Butadienyl Ketene: An Unexplored Intermediate in Organic Synthesis

Abstract

Butadienyl ketene is a useful intermediate because of its role as a 2p-component in cycloaddition reactions with a variety of substrates such as simple or conjugated imines and dienes. This review article summarizes recent reports on the generation of butadienyl ketene in situ and their cycloaddition reactions to afford heterocyclic systems. The chemistry of butadienyl ketene is explored with a focus on its [2+2] and [4+2] cycloaddition reactions with a variety of imines and azadiene derivatives such as 1,3-diazabuta-1,3-dienes, for the synthesis of four- and six-membered heterocycles, respectively.

Key words

ketenes - butadienyl ketene - dienyl ketene - [2+2] cycloaddition - [4+2] cycloaddition - lactams - pyrimidinones

Biographical Sketches

Maninderjeet Kaur Mann completed her PhD in chemical sciences under the supervision of Dr. Gaurav Bhargava at IK Gujral Punjab Technical University, Jalandhar. She has research experience in synthetic chemistry.

Simranpreet K. Wahan is DST Inspire JRF at IK Gujral Punjab Technical University, Jalandhar. She is a gold medalist in Masters of Science (Chemistry) at Punjab University, Chandigarh. She has many publications in various reputable journals.

Nitin Tandon works as Associate Professor at Lovely Professional University, Jalandhar. His research work includes the synthesis of active pharmaceutical ingredients and the synthesis of novel organic molecules for medicinal use.

Gaurav Bhargava is Head of Department in the Department of Applied Sciences, IK Gujral Punjab Technical University, Jalandhar. He has rich research experience in green chemistry and synthetic organic chemistry and various publications in reputable international journals.

1

Introduction

Ketenes are one of the most well-known and versatile organic synthetic intermediates (Figure [1]). Ketenes, commonly presented as the ‘neutral’ cumulene form (H₂C_β=C_α=O), are generally in resonance with the ‘zwitterionic’ form with the oxygen atom bearing a partially positive charge and the C_β atom bearing a partial negative charge.[1] Because of the fascinating electronic structure of ketenes, these species have been the subject of intense investigation,[1] [2] and the appearance of ketenes in organic synthesis has become more frequent over the past few decades.[3,4] A very common reaction of ketenes – the Staudinger reaction – involves [2+2] cycloaddition of ketene derivatives and imines and proceeds via zwitterionic intermediate,[5] providing a useful method for the preparation of biologically potent lactams. The syntheses of carbo- and heterocyclic systems involving the [2+2] cycloaddition of ketenes with alkenes and iminic systems have been explored extensively.[3] Furthermore, there are many reports on the exploration of conjugated ketenes, namely vinyl and isopropenyl ketenes, for the synthesis of functionalized heterocyclic compounds.[6] [7] The reactions of various Schiff bases with vinyl/isopropenyl ketenes resulted in β-lactams with trans-, cis-, or a mixture of trans- and cis-isomers.[8] [9] [10]

Figure 1 Ketenes explored in chemical reactions

However, compared with other conjugated ketenes such as vinyl and isopropenyl ketene, butadiene ketene has been less extensively explored in [m+n] cycloaddition reactions with different substrates acting as 2π- or 4π-components. There are some reports on [2+2] and [4+2] cycloaddition reactions of the butadienyl ketene with imines and dienes, respectively, to afford functionalized heterocycles with rich synthetic potential. In an effort to highlight the synthetic potential of butadienyl ketene and to arouse the interest of the synthetic community in capturing the unleashed potential of the butadienyl intermediate, this review article summarizes the generation of butadienyl ketene and applications of the cycloaddition reaction reported since 1982.

2

Generation of Butadienyl Ketene

Butadienyl ketene was first observed during the preparation of 3,5-hexadienoic esters by Thomas R. Hoye et al. in 1982.[3g] Sorboyl chloride 2 was prepared by refluxing sorbic acid and thionyl chloride. For the preparation of conjugated methallyl ester 1a, triethylamine was used to catalyze the acylation of sorboyl chloride 2 using methallyl alcohol. However, the formation of a substantial portion of conjugated isomer 5a was observed in addition to 1a (Table [1]). This side reaction proceeded via butadienyl ketene 4. The addition of one equivalent of triethylamine to sorboyl chloride resulted in the formation of acyl triethylammonium ion 3.[2] Acyl triethylammonium ion 3 then underwent direct addition reaction with alcohol to afford conjugated ester 1; however, acyl triethylammonium ion 3 also formed ketene 4, which, on reaction with a second molecule of triethylamine, resulted in the formation of conjugated ester 5 on reaction with alcohol.[3]

Table 1 Generation of Butadienyl Ketene 4 and Conversion into Conjugated Ester 5

Compound	ROH	Yield (%)	Ratio 1/5
a	CH2=C(CH3)CH2OH	76	1:>10
b	CH2=CHCH2OH	68	1:>10
c	MeOH	100	1:2
d	EtOH	88	1:>10
e	tBuOH	70	1:>10
f	PhOH	100	1:0
g	CH2=CHCH2NH2	0	~10:1
h	(iPr)2NH	84	1:1
i	H2O	0	conjugated anhydride

2.1 [2+2] Cycloaddition Reactions of Butadienyl Ketene

Nitrogen-containing organic molecules such as amino alkaloids have immense significance in organic chemistry.[11] The synthesis of such nitrogenous compounds by employing cycloadditions of functionalized ketene is a vital methodology in organic chemistry.[12] [13] In 1995, Mahajan and co-workers explored the [2+2] cycloaddition reactions of Schiff bases 6 with butadienyl ketene, generated in situ from sorboyl chloride 2 in the presence of a mild base, to yield trans-3-butadienyl β-lactam derivatives 7 diastereoselectively (48–63%; Table [2]).[14] The synthetic potential of the 3-dienyl-2-azetidinones 7 was explored by employing catalyzed and uncatalyzed Diels–Alder cycloaddition reactions with electron-deficient dienophiles such as dimethylacetylene dicarboxylate (DMAD),[15] [16] [17] maleic anhydride (MA), N-phenylmaleimide (NPM), and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). The cycloaddition reactions of butadienyl ketene with various imines and 1-azabuta-1,3-dienes proved to be a general method for the synthesis of butadienyl-substituted functionalized lactams in good yields.

Table 2 Synthesis of 3-Butadienyl-β-lactams

Compound	R1	R2	Yield of 7 (%)
a	H	H	59
b	H	OCH3	63
c	CH3	H	59
d	CH3	OCH3	48

Table 3 Formation of cis-Butadienyl-4-iminomethyl-azetidin-2-ones and Bis-β-lactams

Compound	R	Yield (%)
		9	10
a	p-CH3-C6H5	47	15
b	o-CH3-C6H5	41	13
c	C6H5	25	0
d	p-OCH3-C6H5	5	0
e	C6H11	0	0

Scheme 1 Regioselective [4+2] cycloaddition reactions for the synthesis of 5-butadienyl pyrimidinones

Scheme 2 Cycloaddition of 1,2-diaryl-4-methylthio-4-secondary amino-l,3-diazabuta-l,3-dienes 21 with butadienyl ketene 4

In 2015, Bhargava et al. explored the [2+2] cycloaddition of butadienyl ketene, generated in situ, with a variety of 1,4-diazadienes.[18a] The diastereoselective [2+2] cycloaddition afforded functionalized butadienyl-4-iminomethyl-azetidin-2-one and butenylidene-butadienyl-[2, 2′-biazetidine]-4, 4′-dione. The butadienyl ketene, generated in situ from sorboyl chloride 2 using a mild base, underwent [2+2] cycloadditions with 1,4-diazabuta-1,3-dienes 4a–e to yield mono- as well as bis-β-lactams (Table [3]). The synthesis of mono-β-lactams 9a–c or bis-β-lactams 10a–c was highly dependent on the concentration of the acid chloride used in the reaction medium. The use of an equimolar amount of sorboyl chloride in [2+2] cycloadditions with 1,4-diazabuta-1,3-dienes afforded mono-β-lactam, i.e., cis-butadienyl-4-iminomethyl-azetidin-2-one derivatives 9, as the major product. The [2+2] cycloaddition reactions using a higher number of equivalents of sorboyl chloride with 1,4 diazabuta-1,3-dienes 8 afforded bis-β-lactams, i.e., 10a–c, as the major product. This is probably due to the tandem [2+2] cycloaddition of the in-situ generated butadienyl ketene with the second imine of the 1,4-diazabuta-1,3-dienes to afford butenylidene-butadienyl-[2,2′-biazetidine]-4,4′-dione 10 as the major cycloadduct.[19]

Scheme 3 [4+2] cycloaddition of butadienyl ketene 4 and 1,3-diazabuta-l,3-dienes 25

Table 4 Synthesis of a Series of α-Alkylidene-β-lactam Derivatives

Entry	R1	R2	Yield (%)
			12	13
a	C6H5	C6H5	15	60
b	p-CH3-C6H4	C6H5	15	62
c	p-Cl-C6H4	C6H5	12	48
d	p-OCH3-C6H4	C6H5	11	46
e	C6H11	C6H5	13	52
f	C6H5	p-Cl-C6H4	10	40
g	p-CH3-C6H4	p-Cl-C6H4	11	15
h	p-Cl-C6H4	p-Cl-C6H4	10	41

Table 5 Synthesis of 3-Dienyl-β-lactams as Inhibitors Targeting a Colchicine Binding Site

Entry	R1	R2	R3	Yield (%)
a	NO2	H	H	33
b	Cl	H	H	32
c	Br	H	H	44
d	F	H	H	20
e	N(CH3)2	H	H	16
f	H	H	H	37
g	CH3	H	H	40
h	OCH3	H	H	31
i	OCH2CH3	H	H	41
j	O(CH2)3CH3	H	H	48
k	OPh	H	H	33
l	OCH2Ph	H	H	41
m	H	1-naphth	1-naphth	27
n	1-naphth	1-naphth	H	53
o	OCH3	OTBDMS	H	37
p	OCH3	OH	H	25
q	OCH3	NO2	H	59
r	OCH3	NH2	H	45

In 2018, Bhargava et al. explored the reactions of sorboyl tosylate at high temperature (80 °C) with a variety of imines to yield mixtures of 3-dienyl lactam 12 and α-alkylidene-β-lactams 13. The formation of dienyl lactam at elevated temperature was mediated through a [2+2] cycloaddition of in-situ generated butadienyl ketene and imines. However, the formation of α-alkylidene-β-lactams 13 involved the addition of the sorbic tosylate to the imine nitrogen of 11 to afford a zwitterionic intermediate 13A, which collapsed to intermediate 13B by ring-closure electrocyclization. Abstraction of an acidic ring proton by the base led to the formation of 3-but-2-enylidene-azetidin-2-ones 13 as the major adduct (Table [4]). Density functional theory calculations were performed to understand the outcome of the cycloaddition reaction and the results were used to predict a plausible mechanism for the reaction. As a result, a mixture of 3-butadienyl-azetidin-2-ones 12 and 3-but-2-azetidin-2-ones 13 was afforded in appreciable yield at elevated temperature.[19]

Wang et al. designed and synthesized three series of 3-dienyl-β-lactams as inhibitors targeting a binding site of colchicine.[20] The imines 16 were accessed via butadienyl ketene generated in situ by the action of sorbic acid and suitable base in dichloromethane to afford 3-(buta-1,3-dien-1-yl)azetidin-2-ones 17 (Table [5]). Derivatives 17 also exhibited in vitro antitumor activity against the MCF-7 breast cancer cell line, with IC₅₀ values of 23–33 nM.[20]

2.2 [4+2] Cycloaddition Reactions of Butadienyl Ketene­

Regioselective [4+2] cycloaddition reaction of N-benzothiazolyl-fused 1,3-diazabuta-1,3-dienes was explored for the synthesis of pyrimidinone-fused benzathiazoles.[21] The [4+2] cycloaddition reaction between benzothiazolyl linked 1,3-diazabuta-1,3-dienes 18 and butadienyl ketene 19, generated in situ, resulted in the formation of 5-butadienyl pyrimidinones 20 (Scheme [1]). The mechanistic approach for the [4+2] cycloadditions involved a nucleophilic attack by the benzothiazole nitrogen on the carbonyl of ketene to form an intermediate that afforded tricyclic condensed pyrimidinones via internal rearrangement and tandem cyclization.[21]

There are reports on the synthesis of 5-dienyl pyrimidinones 22 using [4+2] cycloadditions of 1,3-diazabuta-1,3-dienes 21 with butadienyl ketene.[15] The [4+2] cycloadditions of various 1-aryl-2-phenyl-4-methylthio-4-secondary amino-l,3-diazabuta-l,3-dienes 21a–d with butadienyl ketene 4, generated in situ from sorboyl chloride and triethylamine, involved the initial formation of 5-dienyl-6-methylsulfanyl-2,3-diaryl-5,6-dihydro-3H-pyrimidin-4-ones, which afforded 5-dienyl pyrimidinones 22 via SMe elimination. 5-Dienyl-6-methylsulfanyl-2,3-diaryl-5,6-dihydro-3H-pyrimidin-4-ones also underwent tandem 1,5-hydride and 1,5-SMe shift to yield mixtures of 5-buta-1,3-dienyl-2,3-diaryl-3H-pyrimidin-4-one 23 and 5-(l′-butenyl)pyrimidinones 24 (Scheme [2]).[15]

The interactions of butadienyl ketene with 1,3-diazabuta-l,3-dienes 25, containing one or two secondary amino functionalities at the 4-position, resulted in functionalized 5-dienylpyrimidinones 27. Removal of the secondary amine/-SMe from the initially produced intermediate 26 through [4+2] cycloaddition of butadienyl ketene and 1,3-diazabuta-l,3-dienes 25 resulted in more stable 5-dienylpyrimidinones 27 in high yields (Scheme [3]).[15]

When dialkylamino-substituted N-arylamino-1,3-diazabuta-1,3dienes 28 were treated with butadienyl ketene 4, generated in situ, only 2-dialkylamino-5-(buta-1,3-dienyl)pyrimidinone 30 was produced. However, the reactions between methylthio-modified N-arylamino-1,3-diazabuta-1,3-dienes 31 and 4 resulted in the isolation of a mixture consisting of 5-(buta-1,3-dienyl)-2-methylthiopyrimidin-4(3H)-one 34, 2-methylthio-5-[1-(N-phenylamino)but-2-enyl]pyrimidin-4(3H)-one 36 and 2-methylthio-5-[3-(N-phenylamino)but-1-enyl]pyrimidin-4(3H)-one 37 (Table [6]).[16]

Table 6 Preparation of 2-Dialkylamino-5-(buta-1,3-dienyl)pyrimidinone Derivatives

Compound	Ar1	Ar2	R	Yield (%)
				30	34	36	37
a	Ph	Ph	Piperidino	86	33	21	30
b	4-Tol	Ph	Piperidino	82	29	26	29
c	4-Tol	4-Tol	Piperidino	80	25	21	27

Conclusion

This mini-review has focused on the reactivity of dienyl ketenes. Ketene chemistry is an area of interest for chemists due to the atom-economical formation of cycloadducts with a variety of functionalities at different positions. [2+2] and [4+2] cycloaddition reactions of dienyl ketene with imines and heterodienes, respectively, are well-established methods that afford a variety of four- and six-membered heterocycles. However, the synthesis of carbo- and heterocyclic systems through cycloaddition reactions of dienyl ketene are less extensively explored and cycloaddition reactions of butadienyl ketene with aldehyde, enamine, and ynamines, etc. are potentially useful for the development of new routes to functionalized heterocycles. Moreover, the synthetic potential of dienyl ketene as a 4π-component in cycloadditions with various substrates has not yet been tested. We hope that this mini-review has highlighted the work carried out using butadienyl ketene and underscored the synthetic potential of this important compound in organic chemistry.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We gratefully acknowledge I. K. Gujral Punjab Technical University, Kapurthala for generous support of this work.

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Publication History

Received: 13 February 2024

Accepted after revision: 25 March 2024

Accepted Manuscript online:
09 April 2024

Article published online:
22 April 2024