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Nickel-Catalyzed	Reductive	[2+2]	Cycloaddition	of	Alkynes	
Santiago	Cañellas,	John	Montgomery,	and	Miquel	A.	Pericàs		
DepartamentdeQuı́micaInorgaǹicaiOrgaǹica,UniversitatdeBarcelona,08028Barcelona,Spain		
DepartamentdeQuı́micaAnalı́ticaiQuı́micaOrgaǹica,UniversitatRoviraiVirgili,Marcel·lı́Domingo,1,43007Tarragona,Spain	
Department	 of	 Chemistry,	 University	 of	 Michigan,	 930	 North	 University	 Avenue,	 Ann	 Arbor,	 Michigan	 48019-1055,	
United	States	

Since	 the	 pioneering	 work	 by	 Reppe	 and	 Wilke	 on	 the	
cyclotetramerization	 of	 acetylene	 and	 ensuing	 ligand-	
influenced	 outcomes	 in	 catalytic	 cycloadditions,1	 nickel	

catalysis	 has	 contributed	 to	 the	 development	 of	 many	 C−C	
and	 C−heteroatom	 bond-forming	 processes.2	 Building	 on	

these	 early	 studies,	 nickel-catalyzed	 methods	 have	 led	 to	
many	 advances	 in	 cycloadditions,	 allowing	 the	 assembly	 of	
various	ring	sizes	from	simple	π-components	depending	on	
the	 ligand	 system	 and	 precursors	 employed.2a,d	 While	 the	
assembly	of	six-	and	eight-membered	rings	have	been	well	
developed,	accessing	cyclobutane	and	cyclobutene	products	
is	 more	 limited	 and	 typically	 requires	 conjugated	 and	
activated	substrates	such	as	allenes,	1,3-enynes,	or	strained	
rings	 such	 as	 norbornene	 derivatives.	 The	 assembly	 of	
cyclobutanes	and	cyclobutenes	by	the	catalytic	cycloaddition	
of	 simple,	 nonconjugated	 π-	 components	 has	 thus	 proven	
elusive	by	using	existing	methods.	
Cyclobutenes	 in	 particular	 are	 highly	 versatile	 synthetic	
intermediates	 because	 of	 their	 ring	 strain	 and	 high	
reactivity.3	In	addition,	they	are	also	found	in	many	bioactive	
metabolites,	 natural	 products,	 drugs,	 and	 organic	 dyes.4	 In	
recent	years,	much	progress	has	been	made	in	strategies	for	
the	 direct	 formation	 of	 the	 cyclobutene	 skeleton.	 Most	
commonly,	 the	 catalytic	 synthesis	 of	 cyclobutenes	 involves	
the	 use	 of	 an	 alkene-alkyne	 [2+2]-cycloaddition	 reaction	
typically	 involving	 conjugated	 and	 activated	 substrates	
(Figure	1a).	Using	this	approach,	many	useful	methodologies	
have	 been	 reported	 using	 transition	 metal5,6	 and	 Lewis	

acid7	catalysis.	An	alternate	approach	involves	the	reductive	
cyclodimerization	 of	 two	 alkynes.	 This	 latter	 approach	 has	
been	 developed	 using	 a	 zirconium-mediated	 pyridinedirected	strategy	(Figure	1b),8	but	variations	of	this	process	
that	 involve	 substoichiometric	 catalyst	 loadings	 or	 simple	

alkynes	that	lack	directing	groups	have	not	been	previously	
described.	Despite	the	advances	
Figure	1.	Approaches	toward	the	synthesis	of	cyclobutenes	
realized,	 the	 development	 of	 an	 intermolecular	 catalytic	
route	 with	 two	 different	 alkyne	 coupling	 partners	 is	
currently	 not	 available.	 We	 recognized	 that	 such	 a	 process	
would	 provide	 new	 opportunities	 for	 rapidly	 building	 up	
useful	 synthetic	 intermediates	 from	 simple	 starting	
materials.	
In	the	course	of	exploring	new	types	of	catalytic	additions	to	
alkynes,	 we	 unexpectedly	 found	 that	 the	 reductive	
dimerization	of	alkynes	to	produce	cyclobutenes	is	the	major	
pathway	 when	 primary	 aminophosphine	 ligands	 are	
employed	 (Figure	 1c).	 Primary	 β-aminophosphines	 have	
rarely	been	used	as	ligands	in	catalysis,9	and	are	not	typically	
employed	 in	 ligand	 screens	 of	 nickel-catalyzed	 processes.	
The	 reactivity	 is	 notable	 given	 that	 many	 nickel-catalyzed	
reductive	transformations	have	been	described	with	alkynes,	
whereas	 the	 alkyne	 reductive	 cyclo-	 dimerization	 has	 not	
previously	 been	 described.	 Other	 cycloadditions	 and	
reductive	 couplings	 involving	 nickel	 catalysis	 typically	
involve	 monodentate	 phosphines	 or	 NHC	 ligands,2d	

suggesting	 that	 the	 unique	 behavior	 of	 primary	
aminophosphines	will	serve	as	an	important	counterpart	to	
these	well-studied	catalytic	systems.	Given	the	novelty	and	
potential	utility	of	the	reductive	cyclodimerization	of	alkynes	
in	the	assembly	of	stereo-	and	regiochemically	defined	cyclo-	
butenes,	as	well	as	the	lack	of	information	about	the	unique	
reactivity	 of	 nickel	 complexes	 of	 primary	
aminophosphines,	we	

report	 here	 the	 development,	 scope,	 and	 mechanistic	
insights	of	this	newly	discovered	process.	
We	began	our	investigations	by	studying	the	reaction	of	1a	
in	a	high	throughput	experimentation	(HTE)	platform	with	
Ni(COD)2.	We	screened	a	wide	variety	of	ligands	(L1−L23)	
such	 as	 aminophosphines,	 phosphoramidites,	 phosphines,	
amines,	 heterocyclic	 amines,	 NHCs	 and	 diols	 (Table	 1,	
entries	

optimization	 of	 reaction	 conditions,10	 the	 head-to-tail	
trans-cyclobutene	 2a	 was	 obtained	 in	 73%	 isolated	 yield.	
Excellent	regio-	and	stereoselectivities	were	observed,	and	
all	 reagents	 and	 catalysts	 are	 commercially	 available,	 thus	
making	the	procedure	simple	and	selective	for	the	desired	
cyclobutenes.	
We	 then	 turned	 our	 attention	 to	 the	 generality	 of	 this	
transformation.	 First,	 a	 robustness	 screen	 was	 performed,	
showing	a	high	functional	group	tolerance.11	Then,	a	series	
of	 examples	 of	 nickel-catalyzed	 reductive	 [2+2]	
cycloadditions	 of	 alkynes	 to	 produce	 trans-cyclobutenes	
were	 illustrated	 under	 optimized	 conditions	 (Scheme	 1).	

4	 and	 5),	 several	 Brønsted	 acids	 such	 as	 methanol,	
isopropyl	 alcohol	 and	 benzoic	 acid	 (Table	 1,	 entries	 4,	 12	
and	 13),	 and	 reducing	 agents	 such	 as	 triethylborane	 and	
dimethylphenylsi-	 lane	 (Table	 1,	 entries	 4	 and	 14).10	

Interestingly,	 we	 only	 found	 significant	 amounts	 (>10%	
yield)	of	the	desired	cyclobutene	2a	with	a	combination	of	
the	 primary	 aminophosphine	 ligand	 L1,	 methanol	 or	
isopropyl	 alcohol,	 and	 triethylborane.	 Notably,	 traces	 of	
product	were	found	with	a	binary	ligand	system	consisting	
of	 a	 primary	 amine	 (BuNH2)	 and	 a	 tertiary	 phosphine	
(PPh3),	 thus	 reinforcing	 the	 need	 for	 a	 tethered	
aminophosphine	backbone.	No	significant	amount	of	cyclo-	
butene	product	was	observed	when	using	NiCl2	 reduced	in	
situ	by	Mn	or	Zn	(Table	1,	entry	15)	or	the	corresponding	
control	experiments	(Table	1,	entries	2	and	3).	
Several	ligands	of	this	class	(L1,	L24−L28)	were	screened	on	
a	preparative	scale	(Table	1,	entries	6−11),	after	which	L1	
was	 revealed	 as	 the	 ligand	 of	 choice.	 After	 further	

The	reaction	was	efficient	with	alkynes	bearing	alkyl	groups	
with	different	chain	lengths	(2a−d).	Electronic	properties	of	
the	 alkyne	 were	 evaluated	 by	 introducing	 electronwithdrawing	 and	 electron-donating	 groups	 on	 the	 aryl	
moiety.	 Although	 electron	 rich	 alkynes	 (2f	 and	 2h)	
underwent	coupling	faster	than	electron-poor	ones	(2g),	the	
desired	cyclobutene	was	successfully	obtained	in	all	cases.	
The	 reaction	 was	 effective	 in	 the	 presence	 of	 unprotected	
polar	 functional	 groups	 such	 as	 an	 alcohol	 (2e),	 aldehyde	
(2k),	amide	(2j),	aryl	ether	(2f	and	2i)	or	amine	
	

(2h).	 Alkynes	 bearing	 heterocyclic	 moieties	 such	 as	 2pyridyl	(2l−m),	2-pyrimidinyl	(2n)	and	2-thiazolyl	(2o)	also	
gave	rise	to	the	desired	cyclobutenes.	TMS-alkynes	showed	
a	 silyl	 group	 migration	 on	 the	 cyclobutene	 products	 (2p	
and	 2q).12	 Surprisingly,	 aldehyde/alkyne	 reductive	

coupling13	 or	 deme-	 thoxylation14	 pathways	 were	 not	
observed.	 The	 scalability	 of	 this	 protocol	 was	 tested	
through	synthesis	of	the	cyclobutene	2e	on	a	2	g	scale.	In	
this	case,	the	catalyst	loading	was	successfully	lowered	to	2	
mol	%	and	the	desired	cyclobutene	was	obtained	in	62%	
isolated	yield.	
The	 suppression	 of	 alkyne	 homocoupling	 presents	 a	
clear	 challenge	 in	 the	 development	 of	 synthetically	
desirable	 reductive	 heterocouplings	 of	 two	 different	
alkynes.16	 In	 order	 to	 explore	 the	 feasibility	 of	 this	
approach,	 alkynes	 of	 different	 electronic	 and	 steric	
properties	 were	 examined	 to	 achieve	 the	 desired	 crossreductive	[2+2]	alkyne	cycloaddition.	First,	we	attempted	
the	reaction	using	two	electronically	opposed	alkynes,	1g	
and	 1f.	 To	 our	 delight,	 the	 corresponding	 heterocoupling	
product	 2r	 was	 obtained	 in	 62%	 yield,	 accompanied	 by	
minor	 amounts	 of	 the	 homocoupling	 products	 (7%	 of	 2g	
and	21%	of	2f).	Nonetheless,	the	two	regioisomers	arising	
from	 the	 position	 of	 the	 double	 bond	 in	 the	 cyclobutene	
ring	 were	 formed	 in	 1:1	 ratio.	 Then,	 we	 subjected	 the	
steroid	 phenyl-17α-ethynylestradiol	 1s	 to	 the	 reductive	
[2+2]	 cycloaddition	 reaction	 with	 1a.	 Because	 of	 the	
bulkiness	 of	 the	 steroid,	 it	 was	 unreactive	 toward	 the	
reductive	 homocyclodimerization.	 This	 allow ed	 us	 to	
perform	 the	 heterocoupling	 in	 a	 very	 clean	 manner	 by	
slowly	 adding	 the	 alkyne	 1a	 via	 syringe	 pump.	 The	
corresponding	heterocoupling	product	2s	was	obtained	in	
59%	yield	(10:1	d.r.),	with	40%	of	the	starting	material	1s	
being	recovered.	Furthermore,	diphenylacetylene	3a	gave	
rise	 to	 the	 cis,cis-diene	 4a	 in	 good	 yield	 (Scheme	 2a).17a	

epoxide	6	in	good	yield	and	4:1	dr.20	 This	product	was	then	
subjected	to	acidic	conditions	to	perform	a	ring-	contraction,	
thus	 affording	 the	 cyclopropyl	 ketone	 7	 in	 good	 yield	 and	
excellent	 diastereomeric	 ratio.21	 Finally,	 we	 targeted	 the	

synthesis	 of	 epi-truxillic	 acid,	 a	 naturally	 occurring	
cyclobutanedicarboxylic	 acid	 with	 interesting	 biological	
proper-	 ties.22,23	 To	 our	 delight,	 the	 hydrogenation	 of	

cyclobutene	 2e	 to	 cyclobutane	 8	 took	 place	 with	 exquisite	
diastereoselectivity,	with	8	being	isolated	as	a	single	isomer	
in	 good	 yield.24	 Finally,	 Jones	 oxidation	 afforded	 the	
corresponding	epi-truxillic	acid	9	in	quantitative	yield.25,26	
A	number	of	experiments	were	conducted	to	shed	light	on	the	
mechanistic	 features	 of	 this	 reductive	 cyclodimerization	
process.	 Deuterium-labeling	 studies	 displayed	 90−92%	
deute-	 rium	 incorporation	 using	 CD3OD	 and	 CH3OD	 in	 a	
regio-	 and	 stereoselective	 manner.	 On	 the	 other	 hand,	 no	
deuterium	 incorporation	 was	 observed	 using	 CD3OH	
(Scheme	 4a).	 With	 these	 results	 in	 hand,	 we	 performed	 the	
kinetic	analysis	of	two	parallel	reactions	run	using	CD3OD	and	
CH3OH	respectively.	A	primary	kinetic	isotope	effect	(KIE)	of	
3.0	was	observed,	indicating	that	a	proton	transfer	is	involved	
in	 the	 rate-	 determining	 step.27	 Motivated	 by	 the	 different	

reaction	rate	of	electron-poor	and	electron-rich	alkynes,	we	
studied	 linear	 free-	 energy	 relationships	 to	 unveil	 potential	
cationic	 or	 anionic	 intermediates.	 The	 reactions	 using	
substrates	 1a,	 1f,	 1g	 and	 1h	 were	 monitored	 by	 1H	 NMR	 to	
determine	the	corresponding	kinetic	behaviors	(Scheme	4b).	
The	observed	Hammett	plots,	characterized	by	ρ	<	0,	suggest	
that	 a	 positive	 charge	 accumulates	 in	 the	 rate-determining	
step.28	
We	also	attempted	the	cyclization	of		diynes	to	form	bicyclic	
cyclobutenes	(Scheme	2b).	In	both	cases,	the	dienes	4b	and	
4c	were	obtained	as	the	major	products	in	good	yields.18	

The	 isomer	 obtained	 in	 products	 4a−c	 suggests	 the	
formation	of	the	trans-cyclobutene	followed	by	a	thermal	
conrotatory	electrocyclic	ring-opening	step.17		

With	 this	 mechanistic	 information	 in	 hand,	 a	 plausible	
catalytic	cycle	is	proposed	for	this	reaction	(Scheme	5).	After	
rapid	 ligand	 exchange	 with	 L1	 (I)	 and	 coordination	 of	 two	
alkynes	 to	 the	 nickel	 center	 (II),29	 Ni(0)	 may	 undergo	 an	
oxidative	 cyclization	 to	 form	 the	 first	 C−C	 bond,	 generating	
the	 nickelacycle	 (III).1,2a,30	 Then,	 the	 methanol-

triethylborane	 adduct	 could	 protonate31	 the	 π-system	
The	 potential	 synthetic	 utility	 of	 this	 protocol	 was	 then	 demonstrated	
generating	a	stabilized	
through	 the	 diversification	 of	 the	 cyclobutene	 products	
(Scheme	3).	First,	ozonolysis	of	cyclobutene	2a	afforded	the	
stereodefined	acyclic	1,4-diketone	5	as	a	single	isomer.19	On	
the	other	hand,	epoxidation	of	2a	gave	rise	to	the	cyclobutane	

protonation	 of	 enolate	 motifs	 embedded	 with	 a	 nickel	
metallacycle.37,38	 However,	 the	 only	 previous	 examples	
where	 metallacyclopentadienes	 are	 converted	 to	
cyclobutenes	are	the	stoichiometric	zirconium-mediated	
processes	 described	 above.8	 Notably,	 protonation	 of	 a	
Ni(II)	 metallacyclopentene	 species	 by	 a	 water/borate	
adduct31a	 and	 the	 protonation	 of	 Ni(0)	 species	 by	 a	
similar	methanol/borane	mixture31b,c	have	recently	been	
proposed	in	the	hydroalkylation	and	hydro-	arylation	of	
allenes,	styrenes	and	dienes	under	similar	conditions	to	
our	 study.31	 Although	 Ni(0)	 protonation	 would	 be	
expected	 to	 be	 faster	 than	 protonation	 of	 III,	 products	
resulting	from	hydroalkylation	or	reduction	of	the	alkyne	
are	 only	 observed	 as	 minor	 byproducts.	 Furthermore,	
exogeneous	 alkenes	 such	 as	 styrene	 and	 E/Z-βmethylstyrene	 are	 not	 incorporated	 in	 the	 cyclobutene	
products,39	 suggesting	 that	 nickel	 hydride	 mediated	
reduction	 of	 the	 alkyne	 and	 subsequent	 alkene-alkyne	
[2+2]	 cycloaddition	 reaction	 is	 unlikely	 for	 the	
production	 of	 cyclobutene	 products.	 The	 basis	 for	 the	
unique	promotion	exhibited	by	the	amino-	phosphine	L1	
is	currently	unclear.	The	role	of	this	ligand	architecture	
may	 involve	 features	 other	 than	 simple	 bidentate	
coordination,	such	as	proton	shuttling	or	generation	of	a	
Lewis	 adduct	 with	 the	 borane	 component,	 and	 further	
studies	to	understand	the	unique	behavior	of	this	ligand	
class	are	in	progress.	
In	 summary,	 a	 nickel-catalyzed	 reductive	 [2+2]	 cyclo-	
addition	 reaction	 of	 alkynes	 toward	 the	 synthesis	 of	
trans-	 cyclobutenes	 has	 been	 developed.	 The	 use	 of	 an	
unusual	primary	aminophosphine	ligand	was	key	to	the	
discovery	 of	 this	 new	 reaction.	 Postreaction	
modifications	 highlighted	 the	 synthetic	 versatility	 of	
these	 products,	 including	 the	 synthesis	 of	 the	 natural	
product	epi-truxillic	acid.		

ASSOCIATED	CONTENT	

*S	Supporting	Information	
cationic	 nickel	 carbene	 IV.32,33	 Next,	 a	 1,2-alkyl	
migration	would	generate	the	4-membered	ring	and	the	
second	
C−C	
12,34Finally,anethyltransfertonickel(VI),β-	
bond(V).

elimination35	 (VII)	 and	 reductive	
36	 gives	 rise	 to	 the	 desired	 cyclobutene,	
elimination
regenerating	the	nickel(0)	catalyst.	In	situ	HRMS	(ESI+)	
analysis	 of	 the	 reaction	 mixture	 using	 alkyne	 1e	
revealed	a	very	intense	m/z	signal	at	552.1609	with	the	
characteristic	 isotopic	 distribution	 of	 a	 nickel	 species.	
This	data	suggests	the	presence	of	a	nickel	species	that	
incorporates	the	aminophosphine	and	the	two	units	of	
the	 corresponding	 alkyne	 (i.e.,	 structures	 II−V).	 In	
combination	 with	 the	 Hammett	 studies	 and	 KIE	
experiments,	the	data	overall	is	consistent	with	III	being	
the	catalyst	resting	state.	
hydride	

This	 overall	 mechanism	 bears	 analogy	 to	 [3+2]	
reductive	 cycloadditions	 of	 enals	 and	 alkynes	 that	
proceed	through	the		

	

The	Supporting	Information	is	available	
free	of	charge	on	the	ACS	Publications	
website	at	DOI:	10.1021/jacs.8b09677.	
	

Experimental	procedures	and	spectral	data	
(PDF)	Crystallographic	data	for	4a	(CIF)	
Crystallographic	data	for	4b	(CIF)	
Crystallographic	data	for	10	(CIF)	
	

AUTHOR	INFORMATION		
Corresponding	Author	
*mapericas@iciq.es.	
	

ORCID	

Santiago	Cañellas:	0000-0002-8700-4615	
John	Montgomery:	0000-0002-2229-0585	
MiquelÀ.Pericas̀:0000-0003-0195-8846	
	

Notes	
The	authors	declare	no	competing	financial	
interest.		
ACKNOWLEDGMENTS	
Financial	 support	 from	 the	 MINECO	 (grant	 CTQ201569136-	
R	
(MINECO/FEDER))	
and	
CERCA	
Program/Generalitat	 de	 Catalunya	 is	 gratefully	
acknowledged.	 We	 also	 thank	 the	 MINECO	 for	 support	
through	 the	 Severo	 Ochoa	 Excellence	 Accreditation	 20142018	(SEV-2013-0319).	S.C.	thanks	the	MINECO	for	a	Severo	
Ochoa	FPI	fellowship	(BES-2015-	072152).	J.M.	thanks	the	
National	Institutes	of	Health	(R35-	GM118133)	for	support.	
We	are	grateful	to	the	ICIQ	X-ray	

diffraction	unit	for	the	X-ray	single	crystal	analyses	of	4a,	
4b	and	10.	Prof.	Ruben	Martin	(ICIQ)	and	Dr.	Alex	J.	Nett	
(University	of	Michigan)	are	acknowledged	for	very	useful	
discussions.WethankMr.SergioFernańdez(ICIQ)forthe	
assistance	on	the	headspace	analysis.		
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(9)	For	examples	using	primary	-aminophosphine	ligands,	see:	
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(10)	See	Supporting	Information	for	more	details.	
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and	amine	were	tolerated,	while	imidazole	shut	down	the	
desired	 reaction.	 See	 Supporting	 Information	 for	 more	
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(12)	This	migration	observed	gives	support	to	the	cationic	
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they	lack	chirality.	
(25)	 This	 isomeric	 form	 possessing	 a	 characteristic	 S1	 axis	 is	
easily	distinguished	by	NMR	from	the	other	isomers	of	truxillic	
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(32)	This	transformation	is	possibly	the	rate-determining	
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(39)	Kinetic	profile	of	the	reaction	for	the	formation	of	2c	in	the	
presence	 of	 1	 equivalent	 of	 E-	 and	 Z-β-methylstyrene	 overlap	
with	the	one	where	no	additive	is	added.	See	kinetic	analyses	in	
the	Supporting	Information.