Synthesis of Functionalized Nitriles by Microwave-Promoted Fragmentations of Cyclic Iminyl Radicals

Article abstract of DOI:10.1002/chem.201705728

The synthesis of functionalized nitriles via microwave-promoted radical fragmentations of cyclic O-phenyl oxime ethers is reported. A variety of radical traps can be employed, permitting the generation of diverse adducts via C?O, C?C, C?N, or C?X bond formation. Other salient features include a simple and practical protocol, very short reaction times, and the avoidance of metal catalysts and toxic cyanide reagents. The utility of this method is demonstrated by the ring-distortion of a steroid-derived substrate.

Full text of DOI:10.1002/chem.201705728

A Journal of
Accepted Article
Title: Synthesis of Functionalized Nitriles via Microwave-Promoted
Fragmentations of Cyclic Iminyl Radicals
Authors: Mary M Jackman, Siyeon Im, Seth R Bohman, Concordia C L
Lo, Amanda L Garrity, and Steven L. Castle
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To be cited as: Chem. Eur. J. 10.1002/chem.201705728
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10.1002/chem.201705728
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COMMUNICATION
Synthesis of Functionalized Nitriles via Microwave-Promoted
Fragmentations of Cyclic Iminyl Radicals
Mary M. Jackman, Siyeon Im, Seth R. Bohman, Concordia C. L. Lo, Amanda L. Garrity, and Steven L.
Castle*
Abstract: The synthesis of functionalized nitriles via microwave-
promoted radical fragmentations of cyclic O-phenyl oxime ethers is
reported. A variety of radical traps can be employed, permitting the
generation of diverse adducts via C–O, C–C, C–N, or C–X bond
formation. Other salient features include a simple and practical
protocol, very short reaction times, and the avoidance of metal
catalysts and toxic cyanide reagents. The utility of this method is
demonstrated by the ring-distortion of a steroid-derived substrate.
C–X bonds are accessed via a simple, user-friendly protocol that
is devoid of transition metals and toxic cyanide-containing
reagents.[12–16] Additionally, we show that this method is well-
suited as a “ring-distortion” strategy for generating sets of
diverse compounds from polycyclic natural products.[17] Our
method is also distinguished by its compatibility with 4- and 5-
membered cyclic substrates and very short reaction times.
Advances in nitrogen-centered radical chemistry[1,2] have
given rise to new strategies for constructing cyclic amines, which
are present in several bioactive natural products[3] and
pharmaceuticals.[4] For example, cyclizations of iminyl radicals
are increasing in prominence due to the discovery of
photoredox- and microwave-based methods of generating these
precursors.[5]
In
contrast,
Scheme 1. Fragmentations of cyclic iminyl radicals.
species
from
convenient
fragmentations of cyclic iminyl radicals have been less studied.
These processes, which until recently have been observed
mainly in the context of nitrile translocations,[6,7] produce a
synthetically useful nitrile[8] tethered to an alkyl radical. However,
rapid reduction of the alkyl radical by a hydrogen atom donor
that is often present in the reaction mixture (e.g., Bu3SnH) has
precluded further functionalization.
We selected cyclopentanone-derived O-phenyl oxime ether
1a[18] as the substrate and TEMPO as the radical trap for
identifying suitable conditions for the proposed fragmentation as
summarized in Table 1. We surveyed various temperatures
using trifluorotoluene as solvent due to its utility in our previous
work.[10] The fragmentation was facile above 80 °C, but yields
dropped precipitously below this temperature (entries 1–5).
Although the highest yield was obtained at 80 °C, concurrent
experiments with other substrates and radical traps indicated
that more consistent results could be achieved at 90 °C.
Accordingly, we tested the fragmentation in different solvents at
this temperature. Whereas poor yields were observed with less
polar solvents (entries 6 and 7), good yields were obtained in the
highly polar solvents methanol (entry 8) and trifluoroethanol
(entry 9). Acetonitrile afforded the best results (entry 10).
Recent reports by Selander,[9a] Shi,[9b] and Zhou[9c] have
advanced the state of the art by enabling iminyl radical
fragmentations in the absence of hydrogen atom donors. The
alkyl radicals are trapped by alkenes, forging new C–C bonds in
the adducts (Scheme 1). The iminyl radicals are generated via
reduction of an oxime by a metal catalyst, so the adduct must be
oxidized in order to regenerate the catalyst. This renders only
electron-rich alkenes suitable as radical traps. Additionally, only
4-membered cyclic oximes have undergone the reported
fragmentations, as 5-membered substrates have failed to
react.[9b,9d] Our interest in microwave-promoted iminyl radical
cyclizations[10] led us to posit that cyclic iminyl radicals could be
produced in the absence of metal catalysts and redox cycles via
irradiation of O-phenyl oxime ethers.[11] By eliminating the need
to oxidize the adduct, this method would permit the use of a
number of different radical traps. Herein, we report the
realization of these microwave-induced fragmentations. A range
of functionalized nitriles containing new C–O, C–C, C–N, and
Table 1: Optimization of reaction conditions.
Entry
Solvent
PhCF3
PhCF3
PhCF3
PhCF3
Temperature (°C)
Yield (%)
57
71
74
25
1
2
3
4
5
6
7
8
9
10
90
85
80
75
70
90
90
90
90
90
[*]
M. M. Jackman, S. Im, S. R. Bohman, C. C. L. Lo, A. L. Garrity, Prof.
S. L. Castle
PhCF3
20
ClCH2CH2Cl
t-BuPh[a]
CH3OH
CF3CH2OH
CH3CN
28
27
75
73
Department of Chemistry and Biochemistry
Brigham Young University
Provo, UT 84602 (USA)
E-mail: scastle@chem.byu.edu
85
Supporting information for this article is given via a link at the end of
the document.
[a] The ionic liquid emimPF6 was added to promote microwave heating.
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Using the optimized conditions developed with 1a, we
examined microwave-promoted fragmentations of various oxime
ethers employing TEMPO as the radical trap. The results shown
We were desirous to incorporate a C–C bond-forming event
into the reaction. We were pleased to find that allylsulfone 3[19] is
a suitable radical trap, furnishing nitriles 4a–g containing an
enoate moiety from oxime ethers 1a–g in good yields (Table 3).
Although larger quantities of 3 were required in comparison to
TEMPO (ca. 3.5 equiv versus ca. 2 equiv), reactions involving
the two radical traps were conducted under otherwise identical
conditions. Yields of fragmentations employing 3 were generally
slightly lower than the corresponding reactions utilizing TEMPO.
However, fragmentation of 1g was higher yielding with 3 as the
radical trap. This result can at least partly be attributed to the
greater stability of 4g than hemiaminal 2g to chromatography.
As anticipated, nitrile 4h was produced in low yield from
fragmentation of six-membered cyclic oxime ether 1h. Some
isomerization of the alkene moiety occurred during this reaction.
Since isomerization did not occur when 1h was fragmented in
the presence of TEMPO, this process is probably mediated by
in Table
2 illustrate the broad scope of this process.
Cyclobutanone-derived oxime ether 1b and substituted
cyclopentanone-derived oxime ethers 1c–f afforded the
respective functionalized nitriles 2b–f in good to excellent yields.
The unsymmetrical substrates 1c–e underwent regioselective
fragmentations to deliver the less substituted nitriles, with only
1c producing a very minor amount of the more substituted nitrile.
The modest yield of nitrile 2g obtained from fragmentation of
carbamate-containing oxime ether 1g is likely a consequence of
hemiaminal hydrolysis occurring during chromatographic
purification. Attempts at fragmenting a cyclohexanone-derived
oxime ether yielded only trace amounts of nitrile (data not
shown), as the lack of ring strain removes a major driving force
for fragmentation. Six-membered cyclic oxime ether 1h was
more reactive, presumably due to the combination of alkene-
induced ring strain and the ability to form a secondary radical
providing some impetus for fragmentation. However, the yield of
nitrile 2h was modest. A cycloheptanone-derived oxime ether
was not a viable substrate. Phenol was obtained as a readily
removable byproduct in all of the reactions, demonstrating that
the phenoxy radical produced upon fragmentation reacts with an
adventitious hydrogen atom donor. No products derived from
reduction of the alkyl radicals were detected, indicating that
TEMPO is able to rapidly trap these intermediates. The reaction
protocol is highly practical, as no precautions to exclude air or
moisture are required, no toxic organotin reagents or explosive
initiators are utilized, and the fragmentations are typically
complete in just 10 minutes.
•SO2Ph or a related species. Fragmentations involving
3
generated aryl byproducts that are presumably derived from
decomposition of •SO2Ph. In some cases, these byproducts
were challenging to separate from the products.
Table 3: Fragmentations of oxime ethers with trapping by allylsulfone 3.[a],[b]
Table 2: Fragmentations of oxime ethers with TEMPO trapping.[a]
[a] Conditions: 1, 3 (3.4–3.9 equiv), CH3CN, W (90 °C), 10 min. [b] Yields of
isolated product. [c] A 2.4:1 mixture of Z- and E-isomers.
We then tested the viability of additional radical traps in an
effort to expand the scope of the microwave-promoted
fragmentations as summarized in Table 4. Poor solubility of
some traps in CH3CN necessitated the use of different solvents
in certain cases. Benziodoxolone-based hypervalent iodine
reagent 5a[20] and 2-iodopropane (6)[21] each participated in
fragmentations of oxime ether 1a, furnishing alkyne 8a and
iodide 8b in good yields (entries 1 and 2). Interestingly, trapping
the fragmentation of oxime ether 1e with 3-pyridinesulfonyl azide
(7a)[22] afforded benzylic azide 8c as well as the corresponding
styrene derived from elimination of HN3 (entry 3).[23] A similar
result was obtained when hypervalent iodine reagent 5b[24] was
employed as the radical trap (entry 4). Reasoning that basic
functional groups present in these traps might be promoting
elimination, we attempted fragmentation of elimination-resistant
oxime ether 1f in the presence of benzenesulfonyl azide 7b.[25]
Benzylic azide 8d was isolated from this reaction, albeit in low
yield (entry 5). While the formation of C–N bonds by this method
will require further development, the ability to install an alkyne,
an iodide, and a styryl moiety suggests a promising scope for
the microwave-promoted iminyl radical fragmentation.
[a] Conditions: 1, TEMPO (1.5–2.5 equiv), CH3CN, W (90 °C), 10 min. [b]
Yields of isolated product. [c] PhCF3 was used as solvent. [d] 22:1 ratio of
regioisomers favoring 2c. [e] CH3CN–CH2Cl2 4:1 was used as solvent.
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Table 4: Fragmentations of oxime ethers with other radical traps.[a]
azide 7a was employed as the radical trap. Presumably,
elimination of HN3 does not occur since the resulting alkene
[27]
would not be conjugated. We were pleased to find that CCl4
was a suitable trapping agent, delivering tertiary chloride 10d in
good yield as a mixture of diastereomers. The production of
multiple isomers can be an asset in ring-distortion campaigns,
where the goal is to generate a diverse collection of compounds
from
a
single complex precursor. Although Beckmann
fragmentations[28] and Schmidt-type reactions[26a] have been
used to produce ring-opened nitriles from natural-product-
derived substrates, the strongly acidic conditions that are
required limit the scope of these methods.
[a] Microwave irradiation at 90 °C for 10 min was employed unless otherwise
noted. [b] Yields of isolated product unless otherwise noted. [c] Reaction
conducted at 90 °C for 20 min. [d] Obtained as part of a 1:1.2 mixture favoring
the corresponding styrene. [e] Obtained as part of a 1:1.4 mixture favoring the
corresponding styrene. [f] Reaction conducted at 100 °C for 20 min.
Most of the reactions described in Tables 2–4 were
performed on relatively small scales (i.e., ≤0.1 mmol).
Fragmentation of 1 mmol of oxime ether 1a in the presence of
TEMPO afforded nitrile 2a in very good yield (Scheme 2),
demonstrating the scalability of this process.
Scheme 3. Fragmentations of estrone-derived oxime ether 9. Reagents and
conditions: a) TEMPO (2.0 equiv), CH3CN–PhCF3 9:1, W (90 °C), 20 min; b)
3 (3.6 equiv), CH3CN–PhCF3 9:1, W (90 °C), 20 min; c) 7a (3.2 equiv),
CH3CN–PhCF3 9:1, W (90 °C), 20 min; d) CCl4 (3.0 equiv), CH3CN–PhCF3
9:1, W (90 °C), 20 min.
TEMPO adduct 10a underwent further modification as
shown in Scheme 4. Addition of MeMgBr to the nitrile moiety
and subsequent hydrolysis furnished ketone 11. Liberation of the
tertiary alcohol via N–O bond cleavage triggered spontaneous
cyclization and dehydration, delivering tetracycle 12 in four
straightforward steps from estrone.
Scheme 2. Larger-scale fragmentation.
The mild reaction conditions and diverse functionalization
possibilities render the iminyl radical fragmentation well-suited
for the ring-distortion of complex natural products.[26] As an
example, several transformations of estrone-derived oxime ether
9 are shown in Scheme 3. Fragmentations of this complex
substrate required slightly longer reaction times than
fragmentations of simpler substrates (20 min vs 10 min).
Trapping of the intermediate alkyl radical with TEMPO furnished
adduct 10a in good yield and ca. 7:1 dr. The configuration of the
major diastereomer was established via NMR spectroscopy
(NOESY). The use of allylsulfone 3 as the radical trap afforded
10b as a single detectable diastereomer. The modest yield is
Scheme 4. Transformation of adduct 10a.
In summary, we have found that 4- and 5-membered cyclic
O-phenyl oxime ethers undergo rapid and facile iminyl radical
fragmentations upon microwave irradiation, delivering a range of
presumably
a
reflection of the challenges inherent in
constructing a hindered C–C bond. Azide 10c was obtained in
moderate yield as a mixture of diastereomers when sulfonyl
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functionalized nitriles due to the compatibility of the process with
several different radical traps. The protocol is simple and highly
practical. Additionally, no toxic reagents or metal catalysts are
required. The method is useful for creating diverse adducts from
complex natural products, as evidenced by the ring-distortion of
an estrone-derived oxime ether. Accordingly, we envision that
this convenient and powerful chemistry will be adopted at both
early and late stages of synthetic campaigns.
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Acknowledgements
Acknowledgment is made to the donors of the American
Chemical Society Petroleum Research Fund (55514-ND1) for
support of this research. We also thank Brigham Young
University (Undergraduate Research Awards to S.I., S.R.B., and
A.L.G.) for support.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: iminyl radicals • cleavage reactions • microwave
chemistry • radical traps • ring-distortion
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[18] Compound 1a and all other oxime ethers employed in this study were
synthesized via condensation of the corresponding ketones with
PhONH2•HCl; please see the Supporting Information for details.
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10.1002/chem.201705728
Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
No initiators or catalysts required:
Microwave irradiation of cyclic oxime
ethers triggers iminyl radical
Mary M. Jackman, Siyeon Im, Seth R.
Bohman, Concordia C. L. Lo, Amanda L.
Garrity, and Prof. Steven L. Castle *
fragmentations, producing an array of
functionalized nitriles. The process is
characterized by a simple protocol,
short reaction times, and compatibility
with several different radical traps.
Page No. – Page No.
Synthesis of Functionalized Nitriles
via Microwave-Promoted
Fragmentations of Cyclic Iminyl
Radicals
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