Modular Access to Substituted Azocanes via a Rhodium-Catalyzed Cycloaddition-Fragmentation Strategy

Article abstract of DOI:10.1021/jacs.5b05215

A short entry to substituted azocanes by a Rh-catalyzed cycloaddition-fragmentation process is described. Specifically, exposure of diverse N-cyclopropylacrylamides to phosphine-ligated cationic Rh(I) catalyst systems under a CO atmosphere enables the directed generation of rhodacyclopentanone intermediates. Subsequent insertion of the alkene component is followed by fragmentation to give the heterocyclic target. Stereochemical studies show, for the first time, that alkene insertion into rhodacyclopentanones can be reversible.

Full text of DOI:10.1021/jacs.5b05215

Communication
pubs.acs.org/JACS
Modular Access to Substituted Azocanes via a Rhodium-Catalyzed
Cycloaddition−Fragmentation Strategy
Megan H. Shaw,† Rosemary A. Croft,† 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: A short entry to substituted azocanes by a
Rh-catalyzed cycloaddition−fragmentation process is
described. Specifically, exposure of diverse N-cyclo-
propylacrylamides to phosphine-ligated cationic Rh(I)
catalyst systems under a CO atmosphere enables the
directed generation of rhodacyclopentanone intermediates.
Subsequent insertion of the alkene component is followed
by fragmentation to give the heterocyclic target. Stereo-
chemical studies show, for the first time, that alkene
insertion into rhodacyclopentanones can be reversible.
irect and modular entries to eight-membered N-hetero-
Dcyclic ring systems (e.g., azocanes) are rare, and this in turn
limits the ability of medicinal chemists to exploit a potentially
fertile region of chemical space.1 Transition-metal-catalyzed
cycloadditions provide exceptional versatility for the synthesis of
eight-membered-ring carbocycles,2 but related processes that
generate N-heterocyclic systems have been slow to emerge.3,4
Within this area, important methodologies that provide concise
entries to specific classes of bicyclic azocanes include isocyanate-
based (4 + 2 + 2) cycloadditions3a and azetidinone-based (4 + 2 +
2)3b and (4 + 4)3c cycloadditions. Nevertheless, the relative
paucity of available methodologies is notable, especially given the
prevalence of the azocane ring system in a range of biologically
significant targets, such as otonecine,5 nakadomarin A,6 and a
series of recently reported XIAP antagonists (Scheme 1A).7
We have outlined a directing-group-controlled strategy that
enables the regioselective generation of rhodacyclopentanones,
such as 2, from readily available aminocyclopropane derivatives
(Scheme 1B).8,9 Specifically, aminocyclopropanes 1, modified
with carbonyl-based N-protecting groups, direct Rh and CO
insertion into the less hindered proximal C−C bond to afford
adduct 2 selectively at the expense of five other potential
regioisomers. Trapping of 2 with N-tethered alkynes or alkenes
generates (3 + 1 + 2) cycloaddition products 3a or 3b,
respectively.8a,b In this report, we disclose that acrylamides 4
undergo an alternate reaction pathway involving formal
fragmentation10 after alkene insertion (rather than C−C
reductive elimination) to provide a direct and modular entry to
azocanes 7 (Scheme 1C). The overall process is equivalent to a
(7 + 1) cycloaddition−tautomerization sequence and can be
considered a catalytic mimic of classical stepwise bicycle
assembly−fragmentation approaches to medium ring systems.11
We also provide, for the first time, compelling evidence that
migratory insertion of alkenes into rhodacyclopentanones can be
a reversible process, thereby offering key insight into a
fundamental mechanistic step that underpins a range of recently
reported C−C bond activation methodologies.8b,12−14
In preliminary experiments we established that cationic Rh(I)
systems are effective for the transformation outlined in Scheme
1C. The most pertinent studies were conducted on cyclopropane
4e, which was easily prepared in 60% yield over two steps (see the
Supporting Information (SI)). At 150 °C under 1 atm CO, a
series of cationic Rh(I) systems, modified with the electron-
deficient phosphine P(4-(CF3)C6H4)3, were effective in
delivering the azocane target 7e in 34−53% yield (Table 1,
entries 1 and 3−5). The use of PhCN as the solvent was crucial
for reaction efficiency, perhaps because it is able to stabilize active
catalytic species and prevent saturation of the Rh center by CO.
Received: May 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b05215
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Communication
Table 1. Optimization of the Synthesis of Azocane 7e
Table 2. Scope of the Cycloaddition−Fragmentation Process
a
entry
X
ligand
solvent
T (°C) yield (%)
1
2
BARF
BARF
BF4
P(4-(CF3)C6H4)3
P(4-(CF3)C6H4)3
P(4-(CF3)C6H4)3
P(4-(CF3)C6H4)3
P(4-(CF3)C6H4)3
P(4-(CN)C6H4)3
P(C6F5)3
PhCN
1,2-DCB
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
150
150
150
150
150
150
150
150
140
160
38
<5
48
34
53
52
16
63
16
54
3
4
SbF6
OTf
OTf
OTf
OTf
OTf
OTf
5
6
7
8
P(3,5-(CF3)2C6H3)3
P(3,5-(CF3)2C6H3)3
P(3,5-(CF3)2C6H3)3
9
10
a
Isolated yields. Reactions were run until full consumption of starting
material was observed by TLC.
Notably, non-coordinating solvents, such as 1,2-dichlorobenzene
(1,2-DCB), were completely ineffective (entry 2). With
[Rh(cod)2]OTf as the precatalyst, a series of electron-deficient
phosphine ligands were evaluated, and this led to the conditions
outlined in entry 8 (“conditions A”), which delivered 7e in 63%
yield. Lower or higher reaction temperatures resulted in
diminished yields of 7e (entries 9 and 10). Throughout these
studies, iso-7e, which could arise from rhodabicycle 6 via β-
hydride elimination of C4−H, was not observed, and products of
this type were not encountered elsewhere.15
The scope and limitations of the new process are shown in
Table 2. Cyclization of unsubstituted system 4a (R1−3 = H)
delivered azocane 7a in 74% yield. The structure of 7a was
confirmed by single-crystal X-ray diffraction (scXRD), which
revealed an unusual twisted enamide (C7−C8−N−C2 torsion
angle = 50.9°), highlighting the ring strain associated with these
products. A range of substrates 4b−e possessing alkyl, aryl, or
amino substituents at R2 cyclized smoothly to provide the target
azocanes 7b−e in good to excellent yield. The protocol is
relatively insensitive to the steric and electronic demands of the
R2 group, and in all cases efficient cyclization was observed.
However, 1,2-disubstituted alkenes are not well tolerated, and
cyclization of 4f (R3 = Me) generated 7f in only 10% yield. The
structural assignments of 7b−f were made by analogy to 7a and
were also supported by detailed NMR analysis (see the SI).
The development of processes involving substituted amino-
cyclopropanes proved to be challenging and required separate
optimization. This led to “conditions B”, which employ a catalyst
system derived from [Rh(cod)2]BARF and P(4-(CN)C6H4)3.
With this protocol, cyclization of trans-4g to 7g proceeded in
63% yield. In this case, the product arises from insertion of Rh
and CO into the more hindered proximal cyclopropane C−C
bond of 4g. This is inconsistent with our earlier work and the
mechanistic implications of this observation are discussed later.8
Notably, 7g is also accessible from the corresponding cis-1,2-
disubstituted cyclopropane (cis-4g), which cyclized in 50% yield
under the same conditions as used for trans-4g. Extension to a
range of trans-1,2-disubstituted systems 4h−j, possessing linear
or branched alkyl substituents at R1, provides modular access to
the corresponding azocanes 7h−j. In all cases, the products were
formed as single regioisomers, and products derived from Rh/
CO insertion into the less hindered proximal aminocyclopropane
a
b
c
R1−3 = H unless otherwise noted. 160 °C. Using [Rh(cod)2]OTf.
C−C bond were not observed. In favorable cases, substitution on
both the alkene and cyclopropane components is tolerated. For
example, cyclization of trans-disubstituted system 4k provided 7k
in 54% yield as a 4:1 mixture of diastereomers.16 The relative
stereochemistry of the major diastereomer of 7k was assigned by
nuclear Overhauser effect studies (see the SI).
The functionality present in the products described here
provides many opportunities for derivatization. Of particular
interest was the reactivity of the enamide moiety, which, as
revealed by the X-ray structure of 7a, is twisted from planarity.
Thus, on first inspection, its ability to engage in “conventional”
enamide chemistry was unclear.17 To probe this, we evaluated a
cyclization/Pictet−Spengler (PS) sequence leading to challeng-
ing tricyclic derivatives (Scheme 2).18 Carbonylative cyclizations
of 8a and 8b proceeded smoothly under conditions A, giving 9a
in 65% yield and 9b in 68% yield. Brønsted acid-catalyzed PS
cyclization of 9a provided adduct 10a in 59% yield. For 9b,
competing hydrolysis of the enamide was problematic under
protic conditions, but a Au-catalyzed protocol19 was effective,
generating 10b in 54% yield. The structures of 10a and 10b were
confirmed by scXRD (see the SI for the structure of 10b). This
strategy provides access to challenging polycyclic systems and
shows that the strained enamide moiety can engage in reactions
typical of non-strained variants.
Key observations made in our earlier studies underpin a
mechanistic rationale for the processes described here. We have
B
DOI: 10.1021/jacs.5b05215
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Communication
Scheme 2. Tricyclic Systems via Pictet−Spengler Cyclizations
Scheme 3
demonstrated that carbonylative rhodacyclopentanone forma-
tion is highly reversible when cationic Rh(I) systems are
employed.8b We have also shown that cis-1,2-disubstituted
aminocyclopropanes undergo carbonylative (3 + 1 + 2)
cycloadditions via cleavage of the more hindered bond b (i.e.,
via iso-2) (Scheme 3A).8b This regioselectivity is consistent with
that observed here (e.g., for cis-4g to 7g), and stoichiometric
studies have shown that this also reflects the inherent preference
of rhodacyclopentanone formation.8b Conversely, trans-1,2-
disubstituted aminocyclopropanes provide (3 + 1 + 2)
cycloaddition products via cleavage of the less hindered proximal
C−C bond a (i.e., via 2).8a,b This selectivity is the inverse of that
observed here. In previous studies, there was the possibility that
product regioselectivity was subject to Curtin−Hammett effects,
and consequently, we sought confirmation of the regiochemical
preference of rhodacyclopentanone formation from trans-1,2-
disubstituted systems. Accordingly, carbamate 11 was exposed to
stoichiometric quantities of [Rh(CO)2Cl]2, and this generated
complex 12 in 58% yield. The structure of 12 was confirmed by
XRD, which revealed a heterochiral dimer formed by exclusive
insertion of Rh and CO into the less hindered proximal C−C
bond a.20 Consequently, the product regioselectivities observed
in this study for trans-1,2-disubstituted aminocyclopropanes
(e.g., trans-4g to 7g) do not reflect the preferred regioselectivity
for rhodacyclopentanone formation.
On the basis of the considerations outlined above, a plausible
mechanism for cyclizations involving trans-1,2-disubstituted
aminocyclopropanes is proposed in Scheme 3B. Directed
insertion of Rh and CO into bond a or bond b of 13 generates
rhodacyclopentanone 14a or 14b, respectively. Insertion to
provide 14a is favored on steric grounds, but ultimately this
pathway is non-productive because, following directing-group
dissociation and migratory insertion of the alkene into the acyl−
Rh bond, syn-β-hydride elimination via C7−H of 16a is not
possible. However, reversible alkene, CO, and Rh insertion
regenerates cyclopropane 13, and this in turn enables
equilibration to regioisomeric rhodacyclopentanone 14b.
Migratory insertion of the alkene into the Rh−acyl bond of
15b generates regioisomer 16b, which is set up for syn-β-hydride
elimination via C7−H to deliver the observed regioisomer of the
product. To support the proposed mechanism, we prepared
deuterium-labeled substrate 18 (Scheme 3C). Cyclization under
standard conditions provided adduct 19, where deuterium
transfer to C3 is observed solely on the same face as the C6
substituent (cf. 16b to 17b).21 Incomplete levels of deuterium
transfer may be due to the presence of protic impurities (e.g.,
water) in the reaction mixture, which would facilitate exchange at
the stage of the intermediate Rh hydride (not depicted). The
mechanism in Scheme 3B is consistent with the contrasteric
regioselectivities observed in this study for trans-1,2-disubsti-
tuted aminocyclopropanes and invokes, for the first time,
reversibility for alkene insertion into rhodacyclopentanones.
Notably, this is a key step in a number of recently reported
methods,8b,12−14 and the present study highlights a key aspect
that may be important for further development of the area.
Two other points regarding product selectivity require
clarification. First, products of C−C bond-forming reductive
elimination from 6 (see Scheme 1C) have not been observed,
and this presumably reflects the strain associated with the β-
lactam (not depicted) that would result. Second, and in contrast
to related systems,13b β-hydride elimination from 6 is highly
regioselective for C7−H, and products of elimination via C4−H
(e.g., iso-7e; Table 1) are not formed. This may be due to (a) a
reduction in the hydridic character of the C4 protons (relative to
those at C7) as a result of the adjacent ketone and/or (b) the
high strain associated with accommodating five adjacent sp2
centers within the eight-membered ring of, for example, iso-7e.
C
DOI: 10.1021/jacs.5b05215
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Journal of the American Chemical Society
Communication
Takeda, K.; Terada, M. Chem.Eur. J. 2014, 20, 10214. (h) Zhao, C.;
Xie, X.; Duan, S.; Li, H.; Fang, R.; She, X. Angew. Chem., Int. Ed. 2014, 53,
10789. (i) Wu, S.; Zeng, R.; Fu, C.; Yu, Y.; Zhang, X.; Ma, S. Chem. Sci.
2015, 6, 2275.
(5) Niwa, H.; Uosaki, Y.; Yamada, K. Tetrahedron Lett. 1983, 24, 5731.
(6) El Sayed, K. A.; Kelly, M.; Kara, U. A. K.; Ang, K. K. H.; Katsuyama,
I.; Dunbar, D. C.; Khan, A. A.; Hamann, M. T. J. Am. Chem. Soc. 2001,
123, 1804.
(7) Sun, H.; Nikolovska-Coleska, Z.; Lu, J.; Meagher, J. L.; Yang, C.-Y.;
Qiu, S.; Tomita, Y.; Ueda, Y.; Jiang, S.; Krajewski, K.; Roller, P. P.;
Stuckey, J. A.; Wang, S. J. Am. Chem. Soc. 2007, 129, 15279.
(8) (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.
(9) Aminocyclopropanes can be prepared by Curtius rearrangement of
readily available cyclopropane carboxylic acids. See: (a) Lo, M. M.-C.;
Fu, G. C. J. Am. Chem. Soc. 1998, 120, 10270. (b) Lou, Y.; Remarchuk, T.
P.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 14223. (c) Gao, L.; Hwang,
G.-S.; Ryu, D. H. J. Am. Chem. Soc. 2011, 133, 20708.
To conclude, we report a direct approach to functionalized
azocanes by a Rh-catalyzed cycloaddition−fragmentation
sequence. Significantly, these studies expand the scope of the
catalysis platform outlined in Scheme 1B to include processes
that do not afford products of C−C bond-forming reductive
elimination. This in turn suggests that a distinct range of
methodologies may be accessible by harnessing bicyclic
intermediates such as 6. Mechanistic and stereochemical studies
have provided, for the first time, strong support that alkene
insertion into rhodacyclopentanones can be reversible. This
observation is likely to have wider implications given the
emerging family of processes that are dependent upon this key
mechanistic step.8b,13,14 Current studies are focused upon the
development of other medium-ring methodologies inspired by
the mechanistic insights gained here.
ASSOCIATED CONTENT
■
S
* Supporting Information
Methods, characterization data, and crystallographic data (CIF).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b05215.
(10) Heterolytic fragmentations have been defined as processes where
three components are generated and C is an electrofuge. See: Grob, C.
A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535. A formal representation of
the current scenario, which generates an alkene, Rh(I), and an enolate:
AUTHOR INFORMATION
Corresponding Author
*john.bower@bris.ac.uk
■
Notes
(11) Selected examples of this approach in natural product synthesis:
(a) Yang, J.; Long, Y. O.; Paquette, L. A. J. Am. Chem. Soc. 2003, 125,
1567. (b) Mehta, G.; Kumaran, R. S. Tetrahedron Lett. 2005, 46, 8831.
(12) Rhodacyclopentanones can also be generated by oxidative
addition of Rh(I) catalysts into the acyl−carbon bond of cyclo-
butanones. For pioneering studies, see: (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.
(13) Selected methodologies that involve alkene insertion into
rhodacyclopentanones and related species: (a) Murakami, M.;
Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124, 13976. (b) Matsuda,
T.; Fujimoto, A.; Ishibashi, M.; Murakami, M. Chem. Lett. 2004, 33, 876.
(c) Parker, E.; Cramer, N. Organometallics 2014, 33, 780. (d) Souillart,
L.; Parker, E.; Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 3001. (e) Ko,
H. M.; Dong, G. Nat. Chem. 2014, 6, 739. Also see ref 8b.
(14) Processes that involve alkene insertion into rhodaindanones:
(a) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2012, 51, 7567. (b) Xu, T.;
Ko, H. M.; Savage, N. A.; Dong, G. J. Am. Chem. Soc. 2012, 134, 20005.
(c) Xu, T.; Savage, N. A.; Dong, G. Angew. Chem., Int. Ed. 2014, 53, 1891.
(d) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2014, 53, 10733.
(15) Reactions run in the absence of CO result in a complex mixture of
products derived from decomposition of the rhodacyclobutane
intermediate to alkene byproducts (see ref 8a).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the European Research Council for support via the
European Union’s Horizon 2020 Programme (ERC Grant
639594 CatHet). M.H.S. thanks the Bristol Chemical Synthesis
Centre for Doctoral Training, funded by the EPSRC (EP/
G036764/1), and Syngenta for a Ph.D. studentship. We thank
the University of Bristol School of Chemistry X-ray Crystallo-
graphic Service for analysis of 7a, 10a, 10b, and 12. J.F.B. thanks
the Royal Society for a University Research Fellowship.
REFERENCES
■
(1) (a) Lipinski, C.; Hopkins, A. Nature 2004, 432, 855. (b) Nadin, A.;
Hattotuwagama, C.; Churcher, I. Angew. Chem., Int. Ed. 2012, 51, 1114.
(2) Selected methodologies: (a) Wender, P. A.; Ihle, N. C. J. Am. Chem.
Soc. 1986, 108, 4678. (b) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J.
Am. Chem. Soc. 2000, 122, 7815. (c) Evans, P. A.; Robinson, J. E.; Baum,
E. W.; Fazal, A. N. J. Am. Chem. Soc. 2002, 124, 8782. (d) Gilbertson, S.
R.; DeBoef, B. J. Am. Chem. Soc. 2002, 124, 8784. (e) Lee, P. H.; Lee, K.;
Kang, Y. J. Am. Chem. Soc. 2006, 128, 1139. (f) Murakami, M.; Ashida, S.;
Matsuda, T. J. Am. Chem. Soc. 2006, 128, 2166. (g) Wender, P. A.;
Christy, J. P. J. Am. Chem. Soc. 2006, 128, 5354. (h) Wender, P. A.;
Christy, J. P. J. Am. Chem. Soc. 2007, 129, 13402. (i) Fu, X.-F.; Xiang, Y.;
Yu, Z.-X. Chem.Eur. J. 2015, 21, 4242. Review of cycloadditions that
afford eight-membered-ring carbocycles: (j) Yu, Z.-X.; Wang, Y.; Wang,
Y. Chem.Asian J. 2010, 5, 1072.
(16) Factors governing the diastereoselectivity of this process will be a
focus of an in-depth study (also see ref 21).
(17) Twisted amides and enamines display distinct reactivity versus
planar variants. Selected examples: (a) Kirby, A. J.; Komarov, I. V.;
Wothers, P. D.; Feeder, N. Angew. Chem., Int. Ed. 1998, 37, 785.
(b) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang, W.-k.;
Blickensdorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183. (c) Yotphan, S.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2452.
(18) Selected reviews of the Pictet−Spengler reaction: (a) Cox, E. D.;
(3) Cycloadditions: (a) Yu, R. T.; Friedman, R. K.; Rovis, T. J. Am.
Chem. Soc. 2009, 131, 13250. (b) Kumar, P.; Zhang, K.; Louie, J. Angew.
Chem., Int. Ed. 2012, 51, 8602. (c) Thakur, A.; Facer, M. E.; Louie, J.
Angew. Chem., Int. Ed. 2013, 52, 12161.
(4) Other selected approaches: (a) Creighton, C. J.; Reitz, A. B. Org.
Lett. 2001, 3, 893. (b) Sparks, S. M.; Chow, C. P.; Zhu, L.; Shea, K. J. J.
Org. Chem. 2004, 69, 3025. (c) Kaul, R.; Surprenant, S.; Lubell, W. D. J.
Org. Chem. 2005, 70, 3838. (d) Sattely, E. S.; Cortez, G. A.; Moebius, D.
C.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 8526.
(e) Trindade, A. C. L. B.; dos Santos, D. C.; Gil, L.; Marazano, C.; de
Freitas Gil, R. P. Eur. J. Org. Chem. 2005, 1052. (f) Drouillat, B.; Couty,
Cook, J. M. Chem. Rev. 1995, 95, 1797. (b) Stockigt, J.; Antonchick, A.
̈
P.; Wu, F.; Waldmann, H. Angew. Chem., Int. Ed. 2011, 50, 8538.
(19) Youn, S. W. J. Org. Chem. 2006, 71, 2521.
(20) Attempted isolation of an analogous rhodacyclopentanone
complex containing an acrylamide directing group was unsuccessful.
(21) The high diastereoselectivity of this process indicates that the C3
and C6 stereocenters of 19 are not labile under the reaction conditions.
́
F.; Razafimahaleo, V. Synlett 2009, 3182. (g) Nakamura, I.; Sato, Y.;
D
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