl rhodium
species III. In this transformation, allenes act as the one-carbon
component5f−h to construct isoindolinones and 1,5-dihydropyr-
rol-2-ones bearing a tetrasubstituted carbon atom. Since both
isoindolinones8 and pyrrol-2-ones9 contain the γ-lactam skeleton
and present in many bioactive natural products and drug
candidates, this transformation should have profound potential
in synthetic chemistry.
At the outset of our investigation, we tested the reactions of N-
methoxybenzamide (1a) with 1-phenylbuta-2,3-dien-1-ol (2a)
under rhodium(III) catalyzed conditions (Table 1). The 3,3-
disubstituted isoindolin-1-one product 3aa could be obtained via
a [4 + 1] annulation, in which a stoichiometric amount of silver
acetate was inevitable (Table 1, entries 1 and 2). Preliminary
experiments indicated that acetonitrile was an optimal solvent.10
Received: September 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
methyl (3ba), methoxyl (3ca), phenyl (3da), and halogens
(3ea−3ha), were well tolerated in this transformation, furnishing
the corresponding products in moderate to good yields. The
reaction was also compatible with N-methoxybenzamides
bearing electron-withdrawing groups (3ia and 3ja), which
reacted smoothly to give the desired products in moderate
yields. In addition, ortho methyl-substituted N-methoxy-
benzamide was also a good reactant for this transformation
affording 3ka in a yield of 68%. When meta-substituted N-
methoxybenzamide was employed, selective C−H functionaliza-
tion at the less hindered site was observed (3la). Of note, N-
methoxy-1-naphthamide resulted in a good yield of the desired
isoindolinone derivative under standard conditions (3ma, 74%).
Having developed a rhodium(III)-catalyzed coupling reaction
of N-methoxybenzamides for the synthesis of isoindolinones, we
were next intrigued to explore the feasibility of an olefinic C−H
functionalization for the construction of the pyrrol-2-one
skeleton. To our delight, this transformation proceeded
smoothly to afford the desired products with a lower loading
of α-allenol 2a at 80 °C.12 It is noteworthy that a substituent at
the α position of N-methoxyacrylamide was helpful for this
olefinic C−H functionalization (3na−3qa), while the acryl-
amides without an α-substituent (3ra and 3sa) seemed to be less
effective (Scheme 3).13 Moreover, the cyclic olefinic substrate
Table 1. Reaction Conditions Screening
b
entry
oxidant (equiv)
additive (equiv)
yield (%)
1
2
−
CsOAc (0.5)
<5
48
53
73
13
44
52
49
65
57
AgOAc (1)
AgOAc (1)
AgOAc (2)
Cu(OAc)2 (2)
Ag2CO3 (2)
(PhCO2)2 (2)
PhI(OAc)2 (2)
AgOAc (2)
AgOAc (2)
−
−
−
−
c
3
cd
,
4
cd
,
5
cd
,
6
−
cd
,
7
CsOAc (0.5)
cd
,
8
−
cd
,
9
K2CO3 (1)
HOAc (1)
cd
,
10
a
Reaction conditions: 1a (0.1 mmol), 2a (0.14 mmol), [Cp*RhCl2]2
(2.5 mol %), oxidant and additives in solvent (0.2 M) at room
b
c
temperature for 24 h under air. 1H NMR yield based on 1a. CH3CN
d
(0.1 M). 2a (0.3 mmol).
Increasing the amounts of the external oxidant and α-allenol 2a
significantly improved the yield to 73% (Table 1, entry 4). Other
external oxidants were also examined but gave inferior results
compared with AgOAc (Table 1, entries 5−8). Moreover, the
addition of K2CO3 or acetic acid decreased the yield of the
desired product (Table 1, entries 9 and 10). A control
experiment showed that the absence of a rhodium catalyst
resulted in no reaction.11
Scheme 3. Reaction Scope for Olefinic C−H
a
Functionalization with Allenyl Alcohol 2a
Further exploration of the scope of N-methoxybenzamides
was next conducted under the optimized reaction conditions. By
using 2a as the coupling partner, a variety of isoindolinone
derivatives were constructed effectively (Scheme 2). Fortunately,
various commonly encountered functional groups, such as
Scheme 2. Reaction Scope for Aromatic C−H
a
Functionalization with α-Allenol 2a
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), [Cp*RhCl2]2
(2.5 mol %), AgOAc (2 equiv) in CH3CN (0.1 M) at 80 °C for 24 h
under air; isolated yield was reported.
(3ta) and α,β-dimethyl N-methoxyacrylamide (3ua) readily
participated in this annulation, leading to the corresponding
products in good yields. However, when α-methyl-β-phenyl N-
methoxyacrylamide was subjected to the reaction conditions,
only a 33% yield of desired product 3va was obtained. The
electronic property of the phenyl substituent close to the vinylic
C−H bond might result in the low reactivity of 1v.
We subsequently extended the scope of this transformation by
employing a variety of substituted α-allenols 2 (Scheme 4). The
reaction is compatible with both electron-donating and -with-
drawing group substituted 1-phenylbuta-2,3-dien-1-ols (3ab and
3ac). Buta-2,3-dien-1-ol and 1-alkyl-substituted buta-2,3-dien-1-
ols were also tolerated to deliver the corresponding isoindoli-
nones and pyrrol-2-ones in moderate yields (3ad−3ai). Notably,
when 4-alkyl substituted buta-2,3-dien-1-ols were employed, the
specific regioselectivity14 was also observed furnishing the
expected pyrrol-2-ones with a carbonyl group (3ak and 3al).
a
Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), [Cp*RhCl2]2
(2.5 mol %), AgOAc (2 equiv) in CH3CN (0.1 M) at room
temperature for 24 h under air; isolated yield was reported.
B
DOI: 10.1021/acs.orglett.6b02903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Reaction Scope for α-Allenols
Scheme 5. Further Investigation on the Effect of Hydroxy
Group in the Allenes
a b
,
a
Reaction conditions: 1 (0.2 mmol), 4 (0.4 mmol), [Cp*RhCl2]2 (2.5
mol %), AgOAc (2 equiv) in CH3CN (0.1 M) at room temperature for
24 h under air; isolated yield was reported. Reaction was conducted
b
at 80 °C.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), [Cp*RhCl2]2 (2.5
mol %), AgOAc (2 equiv) in CH3CN (0.1 M) at room temperature for
24 h under air; isolated yield was reported. Reaction was conducted
Scheme 6. Proposed Mechanism
b
at 80 °C with 1.5 equiv of α-allenol 2.
We suspected the coordination of the hydroxyl group to rhodium
was mostly involved in controlling the regioselectivity.
To gain more insight into the effect of the hydroxyl group in α-
allenol, a series of controlled experiments were then carried out.
When benzyl substituted allene 2m or benzyl protected buta-2,3-
dien-1-ol 2n was subjected to the reaction with 1a under standard
conditions, the reaction turned out to be complicated, resulting
in an inseparable mixture of complex products (eq 3). These
results indicate that the free hydroxyl group is essential for the [4
+ 1] annulation. Considering that an amide group could also
potentially chelate with the Rh center, substrate 2o was subjected
to the reaction. The expected product 3ad could be constructed
in a relatively low yield (eq 4), which proves the importance of a
coordinating substituent in the allene substrate.
To further test our hypothesis that the hydroxyl group greatly
influenced regio- and chemo-selectivity control by chelating the
Rh, various allenes bearing a hydroxyl group at different positions
(4a−c) were synthesized and subjected to the reaction (Scheme
5). Delightfully, under the standard conditions, the [4 + 1]
annulation proceeded smoothly to yield the mixture of γ-lactam
(5a−5d) and iminolactone (5a′−5d′). The formation of
iminolactone was probably due to the attack of the oxygen
atom rather than the nitrogen atom from the directing group
during the annulation step.15
(OAc)2 is likely generated by anion exchange in the presence of
AgOAc, followed by a facile amide directed C−H activation to
afford intermediate A. The regioselective insertion of an allene
double bond into the C−Rh bond provides a seven-membered
rhodacycle intermediate B. We envisioned that hydroxyl group in
the allene may provide the binding affinity to Rh,16 which would
guide the regioselective migratory insertion to form the η1-allylic
rhodium intermediate B6g and disfavor the formation of the π-
allyl rhodium species B′. Next, β-H elimination followed by
enol−keto tautomerism gives intermediate C′, from which two
possible mechanistic pathways are envisioned. In path a, the
double bond in intermediate C′ might insert into the Rh−H
bond leading to intermediate D, which undergoes reductive
elimination to yield product 3 together with RhI species.
Alternatively, intermediate C′ undergoes reductive elimination
to deliver RhI species and o-alkenyl benzamide intermediate E.
Subsequently, intramolecular hydroamination of an alkene might
take place to deliver the desired product 3.17 Finally, the RhI
On the basis of our experimental results and the previous
literature,5,6 a plausible catalytic cycle is proposed for this
transformation (Scheme 6). Initially, an active catalyst Cp*Rh-
C
DOI: 10.1021/acs.orglett.6b02903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
species could be oxidized by AgOAc to regenerate the RhIII active
catalyst.
Catal. 2016, 6, 3909. (i) Thrimurtulu, N.; Dey, A.; Maiti, D.; Volla, C. M.
R. Angew. Chem., Int. Ed. 2016, 55, 12361.
(6) For other catalytic C−H functionalizations with allenes as the
coupling partner, see: (a) Zhang, Y. J.; Skucas, E.; Krische, M. J. Org. Lett.
2009, 11, 4248. (b) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2010,
49, 8181. (c) Kuninobu, Y.; Yu, P.; Takai, K. Org. Lett. 2010, 12, 4274.
(d) Zeng, R.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2012, 134, 9597. (e) Zeng,
R.; Wu, S.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2013, 135, 18284. (f) Ye, B.;
Cramer, N. J. Am. Chem. Soc. 2013, 135, 636. (g) Wang, H.; Beiring, B.;
Yu, D.-G.; Collins, K. D.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52,
12430. (h) Gong, T.-J.; Su, W.; Liu, Z.-J.; Cheng, W.-M.; Xiao, B.; Fu, Y.
Org. Lett. 2014, 16, 330. (i) Nakanowatari, S.; Ackermann, L. Chem. -
Eur. J. 2015, 21, 16246.
In summary, by using α-allenols as the coupling partners, we
have developed an efficient RhIII-catalyzed C−H functionaliza-
tion of aromatic and vinylic amides for the synthesis of
isoindolinone and 1,5-dihydro-pyrrol-2-one skeletons. The
hydroxyl group in the allene substrate is essential in controlling
the chemo- and regioselectivity of the reaction probably by
coordination interaction with the rhodium catalyst. Further
investigations on the synthetic application of this transformation
are in progress.
(7) (a) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212.
(b) Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta
2012, 45, 31. (c) Mesganaw, T.; Ellman, J. A. Org. Process Res. Dev. 2014,
18, 1097. (d) Zhou, L.; Lu, W. Chem. - Eur. J. 2014, 20, 634. (e) Muzart,
J.; Le Bras, J. Synthesis 2014, 46, 1555. (f) Gandeeoan, P.; Cheng, C.-H.
Chem. - Asian J. 2015, 10, 824.
(8) (a) Bjoere, A.; Bostroem, J.; Davidsson, O.; Emtenaes, H.; Gran,
U.; Iliefski, T.; Kajanus, J.; Olsson, R.; Sandberg, L.; Strandlund, G.; et al.
PCT Int. Appl. WO 2008008022, 2008. (b) Baldwin, J. J.; Cacatian, S.;
Claremon, D. A.; Dillard, L. W.; Flaherty, P. T.; Ishchenko, A. V.; Jia, L.;
McGeehan, G.; Simpson, R. D.; Singh, S. B.; et al.PCT Int. Appl. WO
2008156816, 2008.
(9) (a) Floch, L.; Nydegger, F.; Gossauer, A. Helv. Chim. Acta 1994, 77,
445. (b) Ito, M.; Okui, H.; Nakagawa, H.; Mio, S.; Iwasaki, T.; Iwabuchi,
J. Heterocycles 2002, 57, 881. (c) Chatzimpaloglou, A.; Yavropoulou, M.
P.; Rooij, K. E.; Biedermann, R.; Mueller, U.; Kaskel, S.; Sarli, V. J. Org.
Chem. 2012, 77, 9659. (d) Shionozaki, N.; Yamaguchi, T.; Kitano, H.;
Tomizawa, M.; Makino, K.; Uchiro, H. Tetrahedron Lett. 2012, 53, 5167.
(e) Nicolaou, K. C.; Shi, L.; Lu, M.; Pattanayak, M. R.; Shah, A. A.;
Ioannidou, H. A.; Lamani, M. Angew. Chem., Int. Ed. 2014, 53, 10970.
(f) Chatzimpaloglou, A.; Kolosov, M.; Eckols, T. K.; Tweardy, D. J.;
Sarli, V. J. Org. Chem. 2014, 79, 4043.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02903.
■
S
Experimental procedures and compound characterization
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: guixia@sioc.ac.cn.
*E-mail: xylu@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China
(2015CB856600), the National Natural Science Foundation of
China (21202184, 21232006, 21572255), and the Chinese
Academy of Sciences for financial support.
(10) For detailed optimization studies, see Table S1 in the Supporting
Information.
(11) The following benzamides bearing different substituents on the
amide group were also tested, but no reaction was observed: PhCONHR
(R = Me, Ph, Bn, Ts).
(12) An elevated temperature was necessary for N-methoxy-
acrylamides since most of the starting materials were recovered at
room temperature. In contrast, the reaction of N-methoxybenzamides
can proceed smoothly at room temperature and increasing the reaction
temperature could not improve the yield. These results indicate N-
methoxyacrylamides have lower reactivity compared with N-methoxy-
benzamides in this [4 + 1] annulation.
REFERENCES
■
(1) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-
VCH: Weinheim, 2003. (b) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008,
108, 3395.
(2) (a) Morden Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.;
Wiley-VCH: Weinheim, 2004. (b) Ma, S. Chem. Rev. 2005, 105, 2829.
(c) Ma, S. Pure Appl. Chem. 2006, 78, 197. (c1) Krause, N.; Winter, C.
Chem. Rev. 2011, 111, 1994.
(3) (a) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (b) Lechel,
T.; Reissig, H.-U. Pure Appl. Chem. 2010, 82, 1835. (c) Alcaide, B.;
Almendros, P. Chem. Record 2011, 11, 311. (d) Pinho e Melo, T. M. V.
D. Monatsh. Chem. 2011, 142, 681.
(4) For some recent reviews on transition metal catalyzed C−H
functionalization, see: (a) Rouquet, G.; Chatani, N. Angew. Chem., Int.
Ed. 2013, 52, 11726. (b) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42,
5744. (c) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369.
(d) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (e) Zhang, X.-S.;
(13) (a) Xu, Y.-H.; Lu, J.; Loh, T.-P. J. Am. Chem. Soc. 2009, 131, 1372.
(b) Wen, Z.-K.; Xu, Y.-H.; Loh, T.-P. Chem. - Eur. J. 2012, 18, 13284.
(c) Hu, X.-H.; Zhang, J.; Yang, X.-F.; Xu, Y.-H.; Loh, T.-P. J. Am. Chem.
Soc. 2015, 137, 3169.
(14) The possible regioisomeric product 3′ was not observed.
Chen, K.; Shi, Z.-J. Chem. Sci. 2014, 5, 2146. (f) Ros, A.; Fernan
́
dez, R.;
Lassaletta, J. M. Chem. Soc. Rev. 2014, 43, 3229. (g) Shi, G.; Zhang, Y.
Adv. Synth. Catal. 2014, 356, 1419. (h) Kuhl, N.; Schroder, N.; Glorius,
F. Adv. Synth. Catal. 2014, 356, 1443. (i) Guo, X.-X.; Gu, D.-W.; Wu, Z.;
Zhang, W. Chem. Rev. 2015, 115, 1622.
(5) For C−H functionalization with allenes for the synthesis of
heterocyles, see: (a) Wang, H.; Glorius, F. Angew. Chem., Int. Ed. 2012,
51, 7318. (b) Suresh, R. R.; Swamy, K. C. K. J. Org. Chem. 2012, 77,
6959. (c) Zeng, R.; Ye, J.; Fu, C.; Ma, S. Adv. Synth. Catal. 2013, 355,
1963. (d) Xia, X.-F.; Wang, Y.-Q.; Zhang, L.-L.; Song, X.-R.; Liu, X.-Y.;
Liang, Y.-M. Chem. - Eur. J. 2014, 20, 5087. (e) Wu, S.; Zeng, R.; Fu, C.;
Yu, Y.; Zhang, X.; Ma, S. Chem. Sci. 2015, 6, 2275. (f) Casanova, N.;
̈
(15) (a) Zhao, J.-F.; Duan, X.-H.; Yang, H.; Guo, L.-N. J. Org. Chem.
2015, 80, 11149. (b) Zhang, Z.-Q.; Liu, F. Org. Biomol. Chem. 2015, 13,
6690. (c) Su, B.; Wei, J.-B.; Wu, W.-L.; Shi, Z.-J. ChemCatChem 2015, 7,
2986.
(16) Shimp, H. L.; Hare, A.; McLaughlin, M.; Micalizio, G. C.
Tetrahedron 2008, 64, 3437.
(17) (a) Ding, D.; Mou, T.; Feng, M.; Jiang, X. J. Am. Chem. Soc. 2016,
138, 5218. (b) Ma, W.; Ackermann, L. ACS Catal. 2015, 5, 2822.
Seoane, A.; Mascarenas, J. L.; Gulías, M. Angew. Chem., Int. Ed. 2015, 54,
̃
2374. (g) Gandeepan, P.; Rajamalli, P.; Cheng, C.-H. Chem. - Eur. J.
2015, 21, 9198. (h) Kuppusamy, R.; Muralirajan, K.; Cheng, C.-H. ACS
D
DOI: 10.1021/acs.orglett.6b02903
Org. Lett. XXXX, XXX, XXX−XXX