New Initiation Modes for Directed Carbonylative C-C Bond Activation: Rhodium-Catalyzed (3 + 1 + 2) Cycloadditions of Aminomethylcyclopropanes

Article abstract of DOI:10.1021/jacs.6b08608

Under carbonylative conditions, neutral Rh(I)-systems modified with weak donor ligands (AsPh₃ or 1,4-oxathiane) undergo N-Cbz, N-benzoyl, or N-Ts directed insertion into the proximal C-C bond of aminomethylcyclopropanes to generate rhodacyclope

Full text of DOI:10.1021/jacs.6b08608

Communication
pubs.acs.org/JACS
New Initiation Modes for Directed Carbonylative C−C Bond
Activation: Rhodium-Catalyzed (3 + 1 + 2) Cycloadditions of
Aminomethylcyclopropanes
Gang-Wei Wang,† Niall G. McCreanor,† Megan H. Shaw,† William G. Whittingham,‡
and John F. Bower*,†
†School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom
‡Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom
S
* Supporting Information
Scheme 1
ABSTRACT: Under carbonylative conditions, neutral
Rh(I)-systems modified with weak donor ligands (AsPh3
or 1,4-oxathiane) undergo N-Cbz, N-benzoyl, or N-Ts
directed insertion into the proximal C−C bond of
aminomethylcyclopropanes to generate rhodacyclo-
pentanone intermediates. These are trapped by N-tethered
alkenes to provide complex perhydroisoindoles.
ycloaddition reactions are the most powerful approach for
Cthe construction of complex carbocycles. The emergence of
methodologies mediated by redox metal catalysis (esp. Rh) has
enabled access to ring systems that are inaccessible using classical
organic reactivity.1 Key to this is the identification of new
oxidative initiation modes to provide reactive organometallic
intermediates. We have developed a Rh-catalyzed cycloaddition
platform that relies upon N-protecting group directed carbon-
ylative ring expansion of aminocyclopropanes 2 to provide highly
regiocontrolledaccesstokeyrhodacyclopentanoneintermediates
3 (Scheme 1A).2,3 These can engage pendant alkynes or alkenes
to generate stereochemically rich (3 + 1 + 2)2a,b,d or (7 + 1)2c
cycloaddition products. Notable features of these methodologies
include (a) the unusually high “sp3-character” of the metallacycle4
and (b) easy access to the aminocyclopropane unit by Curtius
rearrangement of readily available and, where appropriate,
new activation mode, which would enhance substantially the
flexibility of any downstream catalytic protocols, motivated the
exploration of aminomethylcyclopropane-based cycloadditions.
The successful realization of this endeavor is described herein,
with the resulting (3 + 1 + 2) cycloaddition methodology
providing exceptionally flexible access to perhydroisoindoles, a
core motif of numerous bioactive compounds (Scheme 1B).8
These studies provide rare examples of C−C activation triggered
cycloadditionswherea3-carbonunitisprovidedbyanelectronneutral
nonactivated cyclopropane.5,9 Existing C−C activation based
cycloadditions using cyclopropane derivatives either require
activated variants9a−d or rely on the incoming π-unsaturate to
direct C−C activation,9e thereby limiting either the stereo-
chemical complexity of the newly formed ring or further
application of the initiation mode.
enantiopure cyclopropane carboxylates 1.
The aminocyclopropane-based cycloadditions outlined in
Scheme 1A are prototypes for a suite of related processes
triggered by directed C−C bond activation. To broaden further
the utility of this approach, expansion to other substrate classes
that can be accessed from cyclopropane carboxylates is required.
Thus, we considered the feasibility of processes based on
aminomethylcyclopropanes 4, which can be synthesized from 1
by an amide formation−reduction sequence. At the outset, this
proposition was considered challenging because (a) 6-ring
chelates form more slowly and are less stable than 5-ring variants
(cf. 3 vs 5);5 (b) the cyclopropane unit of 4 is considerably less
nucleophilic than that of 2, such that C−C oxidative addition is
more difficult;6 and (c) whereas amino-rhodacyclopentanones 3
are relatively stable, homologues 5 can undergo facile exocyclic β-
hydride elimination via C2−H upon dissociation of the directing
group;7 the latter is required for the Rh-center to engage an N-
tetheredπ-unsaturate. Nevertheless, theprospectofestablishinga
Received: August 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b08608
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Journal of the American Chemical Society
Communication
Preliminary experiments sought to confirm the feasibility of the
new activation mode proposed in Scheme 1. Accordingly,
carbamate 4a was exposed to a cationic Rh(I)-system ([Rh-
(cod)2]BF4/PPh3) in the absence of CO, which resulted in
smooth conversion to 10a (via rhodacyclobutane 9) rather than
regioisomer 10b. This result supports the proposed directed C−
C bond activation pathway because in the absence of directing
groups the same catalyst system inserts into the less hindered C−
C bond of monosubstituted cyclopropanes.2a,10 As expected, a
less Lewis acidic neutral Rh(I)-system derived from [Rh(cod)-
Cl]2/PPh3 did not promote directed oxidative addition, and
branched product 10b was generated in low yield (see the
Supporting Information (SI)). Under carbonylative conditions,
coordination of strongly π-accepting CO should enhance the
Lewis acidity of neutral Rh(I)-centers such that carbonyl-directed
C−Cbond activation can occur.2a Thus, bothcationic andneutral
rhodium systems were deemed viable for the process outlined in
Scheme 1B. To probe the facility of aminomethylcyclopropane vs
aminocyclopropane C−C bond activation, we exposed competi-
tion substrate 4b to [Rh(cod)2]BF4/PPh3 at 140 °C for 1 h
(Scheme 2B). This revealed high selectivity for activation of the
Table 1. Evaluation of Different Directing Groups
stereochemistry of the ring junction reflects the inherent
preference of the alkene migratory insertion step.
The choice of directing group for the process in Scheme 1B is
critical, as it must be not only sufficiently Lewis basic to promote
C−C oxidative addition but also sufficiently labile to dissociate
from 7 prior to alkene coordination. Accordingly, a range of
potential directing groups were examined under optimized
conditions. Amide 6d and sulfonamide 6e12 delivered targets
8d and 8e in excellent yield. Strongly coordinating urea (6b) and
2-pyridyl (6a) directing groups were less efficient or provided no
cycloadditionproduct, presumablybecauseofslowdissociationat
the stage of 7. More weakly coordinating p-trifluorobenzamide
(6f) and nosyl (6g) directing groups were less effective than their
parentsystems(6dand6e), likelyduetolessefficientdirectedC−
C bond activation. These results highlight the importance of
selecting an appropriately Lewis basic directing group.
Scheme 2
Extension of the protocol to systems with substitution at R2 or
R3 raised the issue of whether high diastereocontrol could be
achieved for these substituents with respect to the ring junction
(vide infra) (Table 2). Cyclization of N-Cbz substrate 6h
Table 2. Diastereoselective (3 + 1 + 2) Cycloadditions
aminocyclopropane unit, leading predominantly to N-vinyl
carbamate 11a; 11c was not observed. Subsequent activation of
the aminomethylcyclopropane moiety of 11a (to afford 11b) was
much slower, demonstrating the relative difficulty of the 6-ring
chelate driven C−C bond activation pathway.11 Indeed, we have
already shown that (3 + 1 + 2) cycloadditions of amino-
cyclopropanes can be achieved with retention of an amino-
methylcyclopropane unit.2b
Having established the feasibility of the proposed C−C bond
activation mode, its incorporation into a cycloaddition process
was explored. This required the identification of conditions to
suppressβ-hydrideeliminationviaC2−Hatthestageofeitherthe
rhodacyclobutane (cf. 9) or rhodacyclopentanone (7) inter-
mediate. Indeed, carbonylative (3 + 1 + 2) cycloaddition of
carbamate 6c to 8c was not efficient using neutral Rh(I)-
precatalysts modified with a wide range of P-based ligand systems
(Table 1 and the SI). At best, 8c was formed in 37% yield using
P(3,5-(CF3)2C6H3)3 as the ligand with the mass balance
consisting of byproducts derived from β-hydride elimination
triggered decomposition of metallacyclic intermediates. Cationic
Rh(I)-systems were completely ineffective, presumably because
the additional vacant coordination site facilitates β-hydride
elimination at the stage of 7. After extensive investigation, we
found that 8c could be formed in 84% yield and >15:1 d.r. using
AsPh3 as the ligand (“Conditions A”); note that the trans-
delivered 8h in 69% yield but only 3:1 d.r. Here, the ability to use
differentdirectinggroupswasbeneficial, andbyswitchingtoN-Ts
variant 6i, product 8i was generated in 8:1 d.r. and 64% yield. A
similar result was obtained for benzyl substituted system 8j. For
6k, which possesses abulky isopropyl group, “Conditions A” were
not overly effective, generating 8k in only 45% yield and 14:2:1
d.r.13 Efforts to improve conversion by standard parameter
B
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Communication
variance (concentration, temperature, etc.) were not fruitful, so
further ligand systems were investigated. For this hindered
substrate, we hypothesized that ligands less bulky than AsPh3
might provide enhanced efficiencies. In seeking other classes of
weak donor ligand, but with decreased steric demands, we were
drawn to sulfides.14 The coordination chemistry of certain
thioethers to Rh has been studied,15 but they are rarely used as
monodentate ligands in catalysis.16 From a broad screen of
commericial sulfides, we discovered that 1,4-oxathiane, which is
readilyavailableatlowcost,17 coulddeliveradduct 8kin67%yield
and 10:1 d.r. (“Conditions B”). Extension to N-Ts systems 6l−n
proceeded smoothly, and targets 8l−n were formed with good
diastereocontrol. The results for 8n (6:1 d.r.) vs Cbz-variant 8o
(2:1 d.r.) highlight once again the benefits of an N-Ts group to
diastereoselectivity.
(7). Extension to 1,2-disubstituted alkenes offers the option of
exploiting alkene geometry for diastereocontrol; however,
processes of this type are sterically challenging and have not
been realized for aminocyclopropane-based cycloadditions.2b
Gratifyingly, cycloaddition of trans-alkenes 6w and 6x delivered
products 8w and 8x with high diastereocontrol for the three new
adjacent stereocenters, wherein the R4-substituent resides in a
pseudoequatorial position (Scheme 4). Cis-substituted alkene 6x′
Scheme 4. (3 + 1 + 2) Cycloadditions Involving 1,2-
Disubstituted Alkenes and Key Control Factors
We have investigated the scope of the system with respect to
substitution on the cyclopropane unit, and these studies revealed
similar regioselectivity trends to aminocyclopropane-based
processes (Scheme 3).2a−c Trans-1,2-disubstituted cyclopro-
Scheme 3
provided 8x′, the diastereomer of 8x, in 7:1 d.r. favoring a
pseudoaxial ethyl substituent. Thus, the processes are diaster-
eospecific with respect to alkene geometry. By combining this
feature with stereochemically defined cyclopropanes, ring
systems of even higher complexity can be constructed. For
example, cycloaddition of 6y provided 8y in 11:1 d.r. favoring the
indicated (and expected) diastereomer; here, four contiguous
stereocenters are controlled. Systems with α-substitution can also
be exploited: cycloaddition of 6z provided 8z in 13:3:1 d.r., with
good diastereocontrol for the C1-methyl group.
It is pertinent at this stage to clarify key diastereo- and
regiocontrol factors (also highlighted in Scheme 4). For 6y to 8y,
the C3a−C4 stereorelationship is controlled by the trans-
geometry of the alkene, the C3a−C7a stereorelationship reflects
the preference of alkene migratory insertion, and the C7a−C7
stereorelationship is determined by the trans-stereochemistry of
the cyclopropane; the latter also controls C−C bond activation
regioselectivity suchthatbondaiscleaved andtheC7-substituted
product is generated (cf. Scheme 3A vs 3B). An additional and
more intriguing consideration is what controls the C1−C7a
stereorelationship established during conversion of 6z to 8z and
the high diastereoselectivities obtained in Table 2. A plausible
explanation is that rhodacyclopentanone formation is reversible,
such that the relative rate of alkene insertion (k1 vs k2) from π-
complexes 7′ and iso-7′ controls product diastereoselectivity
(Scheme 5). A similar Curtin−Hammett selectivity model is
operative for aminocyclopropane-based processes catalyzed by
cationic Rh(I)-complexes; neutral Rh(I)-systems provided low
diastereocontrol in those cases, likely because they lack the free
coordination site required for retrocarbonylation from 3 (see
Scheme 1A).2b In the cycloadditions described here, which use
panes 6p−t underwent preferential activation of less hindered
proximalC−Cbondatodelivertargets8p−twithexquisitelevels
of regio- and diastereocontrol. Here, the relative stereochemistry
of the cyclopropane is transferred to the C7−C7a stereochemical
relationship of the products. For these processes the use of 1,4-
oxathiane as the ligand conferred substantial advantages; for
example, cyclohexyl system 8q was generated in only 38% yield
under “Conditions A” vs 71% yield with 1,4-oxathiane
(“Conditions B”).13 Cis-1,2-disubstituted system 6u delivered
8u, which is the pseudoregioisomer of 8p, via cleavage of more
hinderedbutmoreelectron-rich bondb. Again, thisresultmirrors
the preferred site of activation for aminocyclopropane-based
systems.2b Thus, the relative stereochemistry of the cyclopropane
unit (cis vs trans) controls both C−C bond activation selectivity
(bond a vs b) and the relative stereochemistry of the product.
Bicyclic system 6v was smoothly desymmetrized to deliver
tricyclic system 8v with complete diastereocontrol; unique to this
example, a diene ligand [(7-t-BuO)-norbornadiene] was found to
be most effective.13
All of the processes described so far involve insertion of a
monosubstituted alkene into the incipient rhodacyclopentanone
C
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Scheme 5. Possible Diastereocontrol Model for Systems with
R2/R3 Substituents
REFERENCES
■
(1) Selected reviews: (a) Lautens, M.; Klute, W.; Tam, W. Chem. Rev.
1996, 96, 49. (b) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39,
2791. (c) Jiao, L.; Yu, Z.-X. J. Org. Chem. 2013, 78, 6842. (d) Ylijoki, K. E.
O.; Stryker, J. M. Chem. Rev. 2013, 113, 2244.
(2)(a)Shaw, M.H.;Melikhova, E. Y.;Kloer, D. P.;Whittingham, W.G.;
Bower, J. F. J. Am. Chem. Soc. 2013, 135, 4992. (b) Shaw, M. H.;
McCreanor, N. G.; Whittingham, W. G.; Bower, J. F. J. Am. Chem. Soc.
2015, 137, 463. (c) Shaw, M. H.; Croft, R. A.; Whittingham, W. G.;
Bower, J. F. J. Am. Chem. Soc. 2015, 137, 8054. (d) Shaw, M. H.;
Whittingham, W. G.; Bower, J. F. Tetrahedron 2016, 72, 2731.
(e) McCreanor, N. G.; Stanton, S.; Bower, J. F. J. Am. Chem. Soc. 2016,
138, 11465.
(3) For a review on rhodacyclopentanone-based catalysis, see:
(a) Shaw, M. H.; Bower, J. F. Chem. Commun. 2016, 52, 10817. Selected
recent contributions: (b) Zhou, X.; Dong, G. J. Am. Chem. Soc. 2015, 137,
13715. (c) Ko, H. M.; Dong, G. Nat. Chem. 2014, 6, 739. (d) Souillart, L.;
Parker, E.;Cramer, N. Angew. Chem., Int.Ed. 2014, 53, 3001. (e)Souillart,
L.; Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 9640. (f) Matsuda, T.;
Tsuboi, T.; Murakami, M. J. Am. Chem. Soc. 2007, 129, 12596.
(g)Murakami, M.;Itahashi, T.;Ito, Y. J. Am. Chem. Soc. 2002, 124, 13976.
(4) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.
(5) The use of 6-ring chelates to trigger C−C activation is unusual:
Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410.
(6) Review on aminocyclopropanes: Rassadin, V. A.;Six, Y. Tetrahedron
2016, 72, 4701. Our observations are consistent with electron donation
from the cyclopropane unit to Rh being a key factor in C−C activation.
(7) Chen, P.-h.; Sieber, J.; Senanayake, C. H.; Dong, G. Chem. Sci. 2015,
6, 5440.
neutral Rh(I)-complexes, the requisite free coordination site may
be provided by relatively facile dissociation of the directing group
of the weaker 6-ring chelate. Indeed, in the absence of directing
groups, Murakami and Ito have shown that cyclobutanone-
derived neutral rhodacyclopentanone complexes undergo
retrocarbonylation and C−C reductive elimination to provide
cyclopropanes.18 The enhanced diastereoselectivities observed in
Table 2 for N-Ts vs N-Cbz protected systems may reflect
increased reversibility for rhodacyclopentanone formation and/
or enhanced conformational preferences for alkene insertion due
to the greater sp3 character at nitrogen.
In summary, we show that directed carbonylative C−C bond
activation can be extended beyond aminocyclopropane-based
systems to readily available aminomethylcyclopropane deriva-
tives. The resulting (3 + 1 + 2) cycloaddition methodology
provides exceptionally flexible and controlled access to stereo-
chemically complex perhydroisoindoles. This study represents a
significant extension to the cycloaddition strategy outlined in
Scheme 1A, validating for the first time electronically distinct
cyclopropanes and 6-ring chelate driven processes. Applications
of the new initiation mode described here to other diverse
processes can easily be envisaged. Indeed, in addition to (3 + 1 +
2) cycloadditions,2a,b,d carbonylative C−C bond activation of
aminocyclopropanes now underpins (7 + 1) cycloadditions2c and
capture−collapse heterocyclizations.2e
(8) Review: Speck, K.; Magauer, T. Beilstein J. Org. Chem. 2013, 9, 2048.
(9) Carbonylative (3 + 1 + 2)/(3 + 2 + 1) cycloadditions of
cyclopropane-based systems with alkenes: (a) Vinylcyclopropanes: Jiao,
L.; Lin, M.; Zhuo, L.-G.; Yu, Z.-X. Org. Lett. 2010, 12, 2528. (b)
Cyclopropenes: Li, C.; Zhang, H.; Feng, J.; Zhang, Y.; Wang, J. Org. Lett.
2010, 12, 3082. (c) Alkylidenecyclopropanes: Mazumder, S.; Shang, D.;
Negru, D. E.;Baik,M.-H.;Evans, P.A. J. Am. Chem. Soc. 2012,134,20569.
(d) Vinylidenecyclopropanes: Lu, B.-L.; Wei, Y.; Shi, M. Organometallics
2012, 31, 4601. Under forcing conditions, electron neutral cyclo-
propanes engage incarbonylative (3 +1+2) cycloadditionswith alkynes,
withthelatterdirectingC−Cactivation:(e)Narasaka, K.;Koga, Y. Chem.
Lett. 1999, 28, 705.
(10) For the processes described later we cannot definitively rule out an
alkenedirectedpathway. InadditiontotheresultsinScheme2A/Table1,
further evidence against this activation mode includes the following: (a)
under optimized conditions, the cycloadditions in Table 2 are insensitive
tothestericsoftheR3-substituent(e.g., underConditionsB, 8i(Pr):61%
yield vs 8k (i-Pr): 67% yield), but sensitive to the sterics of the R2-
substituent, and (b) systems where DG = benzyl (cf. Table 1) are
ineffective.
ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/jacs.6b08608.
■
S
(11)Wehavebeenunabletoisolaterhodacyclopentanones related to5;
analogous 5-ring chelates (3) are easily isolated (see refs 2a−c).
(12) Directed insertion into N-cyclopropylsulfonamides has been
achieved previously (see ref 2d).
Crystallographic data (CIF, CIF, CIF, CIF, CIF, CIF, CIF,
CIF, CIF, CIF)
Experimental details, characterization data (PDF)
(13) Representative product derivatizations and results for alternate
cycloaddition conditions are given in the SI.
(14) Murray, S. G.; Hartley, F. R. Chem. Rev. 1981, 81, 365.
(15) Walton, R. A. J. Chem. Soc. A 1967, 1852.
AUTHOR INFORMATION
Corresponding Author
*john.bower@bris.ac.uk
Notes
■
(16) Sulfides are commonly used as part of P,S-ligand systems: Lam, F.
L.; Kwong, F. Y.; Chan, A. S. C. Chem. Commun. 2010, 46, 4649.
(17) Approximately $3.60/g from Sigma-Aldrich. Binding competition
studies for P(3,5-(CF3)2C6H3)3 vs AsPh3 vs 1,4-oxathiane are in the SI.
(18) Here, neutral Rh(I) systems modified with AsPh3 were especially
effective (cf. Conditions A). (a) Murakami, M.; Amii, H.; Ito, Y. Nature
1994, 370, 540. (b) Murakami, M.; Amii, H.; Shigeto, K.; Ito, Y. J. Am.
Chem. Soc. 1996, 118, 8285.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
WethanktheBristolChemicalSynthesisCDT,fundedbyEPSRC
(EP/G036764/1), and Syngenta for studentships (M.H.S. and
N.G.M.), the Royal Society for a URF (J.F.B.) and a K. C. Wong
Postdoctoral Fellowship (G.-W.W.), and the European Research
Council for financial support (ERC grant 639594 CatHet). We
also thank Emma Blackham (Bristol) for preliminary studies.
D
DOI: 10.1021/jacs.6b08608
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX