Rh(II)-Catalyzed Nitrene-Transfer [5 + 1] Cycloadditions of Aryl-Substituted Vinylcyclopropanes

Article abstract of DOI:10.1021/acs.orglett.9b00594

Formal [5 + 1] cycloadditions between aryl-substituted vinylcyclopropanes and nitrenoid precursors are reported. The method, which employs Rh₂(esp)₂ as a catalyst, leads to the highly regioselective formation of substituted tetrahydropyridines. Preliminary mechanistic studies support a stepwise, polar mechanism enabled by the previously observed Lewis acidity of Rh-nitrenoids. Overall, this work expands the application of nitrene-transfer cycloaddition, a relatively underexplored approach to heterocycle synthesis, to the formation of six-membered rings.

Full text of DOI:10.1021/acs.orglett.9b00594

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh(II)-Catalyzed Nitrene-Transfer [5 + 1] Cycloadditions of Aryl-
Substituted Vinylcyclopropanes
Logan A. Combee, Shea L. Johnson, Julie E. Laudenschlager, and Michael K. Hilinski*
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904-4319, United States
S
* Supporting Information
ABSTRACT: Formal [5 + 1] cycloadditions between aryl-substituted
vinylcyclopropanes and nitrenoid precursors are reported. The method,
which employs Rh2(esp)2 as a catalyst, leads to the highly regioselective
formation of substituted tetrahydropyridines. Preliminary mechanistic
studies support a stepwise, polar mechanism enabled by the previously
observed Lewis acidity of Rh-nitrenoids. Overall, this work expands the
application of nitrene-transfer cycloaddition, a relatively underexplored
approach to heterocycle synthesis, to the formation of six-membered
rings.
he development of nitrenes and metallonitrenes as
reactive intermediates useful for addressing limitations
Scheme 1. Progress and Challenges in Nitrene-Transfer
Cycloaddition
T
in organic synthesis has recently been accelerated by advances
in nitrene-transfer catalysis.1 Yet many potential applications
remain unexplored.2 One area of potential growth is their use
as one-atom components in cycloaddition reactions for the
preparation of nitrogen-containing heterocycles. Even for
common N-heterocycles, which are present in a majority of
FDA-approved small-molecule drugs,3 current synthetic
methods are, in many cases, not sufficiently advanced to
allow for the rapid and flexible preparation of selectively
substituted variants.4 The complementarity of nitrene chem-
istry to other approaches might provide paths to overcoming
these limitations.5 However, only a handful of reports of the
use of nitrene precursors in intermolecular cycloaddition
reactions have appeared in the literature.6 These include [4 +
1] cycloadditions with dienes,7 [2 + 2 + 1] cycloadditions with
alkynes,8 and [2 + 2 + 1] cycloadditions with alkynes and
nitriles (Scheme 1a).9 All are limited to the formation of five-
membered rings. Here, we describe the first examples of six-
membered ring synthesis via nitrene-transfer cycloaddition.
The overall reaction, which employs a strategy and catalytic
approach distinct from the above examples, constitutes a
formal [5 + 1] cycloaddition between a nitrene precursor and a
vinylcyclopropane. In addition, the reactions provide a single
regioisomer of heterocyclic products that are not readily
available through other means.
Our strategy relies on the hypothesis that in certain cases,
nitrene transfer to the olefin of a vinylcyclopropane (VCP)
might produce a substituted cyclopropylcarbinyl cation or
radical, arising either directly from the olefin or from an
intermediate aziridine.10 Either cyclopropylcarbinyl species, if
sufficiently long-lived, would be expected to promote cyclo-
propane C−C bond cleavage, ultimately providing a ring-
expanded [5 + 1] cycloaddition product (specifically a
tetrahydropyridine) after a subsequent cyclization (Scheme
1b).11 One advantage of this strategy is the potential to exert
regiocontrol over the reaction outcome by adjusting
substitution on the VCP to favor selective cleavage of one of
two differentiated cyclopropane C−C bonds.
As part of our initial exploration of this idea, we evaluated
the possibility of achieving the desired tandem nitrene-
transfer/ring expansion outcome by employing Rh(II) catalysis
(Table 1). In addition to their role as catalytic intermediates in
C−H amination12 and aziridination13 reactions, there is
evidence that Rh-nitrenoids can act as mild Lewis acids,
promoting dipolar ring opening of aziridines.13 In our case, we
examined whether this dual nature of the nitrenoid could
enable successful nitrene-transfer [5 + 1] cycloaddition of VCP
Received: February 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00594
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Letter
compared to the initial conditions (0.05 M), a synthetically
useful yield could be obtained.
Table 1. Optimization of a Rh(II)-Catalyzed [5 + 1]
Reaction
a
With the optimized conditions in hand, we surveyed the
scope and limitations of this new reaction with regard to
electronic modification of each aryl substituent (Figure 1,
entry nitrene precursor (equiv) catalyst (mol %)
R
yield (%)
b
c
1
2
3
4
5
6
7
8
9
A (1.1)
B (1.1)
Rh2(esp)2 (2)
Rh2(esp)2 (2)
Rh2(esp)2 (2)
Rh2(esp)2 (2)
Rh2(esp)2 (2)
Rh2(OAc)4 (2)
Rh2(OPiv)4 (2)
Rh2(tpa)4 (2)
Rh2(esp)2 (2)
Rh2(esp)2 (2)
Rh2(esp)2 (2)
None
Ts
<5
b
b
Tces
Tces
Cbz
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
40
0
36
d
B (1.5)
C (1.1)
D (1.1)
C (1.1)
C (1.1)
C (1.1)
C (1.5)
C (2.0)
C (1.5)
C (1.1)
NR
NR
c
10
0
53
35
10
11
12
e
60
NR
a
All reactions were conducted on a 0.2 mmol scale of 1a, with isolated
b
yields reported except where noted. NR = no reaction observed. No
NaOAc used, reaction time 10 min. NMR yield using methyl pivalate
as an internal standard. Formed in situ using 1.5 equiv each of
TcesNH2 and PhI(OAc)2. Reaction concentration 0.05 M in 1a and
c
d
e
reaction time 30 h.
1a. Our initial experiments focused in the use of
iminoiodinanes as nitrene precursors and Rh2(esp)2 as the
catalyst.14 Previous studies have shown a high dependence of
reaction yield for intermolecular Rh2(esp)2-catalyzed nitrene-
transfer reactions on the iminoiodinane structure.15 Consistent
with this, we observed only trace amounts of the desired [5 +
1] product 2a using PhINTs (A, entry 1) as the nitrene
precursor but obtained 40% isolated yield of 2,5-diphenyl-
substituted tetrahydropyridine 3a using PhINTces16 (B, entry
2). In situ formation of the iminoiodinane from TcesNH2 was
not compatible with the reaction conditions (entry 3). Further
reaction optimization enabled the use of benzyl tosyloxycarba-
mate C, providing a product 4a that bears a Cbz protecting
group (entry 4). The use of the Cbz group offers synthetic
advantages over Tces, which requires the use of a large excess
of Zn/Cu under acidic conditions for deprotection,16 rather
than the catalytic hydrogenolysis conditions required for Cbz
removal. Using the related Boc-protected nitrene precursor D,
no formation of product 5a was observed (entry 5). Screening
of alternative Rh(II) catalysts revealed the particular suitability
of Rh2(esp)2 for the desired reaction. Of the other catalysts
evaluated, only the use of Rh2(OPiv)4 provided any amount of
4a at room temperature, albeit in substantially reduced yield.
Given that Rh2(esp)2 was designed to have enhanced stability
over other tetracarboxylate Rh(II) catalysts for the specific
purpose of enabling greater turnover in nitrene-transfer
reactions,14 this might indicate that the efficiency of the
nitrene transfer step is critical to achieving a productive [5 + 1]
cycloaddition. Using the optimal protocol (entry 11), which
employs a slight excess of C and lower concentration
Figure 1. Scope and limitations of the [5 + 1] cycloaddition. Yields
shown are of isolated products. All reactions employed 0.2 mmol of
vinylcyclopropane as the limiting reagent.
examples 4a to 4aa). Overall, the expected [5 + 1]
cycloaddition product could be isolated in each case, with
effects on reaction yield observed as a function of the nature
and position of the substitution. While these effects were
generally moderate, certain trends could be observed. For
example, the inclusion of electron-donating groups in the para
position of the styrenyl aryl group led to reduced yields (e.g.,
4a vs 4b and 4s vs 4u), and a similar effect was observed for
electron-withdrawing groups in the para position of the
cyclopropyl aryl group (e.g., 4i and 4l vs 4a). Reasonable
success was observed with fluorinated and trifluoromethylated
aryl groups in the R2 position, increasing the value of the
method for the potential preparation of medicinal agents.17
Other halogenated products (e.g., 4f, 4o, 4x, 4aa) present
handles for further diversification via cross coupling. The 2,5-
diaryltetrahydropyridine products have rarely appeared in the
literature.18 In addition, more extensively substituted hetero-
B
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cyclic products can also be obtained, as in the tricyclic 4ac. In
many cases, the reaction does not reach 100% conversion, and
a small amount of starting material remains. For selected
examples where a substantial amount of the VCP was
recovered, yields based on recovered starting material are
reported (e.g., 4a, 4d, 4e, and others). In other cases (e.g., 4b),
the starting material is completely consumed. In all cases, VCP
that is unaccounted for appears to be nonselectively converted
to an inseparable mixture of other, unidentifiable products
formed in trace amounts. Finally, at the largest scale evaluated
(1 mmol of 1a), no substantial effect on reaction yield was
observed.19
Scheme 2. Stepwise Hypothesis for the Rh-Catalyzed
Cycloaddition Based on Precedent and Preliminary
Observations
A synthetically advantageous feature of this reaction is, in
each case, the observation of only a single regioisomer of the
product. This is reflected in both the high degree of selectivity
for cleavage of the cyclopropane C−C bond adjacent to the
aryl group, leading to a preference for the 2,5-disubstituted
product, as well as the position of the olefin. This
regioselectivity, which has been confirmed by X-ray crystallog-
raphy,19 would be consistent with a heterolytic ring opening of
the cyclopropane to a stabilized benzylic cation, as part of a
stepwise mechanism promoted by the Lewis acidity of the Rh-
nitrenoid. Further highlighting a potential role for resonance
stabilization of cationic intermediates, alkyl substitution at
either the R1 or R2 positions of the VCP abrogated the
formation of the desired cycloaddition product (4ad and 4ae).
To obtain additional preliminary evidence of the reaction
other carboxylates (e.g., NaOBz, NaOPiv, NaOCOCF3) results
in significantly reduced yields in all cases.19 While these results
could point to a number of potential roles for acetate in the
reaction mechanism beyond serving as a base to deprotonate
the nitrene precursor, one possibility is that it reacts as a
nucleophile with carbocations 7, 8, or 9 to form one or more of
the long-lived intermediates that are observed by NMR. A
similar role for tosylate liberated from C might be envisioned;
nosylate and mesylate analogues of C perform substantially less
well in the reaction.19 Our attempts to synthesize the potential
aziridine and acetate intermediates derived from 1a have so far
been unsuccessful using a variety of reaction conditions;
decomposition of the starting material is observed rather than a
productive reaction. This might indicate that if these
intermediates are formed they are prone to further reactivity
such as that which we observe in the [5 + 1] reaction.
1
mechanism, 24-h H NMR time course experiments were
performed. These data indicate that that the VCP is ∼90%
consumed after 10 h, but at the same time point only ∼50% of
the eventual product formation has occurred. Several long-
lived intermediates can be observed but not conclusively
identified. Therefore, the data are consistent with the
hypothesis of a stepwise [5 + 1] cycloaddition initiated by
nitrene transfer to the olefin of the VCP. An alternative
pathway involving initial cleavage of the cyclopropane ring can
be tentatively ruled out given that we observe no reaction of
cyclopropylbenzene under the reaction conditions. It has
previously been shown that VCP 5 undergoes oxyamination to
provide 6 under Rh2(esp)2-catalyzed conditions using
PhINTces generated in situ. Mechanistic studies of this
reaction suggested the involvement of a benzylic carbocation
intermediate (Scheme 2a).13 These observations and prece-
dent prompt us to propose the stepwise cationic pathway
outlined in Scheme 2b. Aziridination of the substrate20 could
lead, after dipolar ring-opening, to formation of an equilibrium
among 7 and geometric isomers 8 and 9, with the latter
ultimately undergoing ring closure to the observed [5 + 1]
product. This mechanism is also consistent with the
regioselectivity of the reaction and the observed trends in
yield. For example, an electron-deficient R2 group less able to
stabilize a carbocation would disfavor the formation of key
intermediate 9, whereas an electron-rich VCP olefin (depend-
ent on the R1 substituent) might be expected to react in an
unproductive sense with intermediates 7 or 8 at a higher rate
than a comparatively electron-deficient olefin.21 This possi-
bility of oligomerization or other unwanted reactivity of an
intermediate carbocation is consistent with the aforementioned
observation of complete consumption of the unaccounted for
starting material to a complex mixture of products.
Finally, we envision that the tetrahydropyridine products of
this reaction can serve as key intermediates in the synthesis of
regio- and stereoselectively substituted piperidines, which are
the most common N-heterocycles in FDA-approved drugs.3
Preliminary investigations that illustrate this capability are
shown in Scheme 3. Hydrogenation of 4a to the fully saturated
Scheme 3. Derivatization of Product 4a
piperidine, with concurrent removal of the Cbz protecting
group, proceeds in high yield to reveal the free amine 10.
Oxidation or other non-hydrogenative functionalization of the
olefin provides an avenue to access increasingly complex
piperidines. In this regard, epoxidation of 4a proceeds with
remarkably high diastereoselectivity, setting two new stereo-
We have found that the use of 3 equiv of NaOAc as an
additive is essential to achieving the best yields for these
reactions. The use of non-nucleophilic bases (e.g., DIPEA) and
C
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Letter
Opportunities to Transform Drug Discovery. Nat. Chem. 2018, 10,
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centers and providing 2,4,5-trisubstituted piperidine derivative
11.
(5) For selected recent reports of novel cycloaddition reactions to
form N-heterocycles, see: (a) Lin, T.-Y.; Wu, H.-H.; Feng, J.-J.;
Zhang, J. Chirality Transfer in Rhodium(I)-Catalyzed [3 + 2]
Cycloaddition of Vinyl Aziridines and Oxime Ethers: Atom-
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(6) For early investigations of intramolecular variants, see:
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In summary, the first examples of the use of nitrene-transfer
cycloaddition for the preparation of six-membered nitrogen-
containing heterocycles have been presented. The method,
which uses Rh2(esp)2 to catalyze nitrene transfer to a
vinylcyclopropane in an overall [5 + 1] cycloaddition, exhibits
high regioselectivity, enhancing its synthetic utility and
allowing for further derivatization to complex piperidines.
Furthermore, the expansion of the nitrene-transfer cyclo-
addition approach illustrates new possibilities for this under-
explored reaction paradigm. Overall, this strategy offers an
alternative synthetic entry to a class of compounds that are
highly valued in medicinal chemistry, and we anticipate that
further development of this approach could lead to broad
application in the preparation of bioactive compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00594.
Experimental procedures as well as spectroscopic and
analytical data for all new compounds (PDF)
Accession Codes
CCDC 1895862 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hilinski@virginia.edu.
ORCID
(7) Wu, Q.; Hu, J.; Ren, X.; Zhou, J. An Efficient, Overall [4 + 1]
Cycloaddition of 1,3-Dienes and Nitrene Precursors. Chem. - Eur. J.
2011, 17, 11553.
(8) (a) Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Catalytic Formal [2 +
2+1] Synthesis of Pyrroles from Alkynes and Diazenes via TiII/TiIV
Redox Catalysis. Nat. Chem. 2016, 8, 63. (b) Chiu, H.-S.; Tonks, I. A.
Trimethylsilyl-Protected Alkynes as Selective Cross-Coupling Part-
ners in Titanium-Catalyzed [2 + 2+1] Pyrrole Synthesis. Angew.
Chem., Int. Ed. 2018, 57, 6090. (c) Davis-Gilbert, Z. W.; Wen, X.;
Goodpaster, J. D.; Tonks, I. A. Mechanism of Ti-Catalyzed Oxidative
Nitrene Transfer in [2 + 2+1] Pyrrole Synthesis from Alkynes and
Azobenzene. J. Am. Chem. Soc. 2018, 140, 7267.
(9) Saito, A.; Kambara, Y.; Yagyu, T.; Noguchi, K.; Yoshimura, A.;
Zhdankin, V. V. Metal-Free [2 + 2+1] Annulation of Alkynes, Nitriles,
and Nitrogen Atoms from Iminoiodanes for Synthesis of Highly
Substituted Imidazoles. Adv. Synth. Catal. 2015, 357, 667.
(10) For related examples of cycloadditions initiated by an
aziridination/ring opening sequence, see: (a) Stoll, A. H.; Blakey, S.
B. Rhodium Catalyzed Allene Amination: Diastereoselective Synthesis
of Aminocyclopropanes via a 2-Amidoallylcation Intermediate. J. Am.
Chem. Soc. 2010, 132, 2108. (b) Stoll, A. H.; Blakey, S. B. Rhodium
Catalyzed Allene Amidation: A Facile Entry into 2-Amidoallycations
for Unusual [3 + 3] Annulation Reactions. Chem. Sci. 2011, 2, 112.
(c) Gerstner, N. C.; Adams, C. S.; Tretbar, M.; Schomaker, J. M.
Stereocontrolled Syntheses of Seven-Membered Carbocycles by
Tandem Allene Aziridination/[4 + 3] Reaction. Angew. Chem. 2016,
128, 13434.
Michael K. Hilinski: 0000-0003-2861-7099
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Diane Dickie (Department of Chemistry,
University of Virginia) for assistance with X-ray crystallog-
raphy. Partial financial support of this work from the National
Institutes of Health (R01 GM124092) and the University of
Virginia is gratefully acknowledged.
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E
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