Esters as Radical Acceptors: β-NHC-Borylalkenyl Radicals Induce Lactonization by C?C Bond Formation/Cleavage on Esters

Article abstract of DOI:10.1002/anie.201902001

Substituted propargyl acetates are converted into 4-boryl-2(5H)-furanones upon thermolysis in the presence of an N-heterocyclic carbene borane (NHC-borane) and di-tert-butyl peroxide. The acetyl methyl group is lost during the reaction as methane. Evidence suggests that the reaction proceeds by a sequence of radical events including: 1) addition of an NHC-boryl radical to the triple bond; 2) cyclization of the resultant β-borylalkenyl radical to the ester carbonyl group; 3) β-scission of the so-formed alkoxy radical to provide the 4-boryl-2(5H)-furanone and a methyl radical; and 4) hydrogen abstraction from the NHC-borane to return the initial NHC-boryl radical and methane.

Full text of DOI:10.1002/anie.201902001

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Accepted Article
Title: Esters as Radical Acceptors: β-NHC-borylalkenyl Radicals
Induce Lactonization by C‒C Bond Formation/Cleavage on
Esters
Authors: Masaki Shimoi, Katsuhiro Maeda, Steven J. Geib, Dennis P.
Curran, and Tsuyoshi Taniguchi
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Esters as Radical Acceptors: -NHC-borylalkenyl Radicals Induce
Lactonization by C‒C Bond Formation/Cleavage on Esters
Masaki Shimoi,[a] Katsuhiro Maeda,[a,b] Steven J. Geib,[c] Dennis P. Curran,*,[c] and Tsuyoshi
Taniguchi*,[a]
Abstract: Substituted propargyl acetates are converted to 4-boryl-
2(5H)-furanones upon thermolysis in the presence of an N-
heterocyclic carbene borane (NHC-borane) and di-tert-butyl peroxide.
The acetyl methyl group is lost during the reaction as methane.
Evidence suggests that the reaction proceeds by a sequence of
radical events including: (1) addition of an NHC-boryl radical to the
triple bond; (2) cyclization of the resultant -borylalkenyl radical to the
ester carbonyl group; (3) -scission of the so-formed alkoxy radical to
provide the 4-boryl-2(5H)-furanone and a methyl radical; and (4)
hydrogen abstraction from the NHC-borane to return the initial NHC-
boryl radical and methane.
Radical cyclizations involving carbon-carbon, carbon-nitrogen
and carbon-oxygen multiple bonds are powerful reactions that are
commonly used in organic synthesis.[1] Among the various
classes, cyclizations to carbon-oxygen double bonds are probably
the least general because they are restricted to aldehydes and
some ketones. Such radical cyclizations produce alkoxyl radicals
that ultimately lead to either direct cyclization products (usually
alcohols) or -scission products[2] with a migrated aldehyde or
ketone.[3]
The best known radical reaction of ketones is probably the
Dowd-Beckwith rearrangement,[4] which combines radical
cyclization and -scission into a powerful ring expansion method.
Treatment of -keto esters 1 with tin hydride provides ring-
expanded -keto esters 3 via the intermediacy of cyclized alkoxyl
radicals 2 (Figure 1a). Although -keto esters are common
precursors in these reactions,[3] products from competing radical
cyclization to the ester have never been observed. Indeed,
calculations by Ardura and Sordo show that barriers for 5-exo
radical cyclizations to esters are too high in precursors like 1 for
such reactions to be observed under normal laboratory
conditions.[5]
Figure 1. Radical cyclizations to carbonoxygen double bonds. AIBN = 2,2'-
azobis(isobutyronitrile). NHC = N-heterocyclic carbine.
So radical cyclizations to acyclic esters are essentially
unknown, doubtless because ester resonance raises the barriers
to such reactions. However, Lee has reported two examples of
side products formed by transannular cyclizations to
macrolactones (Figure 1b).[6] Reactions of 4a,b with tin hydride
provided bicyclic lactones 5a,b in 25% and 28% yield. These
products presumably arise from sequential 8-endo and 5-exo
cyclizations to provide alkyl radicals 6a,b, which in turn undergo
transannular cyclization to the ester to give alkoxyl radicals 7a,b.
This unusual reaction is aided by the rigid nature of bicyclic radical
6, which holds the radical center in close proximity to the
macrolactone carbonyl group. Transannular -scission of 7a,b
then provides 5a,b.
[a]
M. Shimoi, Prof. Dr. K. Maeda, Dr. T. Taniguchi
Graduate School of Natural Science and Technology
Kanazawa University
Kakuma-machi, Kanazawa 920-1192 (Japan)
E-mail: tsuyoshi@p.kanazawa-u.ac.jp
Prof. Dr. K. Maeda
Nano Life Science Institute (WPI-NanoLSI)
Kanazawa University
Kakuma-machi, Kanazawa 920-1192 (Japan)
Dr. Steven J. Geib, Prof. Dr. D. P. Curran
Department of Chemistry
[b]
[c]
University of Pittsburgh
Pittsburgh, PA 15260 (USA)
E-mail: curran@pitt.edu
Here we describe the discovery that -borylalkenyl radicals 8
bearing an N-heterocyclic carbene (NHC) ligand undergo C‒C
bond formation by 5-exo cyclizations to simple acetate esters.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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The cyclized alkoxyl radicals 9 then undergo C‒C bond cleavage
by -scission to give bench-stable borylated lactones (4-(NHC-
boryl)-2(5H)-furanones) 10 (Figure 1c). These reactions are
surprisingly efficient considering that they are disfavored not only
by ester resonance but also by ester geometry.[7] Ester bonds
strongly prefer the s-trans configuration, but rotation to the higher
energy s-cis conformer is required for cyclization of 8.
Table 1 shows results of reactions of 3˚-propargyl acetate 12b
with different amounts of NHC-borane 11 and DTBP in benzene
at 120 °C. Yields of 14 were estimated by 1H NMR analysis of the
crude products using an internal standard (dimethyl sulfone), with
isolated yields in parentheses. When 2 equiv of NHC-borane 11
and 1 equiv of DTBP were used, the reaction was complete in 19
h and gave lactone 14 in 60% yield (entry 1). Increasing the
amount of DTBP to 1.5 equiv shortened the time to 8 h but did not
improve the yield of 14 (54%, entry 2). A reaction with 4 equiv of
NHC-borane 11 and 1.5 DTBP provided lactone 14 in 76% yield
(74% isolated yield, entry 3). These are the conditions of Scheme
1, which provided 14 in 74% isolated yield. Lactone 14 was
obtained in 66% yield after 9 h when the amount of DTBP was
returned to 1 equiv (64% isolated yield, entry 4). Further
decreasing the amount of DTBP to 0.5 equiv increased the
reaction time to 19 h, but the yield was still 64% (entry 5). When
di-tert-butyl hyponitrite (t-BuON=NOt-Bu, TBHN) was used in
place of DTBP, a 60% yield was obtained with a lower loading of
the initiator (0.4 equiv) and at lower temperature (80 °C) (entry 6).
This implies that the higher temperature with DTBP (120 ˚C) is
needed only for initiation and not for any chain propagation steps.
Only a trace of lactone 14 was detected in 24 h reaction with no
DTBP, and most of both precursors remained unreacted (entry 7).
Overall, the impact of amounts of reagents in this reaction is
relatively small compared to the previous radical hydroboration of
alkynes.[8]
We discovered the new reaction during a scope study of the
recently reported radical trans-hydroboration of aryl-substituted
alkynes with NHC-boranes.[8,9] The reaction of readily available
NHC-borane 11[10,11] (4 equiv) with 1˚-propargyl acetate 12a (R =
H) and di-tert-butyl peroxide (DTBP, 1.5 equiv) in benzene at 120
˚C produced the expected trans-hydroboration product 13 in 53%
yield. In contrast, a similar reaction with 3˚-propargyl acetate 12b
(R = Me) produced a new product that was isolated as a white
solid in 74% yield by flash chromatography. This product lacked
alkenyl proton and acetate methyl group resonances in its 1H
NMR spectrum, and was soon identified as the novel 4-(NHC-
boryl)-2(5H)-furanone 14. Instead of undergoing the expected
trans-hydroboration reaction, substrate 12b combined with 11 in
a novel borylative lactonization reaction.
The structure of 14 was confirmed by X-ray crystallography,
as shown in Figure 2.[12] The unsaturated lactone ring of 14 is
nearly planar, and the NHC ligand on boron orients itself away
from the gem-dimethyl substituents on the lactone ring. In turn,
the phenyl ring twists out of conjugation with the unsaturated
lactone to minimize interactions with the nearby NHC ring.
Table 1. Reactions of tertiary propargyl acetate 12b and NHC-borane 11
under radical conditions[a]
Entry
11 [equiv]
DTBP [equiv]
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
2
2
4
4
4
4
4
1.0
1.5
1.5
1.0
0.5
0.4d]
0
19
8
60
54
5
76 [74][c]
66 [64][c]
64
9
Scheme 1. Discovery of a new borylative lactonization reaction.
19
1
60
24
<5
[a]Conditions: 12b (0.2 mmol), 11 (0.4 or 0.8 mmol), DTBP (00.3 mmol) in
benzene (0.4 mL) at 120 ˚C in a sealed tube. [b]Yield calculated from 1H NMR
spectra of the crude product (internal standard: dimethyl sulfone). [c]Yield
isolated by silica gel chromatography. [d]Di-tert-butyl hyponitrite (TBHN) was
used instead of DTBP at 80 ˚C.
Figure 3 shows products, reaction times and yields in
preparative experiments of about two dozen substituted propargyl
acetates with NHC-borane 11. The reactions were typically
conducted under the conditions of Table 1, entry 4, with 4 equiv
Figure 2. ORTEP representation of the X-ray structure of 4-(NHC-boryl)-2(5H)-
furanone 14 at 50% probability level.
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of 11 and 1 equiv of DTBP. Most of unreacted 11 could be
recovered, except for a few cases where Rfs of the furanone and
11 were too similar. The reactions of some substrates proceeded
smoothly even when the amount of NHC-borane 11 was reduced
to 2 equiv. All products are bench-stable compounds.
reaction was sluggish and gave the corresponding lactone 29 in
moderate yield (30%) in 24 h.
Next, we focused on phenylpropargyl acetates having other
geminal dialkyl tethers. In most cases, reactions were slower than
the reaction of 14, but lactones 30–32 were still obtained in yields
ranging 52–63%. The extended time is probably because boryl
radical addition to alkynes is slowed by the larger geminal
substituents. Interesting spirocyclic lactones 33–36 can be also
be made in 41–55% yields.
Propargyl acetates with p-substituted groups on the aromatic
ring were readily converted to the corresponding lactones 15–20
in yields ranging from 53% to 76%. Heteroatoms having a lone
pair such as methoxy groups and halogen atoms tended to afford
better results, probably due to stabilization of the intermediary
alkenyl radicals (the boryl radical additions step is improved). A
substrate having p-cyano group decomposed at 120 °C,[8] but
gave lactone 20 in 53% yield with TBHN at 80 °C.
Some examples of limitations of the present reaction are
shown in the lower right portion of Figure 3. The boryl radical
addition reaction to a non-conjugated alkyne was very sluggish,
and the starting alkyne was not consumed even in 24 h. In this
reaction, only a trace of the signal based on 37 was detected by
11B NMR analysis of the crude material. This indicates that
formation of alkenyl radicals delocalized to conjugated systems is
o-Substituted groups on the aromatic rings seem to favor the
reactions, and the corresponding lactones 21–23 were produced
in good yields (73–89%) in short reaction times (typically within 5
h). Even a substrate having a bulky mesityl group gave the
corresponding lactone 24 in 82% isolated yield. The reaction of a
substrate bearing 3,5-bis(trifluoromethyl)phenyl group gave
lactone 25 in 57% yield in 5 h, which was similar to the reaction
to give p-CF3 analogue 18. Lactones 26 and 27 having polycyclic
aromatics were obtained in yields similar to that of 14. Application
of a pyridine derivative to the standard conditions complicated the
reaction, but using TBHN at 80°C gave lactone 28 in 54% yield.
When the aromatic ring was replaced with cyclohexene, the
important.
The reaction of the substrate having
a
monosubstituted tether afforded the corresponding hydroboration
product 38 of the alkyne instead of a lactone product. This
indicates again that the Thorpe-Ingold effect is important to help
satisfy the s-cis conformational demand for cyclization.[13] Finally,
we attempted to construct a six-membered bicyclic lactone from
the acetate having a cyclohexane template, but again only
hydroboration product 39 were obtained.
Figure 3. Reactions of various substituted propargyl acetates and NHC-borane 11. Reaction conditions: Acetates (0.2 mmol), 11 (0.8 mmol), DTBP (0.2 mmol) in
benzene (0.4 mL) at 120 ˚C in a sealed tube. Isolated yields are shown unless otherwise noted. [a]Reaction at 1.0 M on 2.0 and 3.0 mmol scales. [b]Yields calculated
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from 1H NMR spectra in the presence of an internal standard (dimethyl sulfone) after silica gel chromatography because unreacted 11 contaminated the products
(see the Supporting Information for the details). [c]2 equiv of borane (0.4 mmol) was used. [d]0.4 equiv of TBHN (0.08 mmol) was used. [e]Reaction at 1.0 M on 2.0
mmol scale (0.5 equiv of TBHN). [f]1.5 equiv of DTBP (0.3 mmol) was used.
Figure 4 shows a putative radical chain mechanism for
formation of the 4-(NHC-boryl)-2(5H)-furanones. The initiation
steps are homolysis of DTBP to give tert-butoxyl radicals (tBuO•),
which in turn rapidly abstract hydrogen atoms from NHC-borane
11 to give NHC-boryl radicals 40. The addition of an NHC-boryl
radical 40 to alkyne 12b to provide -NHC-boryl alkenyl radical 41
has precedent in several recent alkyne transformations.[8,9] Then
the surprising radical cyclization to the ester to provide alkoxyl
radical 42 evidently supersedes hydroboration by bimolecular
heptadecyl radical (nC17H35•) was formed in the reaction of 43 and
therefore supports the -scission and H-transfer steps shown in
Figure 4.
hydrogen atom transfer.
Cycloalkoxyl radicals commonly
undergo -scission reactions to cleave the ring,[2] but such
reactions with 42 would give unstable radicals (either the starting
alkenyl radical or another alkoxyl radical). So instead -scission
occurs at the branch bond to give a methyl radical (CH3•) and
lactone 14. Finally, the methyl radical abstracts a hydrogen atom
from the starting NHC-borane 11 to give methane and the NHC-
boryl radical 40.
Scheme 2. Reaction of stearate 43.
The primary focus of this initial study was to identify the scope
and secure the mechanism of this fundamental new reaction. To
close, we tested several preliminary transformations of the
representative 4-(NHC-boryl)-2(5H)-furanone 14 (Scheme 3).
One-pot oxidation of 14 with N-chlorosuccinimide (NCS), followed
by addition of water and then sodium perborate provided highly
substituted tetronic acid 45 in 83% yield. In contrast, when
sodium carbonate and water were added after treatment of 14
with NCS, protodeborylated 2(5H)-furanone 46 was obtained in
68% yield.[14]
NHC-fluoroboranes are also valuable agents for PET
(positron emission tomography) imaging.[15]
To show
transformation that retains the boron atom, 14 was treated with
Selectfluor[16]
(1-chloromethyl-4-fluoro-1,4-
a
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) to provide
stable NHC-(alkenyl)difluoroborane 47 in 81% yield. These
preliminary transformations hint that 4-(NHC-boryl)-2(5H)-
furanones will be useful synthetic intermediates.
Figure 4. Suggested radical chain mechanism for formation of 4-(NHC-boryl)-
2(5H)-furanones, including the novel step of alkenyl radical cyclization to the
ester (the reaction of 12b is shown).
In principle we could support the -scission step by looking for
methane formation in these reactions, but a positive result might
be ambiguous because methyl radicals can also be formed by -
scission of tert-butoxyl radical.[2] To bypass this problem, we
tested the reaction of stearate 43 with NHC-borane 11 (Scheme
2). The choice of stearate also facilitates analysis by providing a
non-volatile coproduct (heptadecane). Reaction of 43 with NHC-
borane 11 proceeded smoothly over 9 h (same conditions as
acetate 12b), and gave lactone 14 and heptadecane (44) in
similar yields (64% and 70%). This result suggests that
Scheme 3. Transformation of 4-(NHC-boryl)-2(5H)-furanone 14.
In conclusion, we have developed borylative lactonization of
substituted propargyl acetates with an NHC-borane under radical
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[3] a) M. Saladrigas, C. Bosch, G. V. Saborit, J. Bonjoch, B. Bradshaw,
Angew. Chem. Int. Ed. 2018, 57, 182-186; Angew. Chem. 2018, 130, 188-
192; b) L.-A. Chien, C.-C. Chang, J. Org. Chem. 2015, 80, 11294-11301;
c) P. Devin, L. Fensterbank, M. Malacria, Tetrahedron Lett. 1999, 40,
5511-5514; d) R. A. Batey, D. B. MacKay, Tetrahedron Lett. 1998, 39,
7267-7270; e) T. Rajamannar, K. K. Balasubramanian, J. Chem. Soc.,
Chem. Commun. 1994, 25-26; f) M. E. Jung, S. W. T. Choe, Tetrahedron
Lett. 1993, 34, 6247-6250; g) A. Nishida, H. Takahashi, H. Takeda, N.
Takada, O. Yonemitsu, J. Am. Chem. Soc. 1990, 112, 902-904; h) R.
Tsang, J. K. Dickson, Jr., H. Pak, R. Walton, B. Fraser-Reid, J. Am. Chem.
Soc. 1987, 109, 3484-3486.
[4] a) P. Dowd, W. Zhang, Chem. Rev. 1993, 93, 2091-2115; b) W. Zhang,
Ring Expansions. In Radicals in Organic Synthesis, 1st ed.; P. Renaud,
M. P. Sibi, Eds. Wiley-VCH: Weinheim, 2001; Vol. 2, pp 234-245.
[5] D. Ardura, T. L. Sordo, J. Org. Chem. 2005, 70, 9417-9423.
[6] E. Lee, C. H. Yoon, T. H. Lee, S. Y. Kim, T. J. Ha, Y. S. Sung, S. H. Park,
S. Lee, J. Am. Chem. Soc. 1998, 120, 7469-7478.
conditions. The new reaction has two unusual characteristics
from a standpoint of pure chemistry. First, it is a rare example of
radical addition to an ester carbonyl group. Second, a methyl
group behaves as a leaving group, so the lactone-forming
reaction is a net substitution that occurs by addition/elimination.
Addition/elimination is a classic path for nucleophilic substitution
reactions of esters in which the ester C–O bond is substituted and
its C–C bond is retained. The unusual feature of the radical
substitution is that this reverses; the ester C–O bond is retained
and its C–C bond is substituted. The 4-boryl-2(5H)-furanones that
this reaction provides are new class of stable of organoboron
compounds that can have downstream applications in organic
synthesis.
[7] A. Boussonnière, R. Bénéteau, J.-C. Rouaud, C. Despiau, J. Lebreton, F.
Dénès, Pure Appl. Chem. 2016, 88, 215-225.
[8] M. Shimoi, T. Watanabe, K. Maeda, D. P. Curran, T. Taniguchi, Angew.
Chem. Int. Ed. 2018, 57, 9485-9490; Angew. Chem. 2018, 130, 9629-
9634.
[9] a) T. Watanabe, D. Hirose, D. P. Curran, T. Taniguchi, Chem. Eur. J. 2017,
23, 5404-5409; b) S.-C. Ren, F.-L. Zhang, J. Qi, Y.-S. Huang, A.-Q. Xu,
H.-Y. Yan, Y.-F. Wang, J. Am. Chem. Soc. 2017, 139, 6050-6053.
[10] S. Gardner, T. Kawamoto, D. P. Curran, 1,3-Dimethylimidazoyl-2-ylidene
Borane. Org. Synth. 2015, 92, 342-355.
[11] a) J.-K. Jin, F.-L. Zhang, Q. Zhao, J.-A. Lu, Y.-F. Wang, Org. Lett. 2018,
20, 7558-7562; b) J. Qi, F.-L. Zhang, Y.-S. Huang, A.-Q. Xu, S.-C. Ren,
Z.-Y. Yi, Y.-F. Wang, Org. Lett. 2018, 20, 2360-2364; c) T. Kawamoto, S.
J. Geib, D. P. Curran, J. Am. Chem. Soc. 2015, 137, 8617-8622; d) X.
Pan, E. Lacôte, J. Lalevée, D. P. Curran, J. Am. Chem. Soc. 2012, 134,
5669-5675.
Acknowledgements
We thank Mr. Kosuke Takahashi (Kanazawa University) for
checking a reproducibility of some reactions. This work was
supported by JSPS KAKENHI Grant-in-Aid for Scientific
Research (C) (Grant No. 16K08159). D.P.C thanks the US
National Science Foundation (CHE-1660927) for support.
[12] CCDC 1892188 (14) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
Keywords: Alkynes • Boranes • Lactonization • Radical reactions
• Synthetic methods
[13] M. E. Jung, G. Piizzi, Chem. Rev. 2005, 105, 1735-1766.
[14] P. A. Cox, M. Reid, A. G. Leach, A. D. Campbell, E. J. King, G. C. Lloyd-
Jones, J. Am. Chem. Soc. 2017, 139, 13156-13165.
[15] K. Chansaenpak, M. Wang, Z. Wu, R. Zaman, Z. Li, F. P. Gabbaï, Chem.
Commun. 2015, 51, 12439-12442.
[1] a) K. J. Romero, M. S. Galliher, D. A. Pratt, C. R. J. Stephenson, Chem.
Soc. Rev. 2018, 47, 7851-7866; b) C. P. Jasperse, D. P. Curran, T. L.
Fevig, Chem. Rev. 1991, 91, 1237-1286.
[2] a) M. Murakami, N. Ishida, Chem. Lett. 2017, 46, 1692-1700; b) E. Suárez,
M. A. Rodriguez, -Fragmentation of Alkoxyl Radicals: Synthetic
Applications. In Radicals in Organic Synthesis, 1st ed.; P. Renaud, M. P.
Sibi, Eds. Wiley-VCH: Weinheim, 2001; Vol. 2, pp 440-454.
[16] S. Nerkar, D. P. Curran, Org. Lett. 2015, 17, 3394-3397.
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Masaki Shimoi, Katsuhiro Maeda,
Steven J. Geib, Dennis P. Curran,*
Tsuyoshi Taniguchi*
Page No. – Page No.
Esters as Radical Acceptors: -NHC-
borylalkenyl Radicals Induce
Lactonization by C‒C Bond
Formation/Cleavage on Esters
Radical lactonization of substituted propargyl acetates with N-heterocyclic carbene
boranes (NHC-boranes) has been developed. The reaction proceeds via cyclization
of a -borylalkenyl radical to an ester followed by elimination of a methyl group.
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