Palladium-catalyzed intermolecular dearomatic allenylation of hydrocycloalk[b]indoles with 2,3-allenyl carbonates

Abstract

A palladium-catalyzed intermolecular dearomatic allenylation of hydrocycloalk[b]indoles with 2,3-allenyl carbonates has been developed, providing access to functionalized allenes containing an indoline unit under optimized conditions. Both terminal and non-terminal allenes could react smoothly with an exclusive chemoselectivity and good yields by applying different reaction parameters.

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Indoles are attractive and fundamental structural motifs in numerous natural products and pharmaceuticals.¹ In addition, the nucleophilicity of C-3 of indoles leads to numerous transformations.² In 2004, Ma's group developed a palladium-catalyzed functionalization of 2-electron-deficient group-substituted acetates with indoles (Scheme 1A).^2e Starting from 2008, Rawal (Scheme 1B),^3a Du,^3b and You^3c,d reported that 2,3-disubstituted indoles could react with allylic carbonates in the presence of a palladium catalyst. On the other hand, allenes are playing an increasingly important role in organic chemistry and medicinal chemistry.^4,5 Much attention has been paid to the reaction of 2,3-allenol derivatives with different nucleophiles.^6–8 Herein, we wish to provide an efficient method for synthesizing functionalized allenes via the dearomatization of hydrocycloalk[b]indoles (Scheme 1C).

Scheme 1 (A) Palladium-catalyzed functionalization of electron-deficient alkenes with indoles. (B) Dearomatization of indoles derivatives with allylic carbonate. (C) Dearomatization of hydrocycloalk[b]indoles with 2,3-allenyl carbonates.

In principle, there are two types of reactivities for such a coupling reaction of 2,3-allenyl carbonates, generating two different products, allenes A and 1,3-dienes B, upon the treatment with an electrophile. We initiated our study with 1,2,3,4-tetrahydrocyclopenta[b]indole 1a ⁹ and buta-2,3-dienyl methyl carbonate 2a ^10a–c followed by an immediate trapping of the possible imine product Int A or Int B with methyl chloroformate. The formation of enamine 4aaa was observed, albeit in <10% yield using P, N ligand L1 or monophosphine ligand L2. Bisphosphines with the difference of a length of carbon chain had a very limited influence on the reaction. Interestingly, decent levels of the reaction were observed by using commercially available dpbp L8 and DPEphos L9 (Table 1).

Table 1 Identifying the ligand^a

Entry	Ligand	t 1/t2 (h)	NMR yield of 4aaa^b (%)
a Reaction conditions: The reactions were carried out using 0.2 mmol of 1a, 0.26 mmol of 2a, 2.5 mol% of Pd2(dba)3, 5.5 mol% of L and 2 mL of DCM at 50 °C. After the reactions were complete, 0.8 mmol of pyridine and 0.6 mmol of ClCO2Me were added at room temperature. b Determined by using CH2Br2 as the internal standard. c 11 mol% of L was added.
1^c	L1	6.5/10	6
2^c	L2	9.7/11.3	5
3	L3	6.5/10	10
4	L4	6.5/10	NR
5	L5	9.7/11.3	8
6	L6	9.7/11.3	26
7	L7	9/13	8
8	L8	32.7/overnight	53
9	L9	8.7/overnight	64

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Further optimization of the reaction conditions indicated that increasing the amount of substrate 2a to 2.0 equiv. had no influence on the reaction. Elevating the reaction temperature even led to a worse result (entry 3, Table 2). Adding molecular sieves had a slight influence on the reaction (entries 4 and 5, Table 2). Interestingly, there is a profound base effect: with N,O-bis-(trimethylsilyl)-acetamide (BSA) as the base, the reaction afforded the best result (entries 6–9, Table 2). By reducing the concentration, the yield could be further improved (entry 10, Table 2).

Table 2 Optimization of reaction conditions: reaction of 1,2,3,4-tetrahydrocyclopenta[b]indole 1a and 2,3-butadienyl carbonate 2a^a

Entry	Additives	t 1/t2 (h)	Yield of 4aaa^b (%)
a Reaction conditions: Unless otherwise specified, the reactions were carried out using 0.2 mmol of 1a, 1.3 equiv. of 2a, 1.0 equiv. of additive, 2.5 mol% of Pd2(dba)3, and 5.5 mol% of L9 in 2.0 mL of DCM at 50 °C. After the reactions were complete, 0.8 mmol of pyridine and 0.6 mmol of ClCO2Me were added at room temperature. b The yield was determined by NMR analysis of the crude product. c The reaction was carried out with 2.0 equiv. of 2a. d The reaction was carried out at 80 °C. e 100 mg of additive was added. f The reactions were carried out using 0.2 mmol of 1a, 1.3 equiv. of 2a, 1.0 equiv. of additive, 2.5 mol% of Pd2(dba)3, and 5.5 mol% of L9 in 2.0 mL of DCM at 50 °C. After the reactions were complete, the additive was filtered from the solution. 2 mL of DCM, 0.8 mmol of pyridine and 0.6 mmol of ClCO2Me were added at room temperature. g The reaction was carried out in 4 mL of DCM. h Isolated yield. i The reaction was carried out in 1 mL of DCM.
1	—	8.7/overnight	64
2^c	—	11.5/15	64
3^d	—	3.5/13.5	56
4^e^,^f	3 Å MS	8/overnight	66
5^e^,^f	4 Å MS	8/overnight	58
6^f	KO^tBu	8.5/13.5	13
7^f	K3PO4	7.5/15.5	61
8^f	MgSO4	9.6/12.5	59
9	BSA	6.5/15.5	83
10^g	BSA	10/3	87 (80^h)
11^i	BSA	6.7/16.8	83

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The scope for the electrophilic trapping reagent was also studied. In addition to chloroformate, different acyl chlorides such as acetyl chloride, propionyl chloride, isobutyryl chloride, chloroacetyl chloride, benzoyl chloride, cinnamoyl chloride, and benzenesulfonyl chloride may be applied (Table 3).

Table 3 The scope of the electrophilic trapping reagents for the reaction of 1a and 2a

Entry	R′	Conditions (A/B)	t 1/t2 (h)	Yield of 4^c (%)
a Conditions A: The reaction was carried out using 0.2 mmol of 1a, 1.3 equiv. of 2a, 1.0 equiv. of BSA, 2.5 mol% of Pd2(dba)3, and 5.5 mol% of L9 in 4.0 mL of DCM at 50 °C and monitored by TLC or LC-MS. After the reaction was complete, 4.0 equiv. of pyridine and 3.0 equiv. of corresponding 3 were added at room temperature. b Conditions B: The reaction was carried out using 0.2 mmol of 1a, 1.3 equiv. of 2a, 1 equiv. of BSA, 1 equiv. of Et3B, 4 mol% of Pd(acac)2, and 6 mol% of L9 in 4.0 mL of DCM at room temperature and monitored by TLC or LC-MS. After the reaction was complete, 4.0 equiv. of pyridine and 3.0 equiv. of corresponding 3 were added at room temperature. c Isolated yield.
1		A	6.5/21	79 (4aab)
2		A	6.3/16.8	86 (4aac)
3		B	8/3	91 (4aad)
4		B	8/3	88 (4aae)
5		A	6.4/21.3	63 (4aaf)
6		A	6.3/29.8	58 (4aag)
7		B	8/3	58 (4aah)

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However, when non-terminal hepta-2,3-dienyl methyl carbonate 2b ^10c,d was applied under conditions A, only 38% yield of 4abb was obtained (entry 1, Table 4). Thus, we commenced to optimize the reaction conditions for the substituted allenylic carbonates. With ZnCl₂, no product was generated (entry 2, Table 4). There was a slight increase in the yield when 1 equiv. Et₃B was added since Et₃B may further activate indoles by forming a N–B bond¹¹ (entry 3, Table 4).

Table 4 Further optimization with hepta-2,3-dienyl methyl carbonate 2b^a

Entry	[Pd]	T (°C)	t 1/t2 (h)	Yield of 4abb ^b (%)
a Reaction conditions: The reaction was carried out using 0.2 mmol of 1a, 1.3 equiv. of 2b, 1 equiv. of BSA, 1 equiv. of Et3B, 2.5 mol% of [Pd] and 5.5 mol% of L9 in 4.0 mL of DCM at room temperature and monitored by TLC or LC-MS. After the reaction was complete, 4 equiv. of pyridine and 3 equiv. of CH3COCl (3b) were added at room temperature. b The yield was determined by NMR analysis. c No Et3B was added. d The reaction was carried out with 2 equiv. of ZnCl2 instead of Et3B. e 0.5 equiv. of Et3B was added. f 0.1 equiv. of Et3B was added. g 4 mol% [Pd] and 6 mol% of L9 were added.
1^c	Pd2(dba)3	50	9/12	38
2^d	Pd2(dba)3	50	7.8/—	—
3	Pd2(dba)3	50	8/8.3	41
4	Pd2(dba)3	45	9/11.2	45
5^e	Pd2(dba)3	45	9/11.2	37
6^f	Pd2(dba)3	45	9/11.2	26
7	Pd2(dba)3	40	8/8	60
8	Pd2(dba)3	35	8/11.3	81
9	Pd2(dba)3	rt	9/11.3	91
10^g	Pd(OAc)2	rt	9/10.8	77
11^g	Pd(cod)Cl2	rt	9/11.3	68
12^g	Pd(acac)2	rt	8/12.3	92

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When we reduced the amount of Et₃B, the yield decreased (entries 4–6, Table 4). To our delight, when we carried out the reaction at room temperature, 91% yield could be obtained (entry 9, Table 4). Unfortunately, the product could not be purified due to the contamination of the dba from the catalyst. Therefore other Pd catalysts were tested (entries 10–12, Table 4). Finally, Pd(acac)₂, DPEphos, BSA and Et₃B in DCM at room temperature were defined as the optimized reaction conditions for further study (conditions B).

With conditions A and B in hand, we began to investigate the scope of this reaction. Satisfactory yields could be observed regardless of the electronic properties on the indole moiety (entries 1–8, Table 5). It is worth noting that the MeO, F, Cl, and Br groups could also be tolerated. For allenylic carbonates, R² may be C₃H₇ and C₇H₁₅, alkenyl, alkynyl and phenethyl groups (entries 9–13, Table 5).

Table 5 The scope for the reaction of 1,2,3,4-tetrahydrocyclopenta[b]indole and 2,3-allenylic carbonate derivative

Entry	R^1	R^2	Conditions (A/B)	t 1/t2 (h)	Yield of 4^c (%)	dr^d
a Conditions A: The reaction was carried out using 0.2 mmol of 1, 1.3 equiv. of 2, 1 equiv. of BSA, 2.5 mol% of Pd2(dba)3, and 5.5 mol% of L9 in 4.0 mL of DCM at 50 °C and monitored by TLC or LC-MS. After the reaction was complete, 4.0 equiv. of pyridine and 3.0 equiv. of CH3COCl (3b) were added at room temperature. b Conditions B: The reaction was carried out using 1.0 mmol of 1, 1.3 equiv. of 2, 1 equiv. of BSA, 1 equiv. of Et3B, 4 mol% of Pd(acac)2, and 6 mol% of L9 in 20 mL of DCM at room temperature and monitored by TLC or LC-MS. After the reaction was complete, 4.0 equiv. of pyridine and 3.0 equiv. of CH3COCl (3b) were added at room temperature. c Isolated yield. d Determined by quantitative ^13C NMR experiment.
1	7-Me (1b)	H (2a)	A	5.6/21.8	83 (4bab)	—
2	6-Me, 8-Me (1c)	H (2a)	B	8/12.3	81 (4cab)	—
3	7-MeO (1d)	H (2a)	A	4.5/20	88 (4dab)	—
4	7-Ph (1e)	H (2a)	A	4.5/19	89 (4eab)	—
5	7-F (1f)	H (2a)	A	4.5/17.4	85 (4fab)	—
6	7-Cl (1g)	H (2a)	A	4.5/16.5	85 (4gab)	—
7	7-Br (1h)	H (2a)	A	5.3/22	78 (4hab)	—
8	6-Br (1i)	H (2a)	B	10/11.5	80 (4iab)	—
9	H (1a)	n-C3H7 (2b)	B	8/13	68 (4abb)	1.2/1
10	H (1a)	n-C7H15 (2c)	B	10/8	60 (4acb)	1.4/1
11	H (1a)		B	10/13	48 (4adb)	1.1/1
12	H (1a)		B	8/11	68 (4aeb)	1.2/1
13	H (1a)		B	8/9	78 (4afb)	1.4/1

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The reaction may be easily conducted on 5 mmol scale of 1a, affording 4aab in 83% yield.

For acyclic indoles, the dearomatization reaction could also be conducted smoothly to afford indoline with an exocyclic C–C double bond 4jab (Scheme 2).

Scheme 2 Dearomatic reaction of acyclic indole 1j.

A possible mechanism is proposed. The oxidative addition of Pd(0) with 2,3-allenyl carbonates would yield, after releasing CO₂, methyleneallylic palladium intermediate I, which could react with the indole to yield the product 4via intermediate II by releasing the catalytically active Pd(0) to finish the catalytic cycle. Since 1,3-diene product 5 was not detected in this reaction, the C3-carbon atom of the indole is acting as a soft nucleophile attacking the C1-atom in allenyl carbonates 2 (Scheme 3).¹²

Scheme 3 A proposed mechanism.

In summary, a palladium-catalyzed intermolecular dearomatization of hydrocycloalk[b]indoles with 2,3-allenyl carbonates was first developed with a high chemoselectivity affording functionalized allene-substituted hydrocycloalk[b]indolines. Both mono-substituted and 1,3-disubstituted allenes could be generated smoothly with nucleophilic indoles. Further exploration of synthesizing optically active allenes with various nucleophiles is ongoing in our laboratory.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the National Basic Research Program of China (2015CB856600 for S. Ma and S.-L. You), the National Natural Science Foundation of China (21572252 for S.-L. You), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000 and QYZDY-SSW-SLH012 for S.-L. You) is greatly appreciated. We thank Penglin Wu for reproducing the results for 4fab and 4adb presented in Table 5 and 4aag presented in Table 3.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Preparation and characterisation data as well as ¹H and ¹³C NMR spectra of all compounds. See DOI: 10.1039/c8qo00163d

‡ These authors contributed equally.

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