Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated alkenes

Article abstract of DOI:10.1126/science.aac7440

Cycloadditions, such as the [4+2] Diels-Alder reaction to form six-membered rings, are among the most powerful and widely used methods in synthetic chemistry. The analogous [2+2] alkene cycloaddition to synthesize cyclobutanes is kinetically accessible by photochemical methods, but the substrate scope and functional group tolerance are limited. Here, we report iron-catalyzed intermolecular [2+2] cycloaddition of unactivated alkenes and cross cycloaddition of alkenes and dienes as regio- and stereoselective routes to cyclobutanes. Through rational ligand design, development of this base metal-catalyzed method expands the chemical space accessible from abundant hydrocarbon feedstocks.

Full text of DOI:10.1126/science.aac7440

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31. V. Trappe, V. Prasad, L. Cipelletti, P. N. Segre, D. A. Weitz,
Nature 411, 772–775 (2001).
32. A. J. Liu, S. R. Nagel, Nature 396, 21–22 (1998).
33. J. H. Page et al., Phys. Rev. E 52, 2763–2777
(1995).
DMR-1420570. M.P.B. is an investigator of the Simons Foundation.
Part of this work was performed at the Center for Nanoscale
Systems (CNS), a member of the National Nanotechnology
Infrastructure Network, supported by NSF award no. ECS-
0335765. CNS is part of Harvard University. We thank
and all the authors contributed to the design and analysis
of the experiments.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/349/6251/956/suppl/DC1
34. R. Laitinen, K. Löbmann, C. J. Strachan, H. Grohganz, T. Rades,
Int. J. Pharm. 453, 65–79 (2013).
35. I. G. Nahtigal, I. M. Svishchev, J. Phys. Chem. B 113,
14681–14688 (2009).
D. C. Bell for acquiring the EDS images and L. R. Arriaga and
D. M. Aubrecht for helpful discussions. Patent applications
have been filed to cover the nebulator device (PCT/US2013/
060522) and the production of a-NPs (PCT/US2014/062785).
Additional data discussed in the main text are available in
the supplementary materials. E.A. conducted the experiments;
M.G. performed the SAXS experiments and analysis; E.A.,
F.S., and D.A.W. did the calculations and wrote the paper;
Materials and Methods
Supplementary Text
Figs. S1 to S8
Movie S1
References (36, 37)
ACKNOWLEDGMENTS
We acknowledge support from BASF SE, NSF grants DMR-
1310266 and DMS-1411694, and Harvard MRSEC grant
5 July 2015; accepted 31 July 2015
10.1126/science.aac9582
ORGANIC CHEMISTRY
stoichiometric Mg, allyl chloride, and an Al re-
agent in the presence of Zr and Pd additives have
also been reported (16).
Iron-catalyzed intermolecular [2+2]
cycloadditions of unactivated alkenes
Jordan M. Hoyt, Valerie A. Schmidt, Aaron M. Tondreau, Paul J. Chirik*
Our group has found that iron and cobalt
complexes bearing redox-active pyridine(diimine)
ligands, which undergo reversible one-electron
transfer with the transition metal, promote the
intramolecular [2+2] cycloadditions of a,w-dienes
to yield the corresponding bicyclo[2.3.0]heptanes
(Fig. 1A) (17–19). These base metal–catalyzed
reactions proceed with unactivated dienes at
ambient temperature, and mechanistic studies
support reductive elimination from metallacyclic
intermediates as the key C–C bond–forming step.
In both iron (18) and cobalt (19) examples, the
redox active pyridine(diimine) adopts its one-
electron-reduced form, resulting in a more-
oxidized metal center, and likely facilitates the
directional, cyclobutane-forming C(sp3)-C(sp3)
reductive elimination.
Cycloadditions, such as the [4+2] Diels-Alder reaction to form six-membered rings,
are among the most powerful and widely used methods in synthetic chemistry.
The analogous [2+2] alkene cycloaddition to synthesize cyclobutanes is kinetically
accessible by photochemical methods, but the substrate scope and functional
group tolerance are limited. Here, we report iron-catalyzed intermolecular [2+2]
cycloaddition of unactivated alkenes and cross cycloaddition of alkenes and dienes
as regio- and stereoselective routes to cyclobutanes. Through rational ligand design,
development of this base metal–catalyzed method expands the chemical space
accessible from abundant hydrocarbon feedstocks.
ycloaddition reactions as exemplified by
the venerable [4+2] Diels-Alder reaction
are among the most powerful in organic
chemistry, providing an atom-economical
method for the synthesis of six-membered
for their synthesis (6). One challenge in realizing
a practical method is overcoming the high ki-
netic barrier imparted by the thermal constraints
of orbital symmetry (7). The use of activated al-
kenes (8) and substrates that have the appropri-
ate redox potentials to interact with photocatalysts
(9, 10) have been described that overcome these
challenges, and examples with high degrees of
regio- and stereoselectivity have recently been
reported (11, 12). Unactivated alkenes, such as
those available in vast excess from shale gas
reserves and biorenewable sources, are cur-
rently outside the scope of these methods (13).
Although theoretical methods predict the pho-
tochemical feasibility of such cycloadditions (7),
photodimerization of unactivated alkenes, typi-
cally conducted in the presence of copper cata-
lysts, is limited to selected cyclic alkenes and
often yields mixtures of products, highlighting
the potential utility of alternative methods for
cyclobutane synthesis (14).
Transition metal catalysis offers the prospect
of promoting the [2+2] cycloaddition of unacti-
vated alkenes by virtue of valence d-orbitals and
low-energy pathways to metallacyclic intermedi-
ates (15). Nickel-phosphine combinations have
been reported for the synthesis of cyclobutanes
from dienes and unactivated alkenes, although
both yields and selectivities are not synthetically
useful (8). Related examples with Ti, Mn, and Fe
have also been described and suffer from the same
limitations in yield and selectivity (8). Examples of
more-selective alkene [2+2] cycloadditions with
The identification of selective, intermolecular
variants of the base metal–catalyzed [2+2] cyclo-
addition is key to the development of a more
broadly useful method compatible with abundant,
unactivated alkenes. With the first-generation
iron precatalyst, (iPrPDI)Fe(N2) [iPrPDI = 2,6-
(2,6-iPr2-C6H3-N=CMe)2C5H3N, iPr is an isopropyl
group, and Me is a methyl group], addition of
common unfunctionalized terminal alkenes, such
as propylene or 1-hexene, resulted in formation of
a stoichiometric quantity of the corresponding
alkane, arising from transfer hydrogenation from
one of the isopropyl aryl groups on the iron cata-
lyst (20). New approaches to catalyst design
were therefore necessary to promote C–C bond
formation via an iron metallacycle followed by
C(sp3)-C(sp3) reductive elimination. Here, we re-
port that iron precatalysts attained through
rational ligand design enable the regio- and ste-
reochemically controlled synthesis of 1,2- and
1,3-disubstituted cyclobutanes by thermal [2+2]
cycloaddition.
In an attempt to prevent transfer dehydro-
genation, we synthesized an iron precatalyst
lacking b-hydrogens on the aryl substituents,
[(MePDI)Fe(N2)]2(m-N2)], and observed catalyt-
ic turnover with propylene to produce a 2:1
mixture of 2,3-dimethylbutene and trans-1,2-
dimethylcyclobutane. It is likely these products
derive from a common iron metallacyclic inter-
mediate, where b-hydrogen elimination followed
by C-H reductive elimination yields the “tail-to-
tail” dimerization product—a precursor to an
C
rings (1). Despite their widespred utility and
applications, these reactions require the use of
activated substrates and are often ineffective for
unactivated alkene coupling partners. Pure hydro-
carbons are the principal feedstocks of the chem-
ical industry, serving as essential precursors to
fuels, films, liquid crystal displays, materials, and
medicines (2). Among these, ethylene and pro-
pylene are the most abundant and are produced
in 130 and 85 million metric tons annually,
respectively, serving principally as monomers for
the multibillion-dollar polyolefins industry (3, 4).
Ethylene is also selectively trimerized and tetra-
merized on large scale rendering 1-hexene and
1-octene commodity alkenes (5), motivating the
development of new cycloaddition methods that
incorporate these fundamental industrial building
blocks.
Although analogous [2+2] cycloadditions to
prepare cyclobutanes are thermodynamically fa-
vorable and could be similarly transformative in
synthesis, the exploration of the chemical space
of four-membered carbocycles has been substan-
tially hindered by the lack of selective methods
Department of Chemistry, Princeton University, Princeton, NJ
08544, USA.
*Corresponding author. E-mail: pchirik@princeton.edu
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important fuel additive used to boost octane
ratings (21). Although selectivity for 2,3-dime-
thylbutene has been previously observed in
nickel catalysis and is used industrially, such
reactivity has not been observed previously with
iron (10).
These observations inspired the catalyst de-
sign strategies illustrated in Fig. 1. Two sites of
ligand modifications were explored with the
goal of promoting reductive elimination over
b-hydrogen elimination chemistry. Replacement
of the imine methyl groups with ethyl sub-
stituents (1, Fig. 1C) was explored to prevent
imine dissociation, a process that opens a co-
ordination site for b-hydrogen elimination. The
second modification installed cyclopentyl in
place of isopropyl groups on the aryl rings (2,
Fig. 1C). The cyclic substituents are constrained
to minimize transfer dehydrogenation but re-
main sufficiently large to promote C-C reductive
elimination.
Both 1 and 2 are effective precatalysts for the
intermolecular [2+2] cycloaddition of unactivated
alkenes. The reactions proceeded efficiently at
ambient temperature and in neat substrate, ob-
viating the need for solvent or separations. In
each case, the cycloaddition product was identi-
fied as the trans-1,2-disubstituted cyclobutane,
with selectivity resulting from preferential reduc-
tive elimination from the metallacycle where the
alkyl substituents are distal from the iron (Fig.
1B). As presented in Fig. 2, the cyclopentyl-
substituted catalyst 2 proved to be highly selective,
forming exclusively cyclobutane products. The
commodity terminal alkenes, propylene and 1-
hexene, underwent efficient [2+2] cycloaddition
over the course of 48 hours at 23°C. Only product
and starting alkene were detected during the
course of the reactions. The Fe-catalyzed cyclo-
addition was sensitive to alkene substitution on
the allylic position indicated by decreased conver-
sion with 4-methyl-1-pentene and allylbenzene.
Improved activity, albeit with slightly reduced
Fig. 1. Catalyst development. (A) Intramolecular [(iPrPDI)FeN2]-catalyzed [2+2] cycloadditions of un-
activated olefins. E=CH2, N-alkyl, aryl, C(CO2Et)2. (B) (PDI)Fe-metallacycle model that allows for control over
product distribution. R, methyl or ethyl groups. (C) (PDI)Fe compounds used in this study of intermolecular
[2+2] alkene cycloadditions. The dots in the chemical structures represent electrons on the ligand.
Fig. 2. Scope of the Fe-catalyzed dimerization. (A) Cyclobutanes from
variously substituted terminal olefins. Values given are % conversion with
isolated yields shown in parentheses. (B) “Tail-to-tail” dimerization of propylene
using meso-(tBuPDI)FeCH3.
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selectivity, was observed with 1; allyl- and 1-
butenyl benzene resulted in the formation of
their corresponding cyclobutanes in high yields.
Consistent with cobalt-catalyzed intramolecular
[2+2] cycloadditions (19), the reduced steric
profile of the methyl (1) versus cyclopentyl (2)
aryl substituents facilitates substrate coordina-
tion and metallacycle formation.
To demonstrate the scalability of the meth-
od, we conducted the cyclodimerization of
allylbenzene on a 3.0-g scale with 1 mole %
(mol %) of 1 and produced trans-1,2-diben-
zylcyclobutane in 93% isolated yield. Catalytic
cycloaddition was also explored with air-stable
iron precursors by using in situ activation
methods as described previously (17). Stirring
neat allylbenzene in the presence of 5 mol %
of (MeEtPDI)FeCl2 (Et, ethyl group) activated
with 10 mol % NaBEt3H produced 97% con-
version of the alkene over the course of 48 hours.
The product mixture contained 62% of the
desired 1,2-trans-dibenzylcyclobutane prod-
uct along with 4% hydrovinylation product
and 31% trans-b-methyl styrene arising from
alkene isomerization. These results high-
light the improved catalytic performance
associated with the isolated iron dinitrogen
precatalysts.
Further support for the selectivity model
presented in Fig. 1B was provided by the
dimerization of propylene to 2,3-dimethylbu-
tene with more open iron catalysts designed
to promote b-hydrogen elimination. Because
of the synthetic inaccessibility of the corre-
sponding iron dinitrogen complex, we explored
meso-(tBuPDI)FeCH3 (3) (tBu, tert-butyl group)
(Fig. 2B). Stirring a benezene-d6 solution of
propylene and 1 mol % of 3 resulted in ex-
clusive formation of 2,3-dimethylbutene in 67%
conversion over the course of 48 hours at 23°C.
Fig. 3. Expanding from homodimerization to heterocoupling. (A) Single-step, Fe-catalyzed 3-
methyl-1-vinylcyclobutane synthesis from commodity chemicals. (B) Catalyst effects on the [2+2]
cycloaddition of myrcene and 1-hexene. (C) Fe-alkyl-allyl intermediate en route to 1,3-disubstituted
cyclobutanes.
1
Monitoring the catalytic reaction by H nuclear
magnetic resonance (NMR) spectroscopy re-
vealed formation of small amounts of methane
and ethane, likely resulting from Fe-CH3 homol-
ysis ensuing from catalyst activation en route to
the intermediate metallacycle that undergoes
preferential b-hydrogen elimination.
the diene component. For example, addition
of ethylene or propylene to isoprene prefer-
entially formed hydrovinylation products
arising from b-hydrogen elimination over cyclo-
butane products.
and 1-hexene—two liquid substrates that are
abundant bio- and fossil hydrocarbon re-
sources, respectively (Fig. 3B). A 1:5 ratio of
diene to alkene was used in all catalytic ex-
periments to suppress diene homodimeriza-
tion. Unfortunately with both 1 and 2, only
slight excesses (1.4:1 and 1.3:1, respectively)
of the desired cyclobutane products were ob-
served, demonstrating that the strategy used
to supress b-hydrogen elimination and favor
C–C bond formation in terminal alkene [2+2]
cycloaddition does not translate into diene-
alkene chemistry.
A more-rigid catalyst design feature was
therefore introduced to favor reductive elim-
ination and suppress hydrovinylation chemistry
(Fig. 3C). An iron dinitrogen precatalyst was
used in which the imine substituents were co-
valently attached to the central pyridine, pre-
venting formation of an open coordination site
for b-hydrogen elimination (18). This approach
proved successful, because stirring a 1:5 mix-
ture of myrcene:1-hexene in the presence of
5 mol % of 4 resulted in exclusive (>20:1) se-
lectivity for cis-1,3-disubstituted cyclobutane
product (Fig. 3B).
To overcome this limitation, we explored
the catalyst design strategies described for
alkene [2+2] cycloaddition to increase the
cyclization selectivity of diene-alkene reac-
tions. Myrcene, a naturally occurring terpene
found as an essential oil in bay, cannabis, pars-
ley, and hops (24), was used as a represent-
ative diene for reaction discovery. Control
experiments wherein neat myrcene was stirred
at 23°C with 1 mol % of 1 or 2 resulted in [2+2]
homodimerization to yield 46 and 74% of the
1,3-disubstituted cyclobutane product, respect-
ively. Complex mixtures of unidentified organic
products account for the mass balance of
the reaction or material. The 1,3-disubstituted
product was obtained with both catalysts, dem-
onstrating preference for iron alkyl-allyl type
metallacycle formation from diene coordination-
insertion (22).
The success of iron-catalyzed [2+2] cyclo-
addition of unactivated alkenes prompted in-
vestigation into a more-general method for
the heterodimerization of abundant dienes
and alkenes to value-added cyclobutanes con-
taining alkene substituents available for fur-
ther elaboration. Iron-catalyzed cycloaddition
of 1,3-butadiene and ethylene with 5 mol %
(
MePDI)Fe(N2) to yield vinyl cyclobutane has
been reported (22) and produced no evidence
for six-membered ring products arising from
competing Diels-Alder chemistry (23). We have
since found that, in the presence of 5 mol % of
(
MePDI)Fe(N2), [2+2] cycloaddition of buta-
diene with propylene resulted in >98% con-
version to 1-methyl-3-vinylcyclobutane as
a
67:33 mix of cis:trans diastereomers (Fig. 3A).
As reported previously (22), this specific iron
catalyst loses selectivity for [2+2] cycloaddi-
tion upon introduction of a substitution on
Evaluation of cross diene-alkene [2+2] cy-
cloadditions were conducted with myrcene
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volving more functionalized alkenes, such as
4-bromo-1-butene, trimethylsilyloxypropene,
and 2-butenyl-6-methylpyridine. The understand-
ing of how ligand design affects the reactivity
of intermediate metallacycles en route to
cyclobutane formation provides important in-
sight for the synthesis of the next generation
of base metal catalysts to expand the scope of
the reaction.
REFERENCES AND NOTES
1. F. Fringuelli, A. Taticchi, The Diels-Alder Reaction:
Selected Practical Methods (Wiley, Chichester, UK,
2002)
2. S. Matar, L. F. Hatch, Chemistry of Petrochemical
Processes (Gulf Professional, Boston, ed. 2,
1991).
3. H. Zimmerman, R. Walzl, Ullmann’s Encyclopedia of
Industrial Chemistry: Ethylene (Wiley, Chichester, UK,
2009).
4. H. Zimmerman, R. Walzl, Ullmann’s Encyclopedia of
Industrial Chemistry: Propylene (Wiley, Chichester, UK,
2009).
5. D. S. McGuinness, Chem. Rev. 111, 2321–2341 (2011).
6. Z. Rappoport, J. F. Liebman, in The Chemistry of
Cyclobutanes (Wiley, Chichester, UK, 2005),
pp. 281–355.
7. R. B. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. Engl.
8, 781–853 (1969).
8. P. Heimbach, Angew. Chem. Int. Ed. Engl. 12, 975–989
(1973).
9. J. D. Winkler, C. M. Bowen, F. Liotta, Chem. Rev. 95,
2003–2020 (1995).
10. E. Lee-Ruff, G. Mladenova, Chem. Rev. 103, 1449–1484
(2003).
11. R. Brimioulle, T. Bach, Science 342, 840–843 (2013).
12. J. Du, K. L. Skubi, D. M. Schultz, T. P. Yoon, Science 344,
392–396 (2014).
13. T. Bach, A. Spiegel, Eur. J. Org. Chem. 2002, 645–654
(2002).
14. R. G. Salomon, K. Folting, W. E. Streib, J. K. Kochi,
J. Am. Chem. Soc. 96, 1145–1152 (1974).
15. J. P. Collman, L. S. Hegedus, J. R. Norton, R. G. Finke,
in Principles and Applications of Organotransition Metal
Chemistry (University Science Books, Mill Valley, USA,
1987), pp. 495-499.
Fig. 4. Scope of the Fe-catalyzed diene-a-olefin cycloaddition. Values reported are % con-
version with isolated yields shown in parentheses. Standard conditions were as follows: 5 mol %
4, 1 equiv diene, 5 equiv olefin, 23°C for 48 hours. The reaction with butadiene and ethylene was
conducted with 5 mol % (MePDI)Fe(N2) dr is diastereomeric ratio as determined by means of
1H NMR.
With an optimized iron precatalyst struc-
ture identified, the scope of the diene-alkene
cross [2+2] cycloaddition was evaluated (Fig.
4). By using myrcene as the diene partner,
we observed highly regio- and diastereose-
lective (>95:5) cycloaddition to form cis-1,3-
disubstituted cyclobutanes with various terminal
alkenes, including 1-hexene, allyl benzene, 4-
methyl-1-pentene, 4,4-dimethyl-1-pentene, and
4-phenyl-1-butene. Introduction of a cyclo-
hexenyl substituent onto the alkene coupling
partner resulted in reduced yields but main-
tained high selectivity, likely because of the
steric inhibition for forming the intermediate
metallacycle. In each of these examples, good
to excellent conversions and isolated yields
were obtained. Products from diene or alkene
homodimerization were not observed, dem-
onstrating a highly selective iron-catalyzed re-
gioselective route to stereodefined cyclobutanes
with alkenyl substituents. The cross [2+2] cyclo-
addition of myrcene and 4,4-dimethylpentene
was also effective with 5 mol % (MePDI)Fe(N2),
an iron catalyst precursor more straightfor-
ward to prepare than 4 and hence easily
obtained in larger quantities. With this pre-
catalyst, the cross cycloaddition was con-
ducted on a 7.0-mmol scale of mycrene and
yielded 1.57 g (96% isolated yield) of the cis-
1,3-disubstituted cyclobutane. Despite the
excess of 4,4-dimethylpentene used in the re-
action, 83% of this olefin was recovered by
vacuum transfer of the volatile components
from the crude reaction mixture. The cyclo-
butane product was then isolated by simple
filtration through a short plug of silica and,
after rinsing with hexanes, was obtained as
an analytically pure material.
Variations in the diene partner were also
tolerated, including the use of commodity
hydrocarbons (Fig. 4). With butadiene:1-hexene,
high 1,3-regioselectivity was maintained with
reduction in diastereoselectivity, likely be-
cause of reduced steric interactions between
the smaller substituents on the alkyl-allyl me-
tallacycle and the supporting pyridine(diimine)
ligand. Introduction of a methyl substituent as
in isoprene returned the diastereoselectivity
to >95:5. Terminal phenyl and pentyl subs-
tituents were also well tolerated on the diene
partner; efficient cross [2+2] cycloaddition of
1-phenyl-1,3-butadiene and 1,3-nonadiene with
1-hexene and 4,4-dimethyl-1-pentene was ob-
served (Fig. 4).
16. U. M. Dzhemilev, A. G. Ibragimov, M. N. Azhgaliev,
A. P. Zolotarev, R. R. Muslukhov, Russ. Chem. Bull. 43,
252–254 (1994).
17. M. W. Bouwkamp, A. C. Bowman, E. Lobkovsky, P. J. Chirik,
J. Am. Chem. Soc. 128, 13340–13341 (2006).
18. J. M. Hoyt, K. T. Sylvester, S. P. Semproni, P. J. Chirik,
J. Am. Chem. Soc. 135, 4862–4877 (2013).
19. V. A. Schmidt, J. M. Hoyt, G. W. Margulieux, P. J. Chirik,
J. Am. Chem. Soc. 137, 7903–7914 (2015).
20. R. J. Trovitch, E. Lobkovsky, P. J. Chirik, J. Am. Chem. Soc.
130, 11631–11640 (2008).
21. D. S. J. Jones, P. R. Pujadó, in Handbook of Petroleum
Processing (Springer, Dordrecht, Netherlands 2006),
pp. 389–399.
22. S. K. Russell, E. Lobkovsky, P. J. Chirik, J. Am. Chem. Soc. 133,
8858–8861 (2011).
23. O. Diels, K. Alder, Justus Liebigs Ann. Chem. 460, 98–122
(1928).
24. A. Behr, L. Johnen, ChemSusChem 2, 1072–1095 (2009).
ACKNOWLEDGMENTS
Financial support was provided by Firmenich. V.A.S. thanks
the NIH for a Ruth L. Kirschstein National Research Award
(F32 GM109594).
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/349/6251/960/suppl/DC1
Materials and Methods
Fig. S1
Tables S1 and S2
References (25–38)
The iron precatalysts used in this work
were ineffective for [2+2] cycloadditions in-
5 June 2015; accepted 23 July 2015
10.1126/science.aac7440
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Iron-catalyzed intermolecular [2+2] cycloadditions of unactivated
alkenes
Jordan M. Hoyt et al.
Science 349, 960 (2015);
DOI: 10.1126/science.aac7440
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