Palladium-catalyzed asymmetric carbamoyl-carbonylation of alkenes

Article abstract of DOI:10.1007/s11426-021-9992-2

An unprecedented palladium-catalyzed asymmetric carbamoyl-carbonylation of tethered alkenes with CO and alcohols has been developed. This reaction provided an efficient route to access oxindoles and γ-lactams bearing β-carbonyl substituted quaternary carb

Full text of DOI:10.1007/s11426-021-9992-2

SCIENCE CHINA
Chemistry
•ARTICLES•
https://doi.org/10.1007/s11426-021-9992-2
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Palladium-catalyzed asymmetric carbamoyl-carbonylation of
alkenes
Ziwen Feng†, Qiuyu Li†, Long Chen, Hequan Yao* & Aijun Lin*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical
University, Nanjing 210009, China
Received February 27, 2021; accepted March 26, 2021; published online May 31, 2021
An unprecedented palladium-catalyzed asymmetric carbamoyl-carbonylation of tethered alkenes with CO and alcohols has been
developed. This reaction provided an efficient route to access oxindoles and γ-lactams bearing β-carbonyl substituted quaternary
carbons in good yields with excellent chemo-, regio- and enantioselectivity. Gram-scale synthetic capability and facile trans-
formations of the products to chiral spirooxindole and other functional molecules further illustrated the practicability of this
reaction.
carbonylation, oxindoles, γ-lactams, asymmetric catalytic synthesis, quaternary carbon stereocenters
Citation:
Feng Z, Li Q, Chen L, Yao H, Lin A. Palladium-catalyzed asymmetric carbamoyl-carbonylation of alkenes. Sci China Chem, 2021, 64, https://doi.org/
10.1007/s11426-021-9992-2
1 Introduction
or cyclization-bicarbonylation of alkenes has been far less
established and still suffers from low yields and enantios-
electivities (Scheme 1(a, b)) [5].
The transition-metal catalyzed carbonylation of alkenes with
carbon monoxide (CO) is a powerful process for the synth-
esis of valuable carbonylative compounds and has drawn
great attention from synthetic communities and industrial
production [1]. Moreover, lots of complex natural products
have been successfully synthesized with carbonylation re-
action as the key step [2]. However, the development of
asymmetric carbonylation is a long-time challenging task
due to the harsh conditions (e.g., high temperature or high
CO pressure) and the strong coordinative ability of CO with
metal. Benefitting from the development of chiral ligands
and newly catalytic systems, the significant advance has
been achieved for the transition-metal catalyzed asymmetric
carbonylation [3] and carbocyclization-carbonylation [4]
over the past few decades. Compared with monocarbonyla-
tion reaction, the transition-metal catalyzed bicarbonylation
Recently, carbamoyl chloride and its analogues tethered
alkenes have emerged as attractive synthons to access chiral
cyclic amides through transition-metal catalyzed cyclization
carbamoylation [6–10]. In 2020, Wang and coworkers [11]
described a nickel/photo-cocatalyzed acyl-carbamoylation of
pendant alkenes with aldehydes, a formal bicarbonylation of
activated alkenes. With our continuous efforts on the palla-
dium-catalyzed asymmetric tandem cyclization-carbonyla-
tion reaction [4d], herein, we describe a palladium-catalyzed
enantioselective carbamoyl-alkoxylcarbonylation via se-
quential carbamoylpalladation, CO insertion and alcoholysis
(Scheme 1(c)). Both activated and unactivated alkenes per-
formed the transformation well, and a series of en-
antioenriched oxindoles and γ-lactams bearing β-carbonyl
substituted quaternary carbons were achieved in good effi-
ciency. Several challenges should be addressed in this sce-
nario, including (1) the carbamoyl chlorides are prone to
esterification in the presence of alcohols; (2) the in situ
†These authors contributed equally to this work.
*Corresponding authors (email: hyao@cpu.edu.cn; ajlin@cpu.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021
chem.scichina.com link.springer.com

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Feng et al. Sci China Chem
room temperature for 5 min, and was allowed to stir at 80 °C
for 48 h. After the reaction vessel was cooled to room tem-
perature, the mixture was filtered and concentrated in vacuo.
The solution was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate = 10/1) to give the
desired γ-lactams 7.
3 Results and discussion
To explore the feasibility of our study, carbamoyl chloride
tethered alkene 1a was chosen as the model substrate (Table
1). After a thorough investigation of the reaction conditions,
Table 1 Optimization of reaction conditions (color online)
Scheme 1 Transition-metal catalyzed bicarbonylation reaction of alkenes
with CO (color online).
formed aminocarbonylpalladium species tend to undergo
decarbonylation; (3) the regioselectivity for the cyclization
carbamoylation should be well-controlled to avoid the six-
membered byproducts.
b)
Yield (%)
3a:4a:5a
a)
Entry
Variation of standard conditions
er of 3a c)
2 Experimental
1
2
none
95:0:0
96.5:3.5
93:7
2.1 General procedure for the asymmetric carbamoyl-
carbonylation of activated alkenes
L2 instead of L1
39:12:14
90:0:0
3
L3 instead of L1
78:22
To an oven-dried 10 mL Schlenk tube equipped with a stirred
bar was added carbamoyl chloride 1 (0.1 mmol, 1 equiv.),
Pd(OAc)2 (1.1 mg, 0.005 mmol, 5 mol%), L1 (5.8 mg,
0.01 mmol, 10 mol%), and K2HPO4 (52.3 mg, 0.3 mmol,
3 equiv.). The vial was thoroughly flushed with CO. Then
alcohol (0.3 mmol, 3 equiv.) and PhCl/acetone (9/1, 1.0 mL)
were added under balloon pressure of CO. Then the reaction
mixture was stirred at room temperature for 5 min, and was
allowed to stir at 80 °C for 30 h. After the reaction vessel was
cooled to room temperature, the mixture was filtered and
concentrated in vacuo. The solution was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate
= 5/1) to yield the desired oxindole 3.
4
L4 instead of L1
60:12:<5 84.5:15.5
5
L5 instead of L1
45:32:<5
n.d.d)
61:39
n.d.d)
6
L6 instead of L1
7
PhCl instead of PhCl:acetone (9:1)
acetone instead of PhCl:acetone (9:1)
MTBE instead of PhCl:acetone (9:1)
87:0:0
90:0:0
85:0:<5
95.5:4.5
93.5:6.5
82.5:17.5
52:48
8
9
10
11
12
CH2Cl2 instead of PhCl:acetone (9:1) 27:<5:35
KH2PO4 instead of K2HPO4
Cs2CO3 instead of K2HPO4
16:<5:<5
8:0:72
95.5:4.5
95:5
2.2 General procedure for the asymmetric carbamoyl-
carbonylation of unactivated alkenes
To an oven-dried 10 mL Schlenk tube with a stirring bar was
added carbamoyl chloride 6 (0.1 mmol, 1 equiv.), Pd(OAc)2
(2.2 mg, 10 mol%), L1 (11.6 mg, 0.02 mmol, 20 mol%) and
KHCO3 (30.0 mg, 0.3 mmol, 3 equiv.). The vial was thor-
oughly flushed with CO. Then alcohol (1 mmol, 10 equiv.)
and MeCN/acetone (1/2, 1.0 mL) were added under balloon
pressure of CO. Then the reaction mixture was stirred at
a) Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), Pd(OAc)2
(5 mol%), L (10 mol%), K2HPO4 (0.3 mmol) in 1.0 mL solvent, 80 °C (oil
bath temperature), 30 h, CO balloon. b) Isolated yields. c) Determined by
HPLC analysis. d) Not determined.

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Feng et al. Sci China Chem
the desired product 3,3-disubstituted oxindole 3a was
achieved in 95% yield with 96.5:3.5 er by employing
Pd(OAc)2 as the catalyst, (S)-MeO-BIPHEP (L1) as the ligand
and K2HPO4 as the base in mixed solvent (PhCl/acetone =
9/1) under balloon pressure of CO (entry 1). The absolute
configuration of 3a was unambiguously confirmed by X-ray
crystallography (see Supporting Information online for de-
tails). (S)-2-Furyl-MeOBIPHEP (L2) afforded 3a in good
enantioselectivity with low chemo- and regioselectivity, ac-
companied with undesired 6-endo-trig cyclization product 4a
in 12% yield and esterification product 5a in 14% yield
(entry 2). Other bidentate phosphine ligands, such as (S)-
Difluorphos (L3), (S,Rp)-Josiphos (L4) and (S,S)-DM-SDP
(L5), provided 3a in moderate enantioselectivities (entries 3–
5). The Box-type ligand L6 inhibited the transformation
(entry 6). Moreover, we investigated other solvents, while no
better results were achieved (entries 7–10). KH2PO4 per-
formed the reaction in low conversion, and Cs2CO3 led to
compound 5a as the major product (entries 11 and 12).
With the optimal reaction conditions in hand, we then in-
vestigated the substrate scope for the synthesis of oxindoles
(Scheme 2). Aryl carbamoyl chlorides 1 with various groups
on the phenyl ring proceeded smoothly to give the corre-
sponding oxindoles 3b–3h in 90%–99% yields with up to
96:4 er. The heteroaromatic ring, such as pyridine, was also a
suitable substrate, providing 3i in 91% yield. This reaction
also demonstrated good compatibility of R1 group. Lots of
(hetero)aromatic ring and alkyl groups were all well com-
patible, delivering 3j–3q in 92%–98% yields. Modifying the
substituent group on N atom with isopropyl or benzyl group,
products 3r and 3s were achieved in moderate yields with
good enantioselectivities. Subsequently, various alcohols
were investigated. Primary alcohols including those with
functional groups, such as acetal and trimethylsilyl groups,
were both accommodated, affording the products 3t–3x in
85%–97% yields with up to 96.5:3.5 er. Cyclic secondary
alcohols also proved to be qualified for this reaction (3y and
3z). With p-methoxyphenol as nucleophile, 3aa could be
furnished in 73% yield with 96:4 er. However, amines pose a
significant
challenge
to
this
carbamoyl-
carbonylation reaction due to their relatively strong amido-
lysis of carbamoyl chloride (see Supporting Information
online for details).
Inspired by these positive results, we turned our attention
to the construction of chiral γ-lactams. After optimizing the
reaction parameters such as ligands, bases, solvents and
temperature (see Supporting Information online for details),
the desired product 7a was ultimately achieved in 83% yield
and 96:4 er with Pd(OAc)2 as the catalyst, L1 as the ligand
and KHCO3 as the base in a mixed solvent (MeCN/acetone =
1/2) under balloon pressure of CO. Under the standard re-
action conditions, chiral γ-lactams 7b–7k were obtained in
good yields with up to 96:4 er (Scheme 3). The absolute
Scheme 2 Substrate scope for the synthesis of oxindoles (color online).
configuration of 7d was confirmed by X-ray crystallography
(see Supporting Information online for details). Replacing
the aryl group with benzyl, no desired product was detected,
and only premature esterification side product was achieved.
This result indicated that the N-protecting group is essential

4
Feng et al. Sci China Chem
Scheme 3 Substrate scope for the synthesis of γ-lactams (color online).
for this carbamoyl-carbonylation reaction.
From the view of versatility, we also investigated this re-
action with phenylboronic acid as the coupling reagent. After
a series of attempts, the corresponding product 3ab was
achieved in 55% yield with 91:9 er (Scheme 4(a), see Sup-
porting Information online for details). Subsequently, the
gram-scale experiment and various transformations of the
product 3a were carried out. As shown in Scheme 4(b),
product 3a (1.012 g) was provided in 98% yield by
prolonging the reaction time to 36 h. Reduction of 3a with 9-
borabicyclo[3.3.1]nonane (9-BBN) offered indoline deriva-
tive 8 in 95% yield. Compound 9 was obtained in 98% yield
through hydrolysis. Then, the manipulation of the acid unit
of 9 delivered the alcohol 10 and amide 11 in good yields.
Interestingly, the chiral spirooxindole 12, which is ex-
tensively prevailing in natural products and pharmaceuticals
[12], was achieved in 90% yield through chloration and
Friedel-Crafts acylation. (S)-3q was achieved in 91% yield
with 96:4 er by employing (R)-L1 as the ligand. Compound
13, the key intermediate for the synthesis of (−)-Physovenine
[13], was prepared in 90% yield from (S)-3q (Scheme 4(c)).
Scheme 4 Further study of the reaction (color online).
excellent yields with high enantioselectivities. The optically
pure spirooxindole, indoline and the precursor for the syn-
thesis of natural product (−)-Physovenine were all ex-
pediently achieved in good efficiency.
Acknowledgements This work was supported by the National Natural
Science Foundation of China (22071267), the Open Project of State Key
Laboratory of Natural Medicines (SKLNMZZ202023) and the Innovation
Team of “the Double-First Class” Disciplines (CPU2018GY35).
Conflict of interest The authors declare no conflict of interest.
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
tirely with the authors.
1
For selected reviews, see: (a) Yin Z, Xu JX, Wu XF. ACS Catal, 2020,
10: 6510–6531; (b) Peng JB. Adv Synth Catal, 2020, 362: 3059–3080;
(c) Chen Z, Wang LC, Wu XF. Chem Commun, 2020, 56: 6016–6030;
(d) Peng JB, Geng HQ, Wu XF. Chem, 2019, 5: 526–552; (e) Peng
JB, Wu XF. Angew Chem Int Ed, 2018, 57: 1152–1160; (f) Wu XF,
Fang X, Wu L, Jackstell R, Neumann H, Beller M. Acc Chem Res,
2014, 47: 1041–1053; (g) Wu XF, Neumann H, Beller M. Chem Soc
Rev, 2011, 40: 4986–5009; (h) Brennführer A, Neumann H, Beller M.
Angew Chem Int Ed, 2009, 48: 4114–4133; (i) Sumino S, Fusano A,
4 Conclusions
In conclusion, we have described an unprecedented palla-
dium-catalyzed asymmetric carbamoyl-carbonylation of al-
kenes. Both oxindoles and γ-lactams bearing β-carbonyl
substituted quaternary carbons were achieved in good to

5
Feng et al. Sci China Chem
Fukuyama T, Ryu I. Acc Chem Res, 2014, 47: 1563–1574; (j) Wu L,
Liu Q, Jackstell R, Beller M. Angew Chem Int Ed, 2014, 53: 6310–
6320; (k) Liu J, Yang J, Baumann W, Jackstell R, Beller M. Angew
Chem Int Ed, 2019, 58: 10683–10687; (l) Yang J, Liu J, Neumann H,
Franke R, Jackstell R, Beller M. Science, 2019, 366: 1514–1517;
(m) Qi X, Yu F, Chen P, Liu G. Angew Chem Int Ed, 2017, 56:
12692–12696; (n) Li M, Yu F, Qi X, Chen P, Liu G. Angew Chem Int
Ed, 2016, 55: 13843–13848
For selected reviews, see: (a) Ma K, Martin BS, Yin X, Dai M. Nat
Prod Rep, 2019, 36: 174–219; (b) Bai Y, Davis DC, Dai M. J Org
Chem, 2017, 82: 2319–2328; (c) Han A, Tao Y, Reisman SE. Nature,
2019, 573: 563–567; (d) Xu L, Wang C, Gao Z, Zhao YM. J Am Chem
Soc, 2018, 140: 5653–5658; (e) Ma K, Yin X, Dai M. Angew Chem Int
Ed, 2018, 57: 15209–15212; (f) Bai Y, Shen X, Li Y, Dai M. J Am
Chem Soc, 2016, 138: 10838–10841; (g) Ebner C, Carreira EM. An-
gew Chem Int Ed, 2015, 54: 11227–11230; (h) Shvartsbart A, Smith
Iii AB. J Am Chem Soc, 2014, 136: 870–873; (i) Jiao L, Yuan C, Yu
ZX. J Am Chem Soc, 2008, 130: 4421–4430
For selected examples, see: (a) Alper H, Hamel N. J Am Chem Soc,
1990, 112: 2803–2804; (b) You C, Li S, Li X, Lan J, Yang Y, Chung
LW, Lv H, Zhang X. J Am Chem Soc, 2018, 140: 4977–4981; (c) Yuan
Y, Wu F, Schünemann C, Holz J, Kamer PCJ, Wu X. Angew Chem Int
Ed, 2020, 59: 22441–22445; (d) Wu FP, Holz J, Yuan Y, Wu XF. CCS
Chem, 2021, 3: 2643–2654; (e) Yao YH, Yang HY, Chen M, Wu F,
Xu XX, Guan ZH. J Am Chem Soc, 2021, 143: 85–91
(a) Carmona RC, Köster OD, Correia CRD. Angew Chem Int Ed,
2018, 57: 12067–12070; (b) Hu H, Teng F, Liu J, Hu W, Luo S, Zhu
Q. Angew Chem Int Ed, 2019, 58: 9225–9229; (c) Chen M, Wang X,
Yang P, Kou X, Ren ZH, Guan ZH. Angew Chem Int Ed, 2020, 59:
12199–12205; (d) Yuan Z, Zeng Y, Feng Z, Guan Z, Lin A, Yao H.
Nat Commun, 2020, 11: 2544–2551
JM. J Am Chem Soc, 1996, 118: 5904–5918; (d) Negishi E, Ma S,
Amanfu J, Copéret C, Miller JA, Tour JM. J Am Chem Soc, 1996, 118:
5919–5931; (e) Olivieri D, Tarroni R, Della Ca' N, Mancuso R,
Gabriele B, Spadoni G, Carfagna C. Adv Synth Catal, 2020, 362: 533–
544; (f) Ukaji Y, Miyamoto M, Mikuni M, Takeuchi S, Inomata K.
Bull Chem Soc Jpn, 1996, 69: 735–742; (g) Carfagna C, Gatti G,
Mosca L, Natanti P, Paoli P, Rossi P, Gabriele B, Salerno G. Dalton
Trans, 2011, 40: 6792–6801; (h) Liang B, Liu J, Gao YX, Wongkhan
K, Shu DX, Lan Y, Li A, Batsanov AS, Howard JAH, Marder TB,
Chen JH, Yang Z. Organometallics, 2007, 26: 4756–4762; (i) Gao Y,
Chang L, Shi H, Liang B, Wongkhan K, Chaiyaveij D, Batsanov A,
Marder T, Li C, Yang Z, Huang Y. Adv Synth Catal, 2010, 352: 1955–
1966
(a) Yasui Y, Kamisaki H, Takemoto Y. Org Lett, 2008, 10: 3303–
3306; (b) Yasui Y, Kamisaki H, Ishida T, Takemoto Y. Tetrahedron,
2010, 66: 1980–1989
Wu X, Qu J, Chen Y. J Am Chem Soc, 2020, 142: 15654–15660
Marchese AD, Wollenburg M, Mirabi B, Abel-Snape X, Whyte A,
Glorius F, Lautens M. ACS Catal, 2020, 10: 4780–4785
Lan Y, Wang C. Commun Chem, 2020, 3: 45–53
2
6
7
8
3
9
10 Li Y, Zhang FP, Wang RH, Qi SL, Luan YX, Ye M. J Am Chem Soc,
2020, 142: 19844–19849
11 Fan P, Lan Y, Zhang C, Wang C. J Am Chem Soc, 2020, 142: 2180–
2186
12 (a) Matsuura T, Overman LE, Poon DJ. J Am Chem Soc, 1998, 120:
6500–6503; (b) Takano S, Moriya M, Ogasawara K. J Org Chem,
1991, 56: 5982–5984; (c) Brossi A, Yu Q, Luo W, Li Y. Heterocycles,
1993, 36: 1279–1285; (d) Luo W, Yu Q, Kulkarni SS, Parrish DA,
Holloway HW, Tweedie D, Shafferman A, Lahiri DK, Brossi A, Greig
NH. J Med Chem, 2006, 49: 2174–2185
13 For selected reviews, see: (a) Singh GS, Desta ZY. Chem Rev, 2012,
112: 6104–6155; (b) Kaur M, Singh M, Chadha N, Silakari O. Eur J
Med Chem, 2016, 123: 858–894; (c) Pandey G, Mishra A, Khamrai J.
Tetrahedron, 2018, 74: 4903–4915
4
5
(a) Tour JM, Negishi E. J Am Chem Soc, 1985, 107: 8289–8291;
(b) Copéret C, Ma S, Negishi E. Angew Chem Int Ed Engl, 1996, 35:
2125–2126; (c) Negishi E, Copéret C, Ma S, Mita T, Sugihara T, Tour