Catalytic Cycloisomerization onto a Carbonyl Oxygen

Article abstract of DOI:10.1021/acs.orglett.0c02272

We have found that terminal N-vinylindoles bearing cycloalkanone substituents are excellent hydrogen atom acceptors, generating α-aminyl radicals with a variety of catalysts (Co(II)/H2 or Co(III)Cl precatalysts with silane reductants). These radicals can

Full text of DOI:10.1021/acs.orglett.0c02272

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Letter
Catalytic Cycloisomerization onto a Carbonyl Oxygen
Shicheng Shi, Jonathan L. Kuo, Tao Chen, and Jack R. Norton*
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ABSTRACT: We have found that terminal N-vinylindoles bearing
cycloalkanone substituents are excellent hydrogen atom acceptors,
generating α-aminyl radicals with a variety of catalysts (Co(II)/H2
or Co(III)Cl precatalysts with silane reductants). These radicals
can be converted to internal vinylindoles but eventually add to the
oxygen of the cycloalkanone substituents. These cyclizations
eventually furnish a densely functionalized dihydrofuran (a net
cycloisomerization). The internal vinylindoles are slowly converted
to the dihydrofurans, but the final cycloisomerization/isomer-
ization ratio is affected by the size of the cycloalkanone ring (seven- and eight-membered rings give the highest ratio). These results
demonstrate how HAT can isomerize substrates in nonintuitive ways, here leading to the first HAT-promoted formation of a C−O
bond.
Scheme 1. Selected Examples of M-HAT-Initiated
Intramolecular Radical Cyclization
ydrogen atom transfer (HAT) from metals to olefins,
1
H
first observed by Sweany and Halpern, has become
(since the seminal work of Mukaiyama2) a powerful method
for hydrofunctionalization of olefins.3 A wide range of inter-
and intramolecular transformations has been documented,4−7
including cyclizations that are useful in the synthesis of
complex natural products.8
Our group9a and the Shenvi group10a independently
introduced Co complexes as catalysts for such diene
cyclizations (Scheme 1A) and olefin isomerizations; we have
employed H2 as the source of the H•, and they have employed
silanes. Since then many Co systems catalyzing isomerization
of olefins have been developed by employing different types of
ligands.10b−f More recently, the Bonjoch group has used Fe
catalysts to generate (from olefins and a silane) carbon-
centered radicals that add to the carbon of carbonyl groups and
eventually give tertiary alcohols (Scheme 1B).11a−d We now
report a complementary cyclization, that of a carbon-centered
radical onto a carbonyl oxygen (Scheme 1C). The resulting
compounds are highly substituted furans, not easily accessible
by other methods,12 with (1) congested quaternary carbons
and (2) a stable hemiaminal attached to a functionalized
indole.
The regiochemistry of radical cyclizations onto CX bonds
(X = O,13 N14) is in general less predictable than that of radical
cyclizations onto CC bonds. It is well-known that the 5-exo
CC cyclization of a 5-hexenyl radical is faster than the 6-
endo one,15 but with a shorter chain (e.g., a 4-pentenyl radical)
the pattern is inverted because the exo cyclization introduces
ring strain.16 (With substituted 4-pentenyl radicals both 4-
exo17 and 5-endo18 products have been reported.)
Received: July 8, 2020
However, both 4-exo (C)19a and 5-endo (O)13,19 products
have been reported from cyclizations onto CO, and the
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Org. Lett. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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outcome of these reactions has not been predictable.20 Endo
additions, onto O, are particularly of interest as they lead to
oxygen-containing heterocycles.21
Scheme 3. Possible Pathways for Olefin/Carbonyl
Cyclization
We have generated our carbon-centered radicals by HAT to
N-vinylindoles 1. Padwa has shown that such enamines are
useful for the synthesis of alkaloids.12,22 The reduction of the
carbonyl of I and generation of a xanthate from the resulting
alcohol led to a radical that adds to the 2-position of the indole
and affords the tetracyclic indole derivatives II (Scheme 2).12
Scheme 2. N-Vinylindole as a Useful Intermediate in
Alkaloid Synthesis
As shown by the first three entries in Table 1, changing the
axial ligands in our cobaloxime catalyst,9b,c from THF in C-1 to
MeOH in C-2 and H2O in C-3, decreases the turnover
number. (Catalysts C-2 and C-3 are known to activate H2 less
effectively than C-1.9a−c) C-1 and C-3 gave roughly the same
product ratios; C-2 gave a somewhat greater ratio of
cycloisomerization to isomerization with low conversion.
Changes in the size of the cycloalkanone ring, however,
significantly affect the 2/3 ratio. A five-membered ring favors
isomerization (entry 4), whereas medium-sized rings (seven-
or eight-membered, entries 1 and 6) favor cycloisomerization;
the larger 12-membered ring (entry 7) shows little selectivity.
The use of CpCr(CO)3H26 as a catalyst (entry 8) induces only
isomerization, with low conversion. Increased C-1 loading
(entry 9) or H2 pressure (entry 10) slightly improves the
selectivity. Control experiments (entries 11 and 12) confirm
that both cobalt and H2 are indispensable to the reaction,
supporting a HAT mechanism. No hydrogenation of cyclized
or uncyclized products has been detected.
We believed that useful radicals might also be generated by
H• transfer onto the vinyl groups of 1. When we tried our
cobaloxime/H2 system9 on an N-vinylindole with a tethered
cyclohexanone (1a), we obtained the cycloisomerized product
2a along with the isomerization product 3a (Scheme 1C and
Table 1, entry 2). It seemed likely that both 2a and 3a had
Table 1. Initial Optimization Studies in the Cyclization of
a
N-Vinylindoles with Cobaloxime/H2
b
b
entry
substrate
catalyst
C-1
C-2
C-3
C-1
C-1
C-1
C-1
CpCr(CO)3H
C-1
conversion (%) ratio (2:3)
1
2
3
4
5
6
7
8
1d, n = 8
1d, n = 8
1d, n = 8
1b, n = 5
1a, n = 6
1c, n = 7
1e, n = 12
1d, n = 8
1d, n = 8
1d, n = 8
1d, n = 8
1d, n = 8
86
45
47
82
88
84
87
29
93
95
<5
<5
55:31
18:27
31:16
14:68
40:48
48:36
49:38
<1:27
61:32
69:26
f
We then considered the Co−salen complexes10a,27 and
silane reductants28,29 that Shenvi had used in the cyclo-
isomerization of dienes.10 We selected N-vinylindole with a
tethered cyclooctanone (1d) as a model substrate for our
cyclizations onto CO and were encouraged when we
obtained 10% 2d along with a trace of the isomerization
product 3d at room temperature(see the SI).
c
Optimization revealed that the best condition (with 12 mol
% catalyst B and silane, at 60 °C for 16 h) had the substrate 0.1
M in benzene. The results of catalyst optimizations are
summarized in Scheme 4. The nature (steric and electronic) of
the salen ligand has a large effect,27,30 with catalysts A, B, C,
and I all being effective, whereas catalysts DG showed lower
reactivity. Catalyst H gave the best selectivity for the
cycloisomerized product 2d, but with only moderate
conversion (see the SI). The auxiliary ligand (Cl, Br, or I) of
the Co(III) salen catalyst affects the selectivity (probably
because it affects the rate at which “Co−H” is generated).The
nature of the silane reductant is crucial:29 tertiary silanes are
less reactive, presumably for steric reasons, whereas Ph2SiH2
shows decent reactivity along with good cycloisomerization
selectivity (up to 9.2:1). We saw the same ring size effects as
with the cobaloxime/H2 system, albeit with higher selectivity
for 2 and higher conversion; again, the cyclopentanone 1b gave
3b as the main product, with only a trace (<1%) of the
cycloisomerization product 2b.
9
d
10
C-1
no [Co]
C-1
11
12
e
f
a
Conditions: 1 (0.2 mmol), 7.0 mol % catalyst, 4.8 atm H2, benzene
b
(0.05M), 50 °C, 3 days. Determined by 1H NMR with internal
c
d
e
standard. 20 mol % C-1. Under 6.1 atm H2. Under Ar without H2.
f
Starting material recovered.
arisen from the α-aminyl radicals23,24 formed by H• transfer
(Scheme 3, pathway B), but they could also have come from
the acid-promoted olefin/carbonyl cyclization (Scheme 3,
pathway A).25 The latter possibility is, however, unlikely in
view of the hydrolytic instability of enamines like 1a in the
presence of acid12 (attempts to take the NMR of 1a in CDCl3
just showed indole and the methyl ketone (eq 1), whereas 1a is
stable in acetone-d6). We believe that both 2a and 3a are the
result of HAT (Scheme 3, pathway B).9a,10a
B
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Scheme 4. Optimization Studies in the Cyclization of N-
Vinylindoles with Co(III)−Salen/Silane
Scheme 5. Substrate scope of Cycloisomerization of N-
a
a
Vinylindoles with Co(III)−Salen/Silane
a
Isolated yield for the major product; the ratio of 2/3 is in
1
parentheses, determined by H NMR with internal standard.
a
Conditions: 1 (0.1 mmol), 12.0 mol % B, 12 mol % Ph2SiH2,
b
benzene (0.10M), 60 °C, 16 h. Isolated yield, ratio determined by
crude H NMR with internal standard. 1.0 mmol scale.
We have also checked the range of functional groups and
substitution patterns that can be tolerated on the indole ring.
All of the cyclooctanone substrates in Scheme 5 gave good
selectivity for cycloisomerization (from 6.1:1 to >20:1), and no
over-reduction was observed. The reaction can be carried out
on a 1.0 mmol scale without losing efficiency (1f). Esters (1g,
1i), nitriles (1j), methoxy (1h), and fluoro (1l) substituents
are well tolerated, as well as conjugated arene (1m). The 6-
chloro substrate 1k gave cycloisomerization almost exclusively
under standard conditions (with a small amount of isomer-
ization occurred at elevated temperature). Substrates with 7-
membered rings (1n−1p) showed reactivity and selectivity
comparable to those of the cyclooctanone substrates.
c
1
Mechanism
The deuterium-labeling experiment in Figure 1A supports
Scheme 3B. Under D2, the transfer of deuterium from the
catalyst (C-1) onto the methylene of 1d results in the
incorporation of deuterium into the methyl groups of 2d and
3d (the deuterium content of the 3d methyl is probably
depleted by D/H exchange during the conversion of that
compound to 2d, described below.)
With the salen catalyst B and Ph2SiH2, the ratio of the
cycloisomerized product 2d to the enamine 3d increases over
time (Figure 1B). This implies that the initial 2d/3d ratio is
kinetic, with the thermodynamic ratio being higher and 3d
slowly converted to 2d under the reaction conditions. This
interpretation is confirmed by the experiment in Figure 1C,
which shows the interconversion of 2d and 3d. Quantitative
analysis of the equilibrium is difficult, as a small percentage of
Figure 1. Mechanistic studies.
1d is also formed in these reactions, but the equilibrium
constant (from 3d to 2d) must be around unity. The
C
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equilibrium amount of the cycloisomerized product 2
decreases when the eight-membered ring in 1d is replaced
by the smaller one in 1apresumably because the strain in 2a
is increased.
The interconversions of 1−3 are summarized in Figure 2.
The red arrows indicate the rate constants that probably
https://pubs.acs.org/10.1021/acs.orglett.0c02272
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Janine M. Abuyuan (Barnard College) is acknowledged for
experimental assistance. Research reported in this publication
was supported by the National Institute of General Medical
Sciences of the National Institutes of Health under Award No.
R01GM124295. J.L.K. was supported by the National Science
Foundation Graduate Research Fellowship Program (DGE-11-
44155), the Arun Guthikonda Memorial Fellowship, and the
National Institutes of Health under the Ruth L. Kirschstein
National Research Service Award (FGM126639A).
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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Experimental procedures, computational details and
compound characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
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Jack R. Norton − Department of Chemistry, Columbia
University, New York, New York 10027, United States;
orcid.org/0000-0003-1563-9555; Email: Jrn11@
columbia.edu
Authors
Shicheng Shi − Department of Chemistry, Columbia University,
New York, New York 10027, United States; orcid.org/
0000-0001-8124-9235
Jonathan L. Kuo − Department of Chemistry, Columbia
University, New York, New York 10027, United States;
orcid.org/0000-0003-1966-9460
Tao Chen − Department of Chemistry, Columbia University,
New York, New York 10027, United States
Complete contact information is available at:
D
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