© 2020 Georg Thieme Verlag. All rights reserved. The reactivity of 1,2-dihydropyridazines under various conditions is described, leading to the formation of a variety of products, including 2-aminopyrroles, phenylenediamines, and several novel heterocyclic motifs

Britten, TK

Coote, SC

Halcovitch, NR

Kemmitt, PD

The reactivity of 1,2-dihydropyridazines under various conditions is described, leading to the formation of a variety of products, including 2-aminopyrroles, phenylenediamines, and several novel heterocyclic motifs. © 2020 Georg Thieme Verlag. All rights reserved

Britten, T.K.

Kemmitt, P.D.

Halcovitch, N.R.

Coote, S.C.

Lancaster E-Prints

Synlett Letter / Cluster / New Tools Template for SYNTHESIS © Thieme  Stuttgart · New York 2020-01-26 page 1 of 3 1,2-Dihydropyridazines as Versatile Synthetic Intermediates 	Received:  Accepted:  Published online:  DOI:  Abstract The reactivity of 1,2-dihydropyridazines under various different conditions is described, leading to the formation of various products, including 2-aminopyrroles, phenylenediamines and varied novel heterocyclic motifs. Key words 1,2-Dihydropyridazines, heterocycles, pyrroles, 1,2-diazetidines, phenylenediamines. 	1,2-Dihydropyridazines	1	have	rarely	been	employed	in	organic	synthesis,	 despite	their	potential	 for	the	preparation	of	various	heterocyclic	motifs.	Nevertheless,	we	recently	demonstrated	the	application	 of	 these	 heterocycles	 in	 4-p-photocyclizations,	generating	bicyclic	1,2-diazetidines	2	that	can	be	used	to	prepare	a	variety	of	novel	molecular	building	blocks	(Scheme	1).1	We	also	introduced	a	robust	new	preparation	of	1,2-dihydropyridazines	1,	which	is	suitable	for	use	on	multigram	scale.2		 Scheme 1 4-p-photocyclization of 1,2-dihydropyridazines 1 to give versatile bicyclic diazetidine products. To	further	expand	the	applications	of	1,2-dihydropyridazines,	we	studied	 their	 reactivity	 under	 a	 range	 of	 different	 conditions.	Herein,	we	report	the	conversion	of	1,2-dihydropyridazines	into	varied	 products,	 including	 phenylenediamine	 derivatives,	 2-aminopyrroles	and	various	novel	heterocyclic	motifs.	Initially,	we	postulated	that	as	a	1,3-diene,	1	might	undergo	Diels-Alder	 reactions	 with	 suitable	 dienophiles	 to	 produce	 bicyclic	hydrazine	derivatives.	However,	attempted	cycloaddition	of	1	(R	=	 Me,	 Et	 or	 iPr)	 with	 reactive	 dienophiles	 (maleic	 anhydride,	dimethyl	acetylenedicarboxylate	or	benzoquinone)	resulted	only	in	 recovered	 starting	 material,	 even	 upon	 heating	 at	 100	 °C.	Conversely,	 reaction	 with	 4-phenyl-1,2,4-triazole-3,5-dione	(PTAD;	 an	 exceptionally	 reactive	 dienophile),	 led	 to	 fast	conversion	 even	 at	 ambient	 temperature,	 but	 generated	 a	complex	mixture	of	products,	and	attempts	to	perform	inverse-electron-demand	Diels-Alder	cycloadditions	of	1	with	a	range	of	electron-rich	dienophiles	were	also	unsuccessful.	The	failure	of	these	reactions	 is	consistent	with	the	findings	of	Fisher	and	co-workers,3	who	reported	that	a	similar	dihydropyridazine	bearing	two	 phenyl	 substituents	 did	 not	 undergo	 Diels-Alder	 reaction	with	PTAD.	This	observation	was	attributed	to	the	presumed	high	energy	of	the	planar	transition	state	that	would	be	required	for	successful	cycloaddition.	Interestingly,	we	 observed	 that	 at	 temperatures	 above	 100	 °C,	dihydropyridazines	 1	 underwent	 isomerization	 into	 2-aminopyrroles	 2.	 The	 isomerization	 is	 proposed	 to	 proceed	through	 initial	 6-p	 electrocyclic	 ring	 opening	 to	 give	 diimines,	which	 then	 undergo	 cyclization	 to	 give	 the	 corresponding	 2-aminopyrroles	 2	 (Scheme	 2).	 Indeed,	 according	 to	 a	computational	 study	 published	 by	 Lautens	 and	 Borden,	 such	dihydropyridazines	 would	 be	 expected	 to	 undergo	 fast	 6-p	electrocyclic	ring	opening	at	elevated	temperatures.4	A	handful	of	examples	of	this	dihydropyridazine-aminopyrrole	isomerization	have	 been	 reported	 to	 take	 place	 photochemically,1,5	 but	 until	now,	 the	 thermal	 promotion	 of	 this	 reaction	 has	 not	 been	described.	The	optimal	reaction	conditions	for	the	isomerization	of	1	into	2	involved	heating	in	xylene	at	150	°C	for	five	hours,	after	which	 pyrroles	2a-c	 were	 obtained	 in	 good	 to	 excellent	 yields	(Scheme	2).6	Conversely,	exposure	of	1d	to	the	same	conditions	resulted	only	in	low	yields	of	pyrrole	2d,	accompanied	by	small	amounts	of	another	pyrrole	containing	only	one	Boc	group;	the	low	yield	of	2d	can	be	explained	by	the	instability	of	Boc	groups	at	the	high	temperatures	required	for	isomerization.	In	addition,	ester-substituted	 dihydropyridazine	 1e	 rearranged	 at	 slightly	lower	temperature	(130	°C	for	 five	hours)	to	give	disubstituted	pyrrole	2e	in	79%	yield.	2-Aminopyrroles	2a-e	can	be	stored	for	several	 months	 under	 inert	 atmosphere	 in	 the	 freezer,	 but	degrade	rapidly	within	a	few	days	under	ambient	conditions.		NNCO2RCO2Rhν (λ = 350 nm)1MeCN NNHHCO2RCO2R2cyclobutenescyclobutanesdiazetidinesdienesThomas K. Brittena Paul D. Kemmittb Nathan R. Halcovitcha Susannah C. Coote*a a Department of Chemistry, Lancaster University, Bailrigg, LA1 4YB, U.K. b Medicinal Chemistry, Research and Early Development, Oncology R & D, AstraZeneca, Cambridge, CB10 1XL, U.K.  s.coote@lancaster.ac.uk   	NHRRHNRʹRʹNNR RTsHN NHTsN NRROHHON NRRversatile intermediateNRO2CRO2CHNSynlett Letter / Cluster / New Tools Template for SYNTHESIS © Thieme  Stuttgart · New York 2020-01-26 page 2 of 3  Scheme 2 Transformation of 1,2-dihydropyridazines 1 into 2-aminopyrroles 2 through 6-p ring opening followed by cyclisation. In	 contrast	 to	 the	 behaviour	 of	 1,2-dihydropyridazine	 1c,	 2-aminopyrrole	2c	underwent	facile	reaction	with	reactive	alkynes	upon	 moderate	 heating,	 presumably	 generating	 Diels-Alder	cycloadducts	 3,	 which	 would	 be	 expected	 to	 collapse	 to	 give	substituted	phenylenediamine	derivatives	4	 (Scheme	3).	 In	this	way,	 reaction	 of	 1c	 with	 benzyne	 and	 dimethyl	 acetylene-dicarboxylate	 furnished	4a	 and	4b	 respectively	 in	good	yields.	However,	 less	 reactive	 alkynes	 (such	 as	 ethyl	 propiolate,	 ethyl	phenylpropiolate	and	diphenylacetylene)	failed	to	react	with	2c	even	at	elevated	temperatures.		 Scheme 3 Diels-Alder/ring-opening/aromatization sequence for the synthesis of tetrasubstituted aromatic products from pyrrole 2c. In	 related	 work,	 Arora	 and	 Mackay	 reported	 that	 a	 similar	phenylenediamine	formed	upon	heating	of	dihydropyridazine	1b	with	 dimethyl	 acetylenedicarboxylate.7	 The	 authors	 presumed	that	 an	 initial	 Diels-Alder	 reaction	 occurred	 to	 give	 a	 bicyclic	hydrazine	 derivative,	 which	 they	 stated	 “would	 aromatize	readily”,	 although	 no	 mechanism	 for	 this	 process	 was	 put	forward.	On	the	basis	of	our	results,	 it	seems	much	more	 likely	that	 the	 1,2-dihydropyridazine	 initially	 isomerized	 to	 the	corresponding	2-aminopyrrole,	which	could	then	be	transformed	into	the	phenylenediamine	product	as	outlined	in	Scheme	3.	The	 propensity	 of	 dihydropyridazine	 1c	 to	 undergo	 common	double	bond	functionalizations	was	also	studied.	The	attempted	mono-epoxidation	of	1c	 using	m-CPBA	 (meta-chloroperbenzoic	acid)	led	to	an	interesting	result	–	instead	of	the	expected	epoxide	5,	 diol	 trans-6	 was	 obtained	 in	 56%	 yield,	 accompanied	 by	recovered	 starting	 material	 and	 small	 amounts	 of	 other	unidentifiable	products	(Scheme	4).	The	relative	configurations	of	the	hydroxyl	groups	were	confirmed	by	X-ray	diffraction,	and	trans-6	 is	 presumed	 to	 arise	 through	 initial	 epoxidation	 to	produce	 5,	 followed	 by	 epoxide	 opening	 under	 the	 acidic	conditions,	 either	 through	 SN2’	 ring-opening	 by	 water,	 or	mediated	by	 the	 lone	pair	on	one	of	 the	nitrogen	atoms.	 In	 the	latter	case,	the	resulting	iminium	ion	would	then	be	trapped	by	water	to	generate	diol	trans-6	(Scheme	4).		 Scheme 4 Attempted epoxidation of 1c using m-CPBA generates diol trans-6. Similarly,	the	attempted	aziridination	of	1c	using	an	iminoiodane	reagent	 (PhI=NTs)	 in	 the	presence	of	 a	 copper	 catalyst	did	not	lead	to	isolation	of	the	expected	aziridine	7.	Complete	conversion	of	 the	 starting	 material	 was	 observed	 within	 15	 minutes,	generating	 bis-sulfonamide	 trans-8	 (Scheme	 5),	 presumably	through	 nucleophilic	 ring-opening	 of	 the	 putative	 aziridine	intermediate	 7	 by	 toluenesulfonamide	 (likely	 generated	 as	 a	degradation	product	of	the	aziridination	reagent	PhI=NTs)	or	by	another	derivative	of	PhI=NTs.	Diamine	trans-8	was	 isolated	in	good	yield	 (62%)	as	a	 single	diastereoisomer,	with	the	relative	configurations	of	the	sulfonamide	groups	being	confirmed	by	X-ray	 diffraction.	 Using	 just	 one	 equivalent	 of	 the	 iminoiodane	reagent	led	to	the	same	product,	but	in	lower	yield	(38%).	Dihydroxylation	of	1c	using	osmium	tetroxide	did	result	in	mono-functionalization	as	anticipated,	although	the	resulting	diol	9	was	obtained	as	a	mixture	of	two	diastereoisomers	(Scheme	6).	The	1H/13C	NMR	spectra	of	both	of	the	diol	products	were	complex	(as	are	 those	 of	 the	 starting	 dihydropyridazines2),	 thus	 the	diastereoisomer	 ratio	 in	 the	 crude	 product	 could	 not	 be	determined	 directly	 by	 1H	 NMR	 spectroscopy.	 However,	 the	diastereoisomers	 could	 be	 separated	 by	 flash	 column	chromatography,	resulting	 in	a	2.7:1	ratio	of	the	 isolated	major	and	minor	diastereoisomers.	Variable-temperature	1H/13C	NMR	experiments	were	also	performed,	but	the	signals	were	not	fully	NNCO2RCO2RN CO2RNHCO2RNNCO2RCO2R NCO2RNRO2CN CO2RNCO2RHo-xylene, 150 °C, 5 h6-π1 2N CO2MeNHCO2Me2a (62%)N CO2EtNHCO2EtN CO2iPrNHCO2iPrN CO2tBuNHCO2tBu2b (86%) 2c (90%) 2d (28%)NNCO2iPrCO2iPrCO2MeN CO2iPrNHCO2iPrCO2Meo-xylene, 130 °C, 5 h 2e(79%)NHCO2iPrNHCO2iPrNHCO2iPrNHCO2iPrCO2MeCO2MeNiPrO2CNRRNH CO2iPrRRH N CO2iPrN CO2iPrNHCO2iPrNHCO2iPrNHCO2iPrRRRR+60 °C[4+2]HCO2iPrPhMe4b (65%)4a (74%)4b2c43NNCO2iPrCO2iPrOHOHNNCO2iPrCO2iPrONNCO2iPrCO2iPrm-CPBA (1.1 eq.)MeCN, rt, 44 h1c6 (56%)5Synlett Letter / Cluster / New Tools Template for SYNTHESIS © Thieme  Stuttgart · New York 2020-01-26 page 3 of 3 resolved	even	upon	heating	at	75	°C,	and	NOESY	experiments	did	not	allow	conclusive	determination	of	the	relative	configurations	of	the	hydroxyl	groups	in	the	two	diastereoisomers.	Potentially,	diols	9	arise	through	ring-opening	of	the	initial	osmate	ester	by	the	 lone	 pair	 on	 the	 adjacent	 nitrogen	 atom,	 generating	 an	iminium	ion	that	 can	be	attacked	by	water	to	generate	the	diol	products	 (Scheme	 6).	 Interestingly,	 upon	 heating	 during	 NMR	experiments,	 the	 minor	 diastereoisomer	 underwent	 slow	conversion	into	the	major	diastereoisomer,	although	the	reverse	reaction	 was	 not	 observed.	 This	 epimerisation	 of	 the	 minor	diatereoisomer	into	the	major	diastereoisomer	starts	to	occur	at	75	 °C	 in	 d6-DMSO,	 and	 takes	 place	 more	 rapidly	 at	 higher	temperatures.			 Scheme 5 Attempted aziridination of 1c using PhI=NTs generates diamine trans-8.  Scheme 6 Dihydroxylation of 1c using osmium tetroxide and N-methyl morpholine N-oxide (NMO). Finally,	the	reaction	of	1c	with	in	situ-generated	dichlorocarbene	resulted	in	the	dichlorocyclopropanation	of	both	double	bonds	to	give	 trans-10	 in	 71%	 yield	 (Scheme	 7),	 with	 the	 relative	configurations	of	the	cyclopropane	rings	being	confirmed	by	X-ray	 diffraction.	 Tricycle	 trans-10	 displayed	 surprising	 thermal	stability,	 as	 it	 remained	 unchanged	 after	 heating	 at	 reflux	 in	xylenes	for	six	hours.	In	conclusion,	this	preliminary	study	explored	the	applications	of	1,2-dihydropyridazines,	allowing	the	preparation	of	a	wide	range	of	different	products	 (e.g.	 2-aminopyrroles,	phenylenediamines	and	 other	 novel	 heterocycles).	 The	 products	 obtained	 from	manipulations	 of	 the	 1,2-dihydropyridazines	 were	 often	unexpected,	but	now	that	the	fundamental	reactivity	patterns	of	these	 under-exploited	 heterocycles	 have	 been	 established,	application	 to	 more	 complex	 1,2-dihydropyrdazines	 will	 allow	access	to	an	even	broader	range	of	novel	products.			 Scheme 7 Double dichlorocyclopropanation of 1c using CHCl3/NaOH. Funding Information Funding	from	AstraZeneca	(CASE	Top-Up	Award	to	T.K.B.;	2015-2019)	is	gratefully	acknowledged.	Supporting Information YES	Primary Data NO	References and Notes (1) Britten,	T.	K.;	Kemmitt,	P.	D.;	Halcovitch,	N.	R.;	Coote,	S.	C.	Org.	Lett.	2019,	22,	9232.	(2) Britten,	T.	K.;	Akien,	G.	R.;	Kemmitt,	P.	D.;	Halcovitch,	N.	R.;	Coote,	S.	C.	Tetrahedron	Lett.	2019,	60,	1497.	(3) Fisher,	T.	H.;	Crook,	J.	C.;	Chang,	S.	Tetrahedron	1987,	43,	2443.	(4) Chen,	B.;	Scott,	M.	E.;	Adams,	B.;	Hrovat,	D.;	Borden,	W.	T.;	Lautens,	M.	Org.	Lett.	2014,	16,	3930.	(5) (a)	Altman,	 L.	 J.;	 Semmelhack,	M.	 F.;	 Hornby,	R.	 B.;	 Vederas,	 J.	 C.	Chem.	 Commun.	1968,	 686;	 (b)	 Sheradsky,	 T.;	 Moshenberg,	 R.	 J.	Org.	Chem.	1984,	49,	587;	(c)	Sheradsky,	T.;	Moshenberg,	R.	J.	Org.	Chem.	1985,	50,	5604.	(6) Representative	 procedure	 for	 the	 thermal	 isomerization	 of	 1,2-dihydropyridazines	 into	 2-aminopyrroles:	 A	 solution	 of	 1,2-dihydropyridazine	1a	(520	mg,	2.62	mmol,	1.0	eq)	in	o-xylene	(5	mL)	was	heated	at	reflux	for	5	hours	under	argon.	Purification	by	flash	column	chromatography	on	silica	gel	(eluent:	hexane-EtOAc,	100%	hexane→9:1)	gave	2-aminopyrrole	2a	(320	mg,	1.61	mmol,	62%)	as	a	white	solid.	Note:	2-Aminopyrroles	must	be	stored	in	the	freezer	under	an	inert	atmosphere	in	order	to	prevent	degradation.	Rf	(Hexane-EtOAc,	2:1)	=	0.35;	m.p.	=	46-47	˚C;	1H	NMR	(400	MHz,	CDCl3);	δ	9.05	(br	s,	1H,	NH),	6.85	(dd,	 J	=	3.6,	1.8	Hz,	1H,	Ar-H),	6.42-6.32	(br	m,	1H,	Ar-H),		6.13	(t,	J	=	3.6	Hz,	1H,	Ar-H),	3.95	(s,	3H,	OMe),	3.77	(s,	3H,	OMe);	13C	NMR	(100	MHz,	CDCl3);	δ	153.1	(C=O),	 152.4	 (C=O),	 130.5	 (Ar-C),	 114.0	 (Ar-CH),	 111.6	 (Ar-CH),	98.4	(Ar-CH),	54.2	(OMe),	52.6	(OMe);	FTIR	(ATR)	ν	(cm-1):	3349	(NH),	 2950,	 1724	 (C=O);	 HRMS	 (APCI):	 m/z	 calculated	 for:	C8H10N2O4	[M+H]+	199.0713,	found	199.0712.		(7) Arora,	P.	C.;	Mackay,	D.	J.	Chem.	Soc.	D	Chem.	Commun.	1969,	677.		NNCO2iPrCO2iPrNHTsNHTsNNCO2iPrCO2iPrTsNNNCO2iPrCO2iPrPhI=NTs (2.0 eq.)MeCN, rt, 30 min1c8 (62%)7Cu(OTf)2 (10 mol%)NNCO2iPrCO2iPr NNCO2iPrCO2iPrHOOH1cOsO4 (5 mol%), NMO (3 eq.)tBuOH/acetone/H2O9 (78%; 2.7:1 dr)NNCO2iPrCO2iPr1cNaOH/CHCl3Bu4NCl, H2O NNCO2iPrCO2iPrClClClCl10 (71%)

1,2-Dihydropyridazines as Versatile Synthetic Intermediates

E-space: Manchester Metropolitan University's Research Repository

Britten, TK and Kemmitt, PD and Halcovitch, NR and Coote, SC (2020) 1,2-Dihydropyridazines as Versatile Synthetic Intermediates. Synlett, 31 (5). pp.459-462. ISSN 0936-5214Downloaded from: http://e-space.mmu.ac.uk/625606/Version: Accepted VersionPublisher: ThiemeDOI: https://doi.org/10.1055/s-0039-1690825Please cite the published versionhttps://e-space.mmu.ac.ukSynlett Letter / Cluster / New Tools Template for SYNTHESIS © Thieme  Stuttgart · New York 2020-01-26 page 1 of 3 1,2-Dihydropyridazines as Versatile Synthetic Intermediates 	Received:  Accepted:  Published online:  DOI:  Abstract The reactivity of 1,2-dihydropyridazines under various different conditions is described, leading to the formation of various products, including 2-aminopyrroles, phenylenediamines and varied novel heterocyclic motifs. Key words 1,2-Dihydropyridazines, heterocycles, pyrroles, 1,2-diazetidines, phenylenediamines. 	1,2-Dihydropyridazines	1	have	rarely	been	employed	in	organic	synthesis,	 despite	their	potential	 for	the	preparation	of	various	heterocyclic	motifs.	Nevertheless,	we	recently	demonstrated	the	application	 of	 these	 heterocycles	 in	 4-p-photocyclizations,	generating	bicyclic	1,2-diazetidines	2	that	can	be	used	to	prepare	a	variety	of	novel	molecular	building	blocks	(Scheme	1).1	We	also	introduced	a	robust	new	preparation	of	1,2-dihydropyridazines	1,	which	is	suitable	for	use	on	multigram	scale.2		 Scheme 1 4-p-photocyclization of 1,2-dihydropyridazines 1 to give versatile bicyclic diazetidine products. To	further	expand	the	applications	of	1,2-dihydropyridazines,	we	studied	 their	 reactivity	 under	 a	 range	 of	 different	 conditions.	Herein,	we	report	the	conversion	of	1,2-dihydropyridazines	into	varied	 products,	 including	 phenylenediamine	 derivatives,	 2-aminopyrroles	and	various	novel	heterocyclic	motifs.	Initially,	we	postulated	that	as	a	1,3-diene,	1	might	undergo	Diels-Alder	 reactions	 with	 suitable	 dienophiles	 to	 produce	 bicyclic	hydrazine	derivatives.	However,	attempted	cycloaddition	of	1	(R	=	 Me,	 Et	 or	 iPr)	 with	 reactive	 dienophiles	 (maleic	 anhydride,	dimethyl	acetylenedicarboxylate	or	benzoquinone)	resulted	only	in	 recovered	 starting	 material,	 even	 upon	 heating	 at	 100	 °C.	Conversely,	 reaction	 with	 4-phenyl-1,2,4-triazole-3,5-dione	(PTAD;	 an	 exceptionally	 reactive	 dienophile),	 led	 to	 fast	conversion	 even	 at	 ambient	 temperature,	 but	 generated	 a	complex	mixture	of	products,	and	attempts	to	perform	inverse-electron-demand	Diels-Alder	cycloadditions	of	1	with	a	range	of	electron-rich	dienophiles	were	also	unsuccessful.	The	failure	of	these	reactions	 is	consistent	with	the	findings	of	Fisher	and	co-workers,3	who	reported	that	a	similar	dihydropyridazine	bearing	two	 phenyl	 substituents	 did	 not	 undergo	 Diels-Alder	 reaction	with	PTAD.	This	observation	was	attributed	to	the	presumed	high	energy	of	the	planar	transition	state	that	would	be	required	for	successful	cycloaddition.	Interestingly,	we	 observed	 that	 at	 temperatures	 above	 100	 °C,	dihydropyridazines	 1	 underwent	 isomerization	 into	 2-aminopyrroles	 2.	 The	 isomerization	 is	 proposed	 to	 proceed	through	 initial	 6-p	 electrocyclic	 ring	 opening	 to	 give	 diimines,	which	 then	 undergo	 cyclization	 to	 give	 the	 corresponding	 2-aminopyrroles	 2	 (Scheme	 2).	 Indeed,	 according	 to	 a	computational	 study	 published	 by	 Lautens	 and	 Borden,	 such	dihydropyridazines	 would	 be	 expected	 to	 undergo	 fast	 6-p	electrocyclic	ring	opening	at	elevated	temperatures.4	A	handful	of	examples	of	this	dihydropyridazine-aminopyrrole	isomerization	have	 been	 reported	 to	 take	 place	 photochemically,1,5	 but	 until	now,	 the	 thermal	 promotion	 of	 this	 reaction	 has	 not	 been	described.	The	optimal	reaction	conditions	for	the	isomerization	of	1	into	2	involved	heating	in	xylene	at	150	°C	for	five	hours,	after	which	 pyrroles	2a-c	 were	 obtained	 in	 good	 to	 excellent	 yields	(Scheme	2).6	Conversely,	exposure	of	1d	to	the	same	conditions	resulted	only	in	low	yields	of	pyrrole	2d,	accompanied	by	small	amounts	of	another	pyrrole	containing	only	one	Boc	group;	the	low	yield	of	2d	can	be	explained	by	the	instability	of	Boc	groups	at	the	high	temperatures	required	for	isomerization.	In	addition,	ester-substituted	 dihydropyridazine	 1e	 rearranged	 at	 slightly	lower	temperature	(130	°C	for	 five	hours)	to	give	disubstituted	pyrrole	2e	in	79%	yield.	2-Aminopyrroles	2a-e	can	be	stored	for	several	 months	 under	 inert	 atmosphere	 in	 the	 freezer,	 but	degrade	rapidly	within	a	few	days	under	ambient	conditions.		NNCO2RCO2Rhν (λ = 350 nm)1MeCN NNHHCO2RCO2R2cyclobutenescyclobutanesdiazetidinesdienesThomas K. Brittena Paul D. Kemmittb Nathan R. Halcovitcha Susannah C. Coote*a a Department of Chemistry, Lancaster University, Bailrigg, LA1 4YB, U.K. b Medicinal Chemistry, Research and Early Development, Oncology R & D, AstraZeneca, Cambridge, CB10 1XL, U.K.  s.coote@lancaster.ac.uk   	NHRRHNRʹRʹNNR RTsHN NHTsN NRROHHON NRRversatile intermediateNRO2CRO2CHNSynlett Letter / Cluster / New Tools Template for SYNTHESIS © Thieme  Stuttgart · New York 2020-01-26 page 2 of 3  Scheme 2 Transformation of 1,2-dihydropyridazines 1 into 2-aminopyrroles 2 through 6-p ring opening followed by cyclisation. In	 contrast	 to	 the	 behaviour	 of	 1,2-dihydropyridazine	 1c,	 2-aminopyrrole	2c	underwent	facile	reaction	with	reactive	alkynes	upon	 moderate	 heating,	 presumably	 generating	 Diels-Alder	cycloadducts	 3,	 which	 would	 be	 expected	 to	 collapse	 to	 give	substituted	phenylenediamine	derivatives	4	 (Scheme	3).	 In	this	way,	 reaction	 of	 1c	 with	 benzyne	 and	 dimethyl	 acetylene-dicarboxylate	 furnished	4a	 and	4b	 respectively	 in	good	yields.	However,	 less	 reactive	 alkynes	 (such	 as	 ethyl	 propiolate,	 ethyl	phenylpropiolate	and	diphenylacetylene)	failed	to	react	with	2c	even	at	elevated	temperatures.		 Scheme 3 Diels-Alder/ring-opening/aromatization sequence for the synthesis of tetrasubstituted aromatic products from pyrrole 2c. In	 related	 work,	 Arora	 and	 Mackay	 reported	 that	 a	 similar	phenylenediamine	formed	upon	heating	of	dihydropyridazine	1b	with	 dimethyl	 acetylenedicarboxylate.7	 The	 authors	 presumed	that	 an	 initial	 Diels-Alder	 reaction	 occurred	 to	 give	 a	 bicyclic	hydrazine	 derivative,	 which	 they	 stated	 “would	 aromatize	readily”,	 although	 no	 mechanism	 for	 this	 process	 was	 put	forward.	On	the	basis	of	our	results,	 it	seems	much	more	 likely	that	 the	 1,2-dihydropyridazine	 initially	 isomerized	 to	 the	corresponding	2-aminopyrrole,	which	could	then	be	transformed	into	the	phenylenediamine	product	as	outlined	in	Scheme	3.	The	 propensity	 of	 dihydropyridazine	 1c	 to	 undergo	 common	double	bond	functionalizations	was	also	studied.	The	attempted	mono-epoxidation	of	1c	 using	m-CPBA	 (meta-chloroperbenzoic	acid)	led	to	an	interesting	result	–	instead	of	the	expected	epoxide	5,	 diol	 trans-6	 was	 obtained	 in	 56%	 yield,	 accompanied	 by	recovered	 starting	 material	 and	 small	 amounts	 of	 other	unidentifiable	products	(Scheme	4).	The	relative	configurations	of	the	hydroxyl	groups	were	confirmed	by	X-ray	diffraction,	and	trans-6	 is	 presumed	 to	 arise	 through	 initial	 epoxidation	 to	produce	 5,	 followed	 by	 epoxide	 opening	 under	 the	 acidic	conditions,	 either	 through	 SN2’	 ring-opening	 by	 water,	 or	mediated	by	 the	 lone	pair	on	one	of	 the	nitrogen	atoms.	 In	 the	latter	case,	the	resulting	iminium	ion	would	then	be	trapped	by	water	to	generate	diol	trans-6	(Scheme	4).		 Scheme 4 Attempted epoxidation of 1c using m-CPBA generates diol trans-6. Similarly,	the	attempted	aziridination	of	1c	using	an	iminoiodane	reagent	 (PhI=NTs)	 in	 the	presence	of	 a	 copper	 catalyst	did	not	lead	to	isolation	of	the	expected	aziridine	7.	Complete	conversion	of	 the	 starting	 material	 was	 observed	 within	 15	 minutes,	generating	 bis-sulfonamide	 trans-8	 (Scheme	 5),	 presumably	through	 nucleophilic	 ring-opening	 of	 the	 putative	 aziridine	intermediate	 7	 by	 toluenesulfonamide	 (likely	 generated	 as	 a	degradation	product	of	the	aziridination	reagent	PhI=NTs)	or	by	another	derivative	of	PhI=NTs.	Diamine	trans-8	was	 isolated	in	good	yield	 (62%)	as	a	 single	diastereoisomer,	with	the	relative	configurations	of	the	sulfonamide	groups	being	confirmed	by	X-ray	 diffraction.	 Using	 just	 one	 equivalent	 of	 the	 iminoiodane	reagent	led	to	the	same	product,	but	in	lower	yield	(38%).	Dihydroxylation	of	1c	using	osmium	tetroxide	did	result	in	mono-functionalization	as	anticipated,	although	the	resulting	diol	9	was	obtained	as	a	mixture	of	two	diastereoisomers	(Scheme	6).	The	1H/13C	NMR	spectra	of	both	of	the	diol	products	were	complex	(as	are	 those	 of	 the	 starting	 dihydropyridazines2),	 thus	 the	diastereoisomer	 ratio	 in	 the	 crude	 product	 could	 not	 be	determined	 directly	 by	 1H	 NMR	 spectroscopy.	 However,	 the	diastereoisomers	 could	 be	 separated	 by	 flash	 column	chromatography,	resulting	 in	a	2.7:1	ratio	of	the	 isolated	major	and	minor	diastereoisomers.	Variable-temperature	1H/13C	NMR	experiments	were	also	performed,	but	the	signals	were	not	fully	NNCO2RCO2RN CO2RNHCO2RNNCO2RCO2R NCO2RNRO2CN CO2RNCO2RHo-xylene, 150 °C, 5 h6-π1 2N CO2MeNHCO2Me2a (62%)N CO2EtNHCO2EtN CO2iPrNHCO2iPrN CO2tBuNHCO2tBu2b (86%) 2c (90%) 2d (28%)NNCO2iPrCO2iPrCO2MeN CO2iPrNHCO2iPrCO2Meo-xylene, 130 °C, 5 h 2e(79%)NHCO2iPrNHCO2iPrNHCO2iPrNHCO2iPrCO2MeCO2MeNiPrO2CNRRNH CO2iPrRRH N CO2iPrN CO2iPrNHCO2iPrNHCO2iPrNHCO2iPrRRRR+60 °C[4+2]HCO2iPrPhMe4b (65%)4a (74%)4b2c43NNCO2iPrCO2iPrOHOHNNCO2iPrCO2iPrONNCO2iPrCO2iPrm-CPBA (1.1 eq.)MeCN, rt, 44 h1c6 (56%)5Synlett Letter / Cluster / New Tools Template for SYNTHESIS © Thieme  Stuttgart · New York 2020-01-26 page 3 of 3 resolved	even	upon	heating	at	75	°C,	and	NOESY	experiments	did	not	allow	conclusive	determination	of	the	relative	configurations	of	the	hydroxyl	groups	in	the	two	diastereoisomers.	Potentially,	diols	9	arise	through	ring-opening	of	the	initial	osmate	ester	by	the	 lone	 pair	 on	 the	 adjacent	 nitrogen	 atom,	 generating	 an	iminium	ion	that	 can	be	attacked	by	water	to	generate	the	diol	products	 (Scheme	 6).	 Interestingly,	 upon	 heating	 during	 NMR	experiments,	 the	 minor	 diastereoisomer	 underwent	 slow	conversion	into	the	major	diastereoisomer,	although	the	reverse	reaction	 was	 not	 observed.	 This	 epimerisation	 of	 the	 minor	diatereoisomer	into	the	major	diastereoisomer	starts	to	occur	at	75	 °C	 in	 d6-DMSO,	 and	 takes	 place	 more	 rapidly	 at	 higher	temperatures.			 Scheme 5 Attempted aziridination of 1c using PhI=NTs generates diamine trans-8.  Scheme 6 Dihydroxylation of 1c using osmium tetroxide and N-methyl morpholine N-oxide (NMO). Finally,	the	reaction	of	1c	with	in	situ-generated	dichlorocarbene	resulted	in	the	dichlorocyclopropanation	of	both	double	bonds	to	give	 trans-10	 in	 71%	 yield	 (Scheme	 7),	 with	 the	 relative	configurations	of	the	cyclopropane	rings	being	confirmed	by	X-ray	 diffraction.	 Tricycle	 trans-10	 displayed	 surprising	 thermal	stability,	 as	 it	 remained	 unchanged	 after	 heating	 at	 reflux	 in	xylenes	for	six	hours.	In	conclusion,	this	preliminary	study	explored	the	applications	of	1,2-dihydropyridazines,	allowing	the	preparation	of	a	wide	range	of	different	products	 (e.g.	 2-aminopyrroles,	phenylenediamines	and	 other	 novel	 heterocycles).	 The	 products	 obtained	 from	manipulations	 of	 the	 1,2-dihydropyridazines	 were	 often	unexpected,	but	now	that	the	fundamental	reactivity	patterns	of	these	 under-exploited	 heterocycles	 have	 been	 established,	application	 to	 more	 complex	 1,2-dihydropyrdazines	 will	 allow	access	to	an	even	broader	range	of	novel	products.			 Scheme 7 Double dichlorocyclopropanation of 1c using CHCl3/NaOH. Funding Information Funding	from	AstraZeneca	(CASE	Top-Up	Award	to	T.K.B.;	2015-2019)	is	gratefully	acknowledged.	Supporting Information YES	Primary Data NO	References and Notes (1) Britten,	T.	K.;	Kemmitt,	P.	D.;	Halcovitch,	N.	R.;	Coote,	S.	C.	Org.	Lett.	2019,	22,	9232.	(2) Britten,	T.	K.;	Akien,	G.	R.;	Kemmitt,	P.	D.;	Halcovitch,	N.	R.;	Coote,	S.	C.	Tetrahedron	Lett.	2019,	60,	1497.	(3) Fisher,	T.	H.;	Crook,	J.	C.;	Chang,	S.	Tetrahedron	1987,	43,	2443.	(4) Chen,	B.;	Scott,	M.	E.;	Adams,	B.;	Hrovat,	D.;	Borden,	W.	T.;	Lautens,	M.	Org.	Lett.	2014,	16,	3930.	(5) (a)	Altman,	 L.	 J.;	 Semmelhack,	M.	 F.;	 Hornby,	R.	 B.;	 Vederas,	 J.	 C.	Chem.	 Commun.	1968,	 686;	 (b)	 Sheradsky,	 T.;	 Moshenberg,	 R.	 J.	Org.	Chem.	1984,	49,	587;	(c)	Sheradsky,	T.;	Moshenberg,	R.	J.	Org.	Chem.	1985,	50,	5604.	(6) Representative	 procedure	 for	 the	 thermal	 isomerization	 of	 1,2-dihydropyridazines	 into	 2-aminopyrroles:	 A	 solution	 of	 1,2-dihydropyridazine	1a	(520	mg,	2.62	mmol,	1.0	eq)	in	o-xylene	(5	mL)	was	heated	at	reflux	for	5	hours	under	argon.	Purification	by	flash	column	chromatography	on	silica	gel	(eluent:	hexane-EtOAc,	100%	hexane→9:1)	gave	2-aminopyrrole	2a	(320	mg,	1.61	mmol,	62%)	as	a	white	solid.	Note:	2-Aminopyrroles	must	be	stored	in	the	freezer	under	an	inert	atmosphere	in	order	to	prevent	degradation.	Rf	(Hexane-EtOAc,	2:1)	=	0.35;	m.p.	=	46-47	˚C;	1H	NMR	(400	MHz,	CDCl3);	δ	9.05	(br	s,	1H,	NH),	6.85	(dd,	 J	=	3.6,	1.8	Hz,	1H,	Ar-H),	6.42-6.32	(br	m,	1H,	Ar-H),		6.13	(t,	J	=	3.6	Hz,	1H,	Ar-H),	3.95	(s,	3H,	OMe),	3.77	(s,	3H,	OMe);	13C	NMR	(100	MHz,	CDCl3);	δ	153.1	(C=O),	 152.4	 (C=O),	 130.5	 (Ar-C),	 114.0	 (Ar-CH),	 111.6	 (Ar-CH),	98.4	(Ar-CH),	54.2	(OMe),	52.6	(OMe);	FTIR	(ATR)	ν	(cm-1):	3349	(NH),	 2950,	 1724	 (C=O);	 HRMS	 (APCI):	 m/z	 calculated	 for:	C8H10N2O4	[M+H]+	199.0713,	found	199.0712.		(7) Arora,	P.	C.;	Mackay,	D.	J.	Chem.	Soc.	D	Chem.	Commun.	1969,	677.		NNCO2iPrCO2iPrNHTsNHTsNNCO2iPrCO2iPrTsNNNCO2iPrCO2iPrPhI=NTs (2.0 eq.)MeCN, rt, 30 min1c8 (62%)7Cu(OTf)2 (10 mol%)NNCO2iPrCO2iPr NNCO2iPrCO2iPrHOOH1cOsO4 (5 mol%), NMO (3 eq.)tBuOH/acetone/H2O9 (78%; 2.7:1 dr)NNCO2iPrCO2iPr1cNaOH/CHCl3Bu4NCl, H2O NNCO2iPrCO2iPrClClClCl10 (71%)

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1,2-Dihydropyridazines as Versatile Synthetic Intermediates

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