Efficient Synthesis of 3,6-Dialkylcarbazole-1-formaldehyde and 3,6-Dialkylcarbazole-1,8-diformaldehyde

doi:10.6023/cjoc202101001

Abstract

The currently reported synthesis methods of carbazole-1-formaldehyde or carbazole-1,8-diformaldehyde have some drawbacks, such as long synthetic steps with low yield, high toxicity of reagents, or high risk of operation, which affected the progress of synthesis and application of subsequent derivatives. In this work, the 9-NH of bromocarbazole was protected by 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl), the subsequent formylation was successfully accomplished by n-butyllithium/N,N-dimethylformamide (DMF) instead of tert-butyllithium/DMF to reduce the risk of operation process. Finally, a safe and efficient method that is more suitable for large-scale preparation of 3,6-dialkylcarbazole-1-formaldehyde or 1,8-diformaldehyde was developed. In addition, the reactivity of carbazole-1-formaldehyde or 1,8-diformaldehyde was explored, and a series of tridentate or bidentate ligands were successfully prepared.

Key words: carbazole, formylation, carbazole-1-formaldehyde, carbazole-1, 8-diformaldehyde

Cite this article

Yu Zhao, Yang Liu, Xinxin Wang, Yingying Hong, Yingxiu Man, Jinjun Wang, Jiazhu Li. Efficient Synthesis of 3,6-Dialkylcarbazole-1-formaldehyde and 3,6-Dialkylcarbazole-1,8-diformaldehyde[J]. Chinese Journal of Organic Chemistry, 2021, 41(6): 2435-2444.

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Entry^a	Protection	PG	Product^a	n-BuLi/DMF (equiv.)^b	T^c/℃	Time^d/h	Deprotection	Yield^e/% of 5
1	n-BuLi/TMSCl	TMS	4a	—	—	—	—	—
2	n-BuLi/CO₂	CO₂^-	4b	—	—	—	—	—
3	DMAP/Boc₂O	Boc	4c	—	—	—	—	—
4	NaH/Boc₂O		4c	—	—	—	—	—
5	n-BuLi/Boc₂O		4c	—	—	—	—	—
6	NaH/ClCO₂Me	CO₂Me	4d	—	—	—	—	—
7	n-BuLi/ClCO₂Me	CO₂Me	4d	—	—	—	—	—
8	NaH/CbzCl	Cbz	4e	—	—	—	—	—
9	n-BuLi /CbzCl	Cbz	4e	—	—	—	—	—
10	NaH/MOMCl	MOM	4f	2.2/5	0/r.t.	0.5/1	—	—
11			4f	2.2/5	–40/r.t.	0.5/1	HCl	18
12			4f	2.2/5	–78/r.t.	0.5/1	HCl	33
13			4f	2.2/10	–78/r.t.	1/2	HCl	56
14			4f	3/20	–78/r.t.	2/12	HCl	55
15	NaH/SEMCl	SEM	4g	2.2/5	–40/r.t.	0.5/1	TBAF	32
16			4g	2.2/5	–78/r.t.	0.5/2	TBAF	67
17			4g	2.2/10	–78/r.t.	0.5/2	TBAF	79
18			4g	2.2/10	–78/r.t.	1/2	TBAF	93
19			4g	2.2/10	–78/r.t.	1/2	HCl^f	92
20			4g	3/20	–78/r.t.	2/12	HCl^f	90

Entry^a	Protection	PG	Product^a	n-BuLi/DMF (equiv.)^b	T^c/℃	Time^d/h	Deprotection	Yield^e/% of 5
1	n-BuLi/TMSCl	TMS	4a	—	—	—	—	—
2	n-BuLi/CO₂	CO₂^-	4b	—	—	—	—	—
3	DMAP/Boc₂O	Boc	4c	—	—	—	—	—
4	NaH/Boc₂O		4c	—	—	—	—	—
5	n-BuLi/Boc₂O		4c	—	—	—	—	—
6	NaH/ClCO₂Me	CO₂Me	4d	—	—	—	—	—
7	n-BuLi/ClCO₂Me	CO₂Me	4d	—	—	—	—	—
8	NaH/CbzCl	Cbz	4e	—	—	—	—	—
9	n-BuLi /CbzCl	Cbz	4e	—	—	—	—	—
10	NaH/MOMCl	MOM	4f	2.2/5	0/r.t.	0.5/1	—	—
11			4f	2.2/5	–40/r.t.	0.5/1	HCl	18
12			4f	2.2/5	–78/r.t.	0.5/1	HCl	33
13			4f	2.2/10	–78/r.t.	1/2	HCl	56
14			4f	3/20	–78/r.t.	2/12	HCl	55
15	NaH/SEMCl	SEM	4g	2.2/5	–40/r.t.	0.5/1	TBAF	32
16			4g	2.2/5	–78/r.t.	0.5/2	TBAF	67
17			4g	2.2/10	–78/r.t.	0.5/2	TBAF	79
18			4g	2.2/10	–78/r.t.	1/2	TBAF	93
19			4g	2.2/10	–78/r.t.	1/2	HCl^f	92
20			4g	3/20	–78/r.t.	2/12	HCl^f	90

3,6-二烃基咔唑-1-甲醛和3,6-二烃基咔唑-1,8-二甲醛的高效合成