Ring-opening iodination and bromination of unstrained cycloalkanols through ?-scission of alkoxy radicals

Article abstract of DOI:10.1039/d0cc01720e

Ring-opening iodination or bromination of unstrained cycloalkanols with NaI or NaBr and PhI(OAc)₂ under visible light irradiation is developed. In this protocol the concentration of I₂is modulated through the generation of triiodide (I₃^-), thus significantly avoiding undesired side reactions. The reaction is under mild conditions and has a wide substrate scope, thus providing a practically useful method for accessing ω-iodo or ω-bromoketones.

Full text of DOI:10.1039/d0cc01720e

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DOI: 10.1039/D0CC01720E
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Ring-Opening Iodination and Bromination of Unstrained
Received 00th January 20xx,
Accepted 00th January 20xx
Cycloalkanols through -Scission of Alkoxy Radicals†
DOI: 10.1039/x0xx00000x
Jiang-Ling Shi, Yuankai Wang, Zixuan Wang, Bowen Dou and Jianbo Wang*
www.rsc.org/
A
ring-opening iodination and bromination of unstrained catalyst is required, which may limit its wide applications. Thus, it is
cycloalkanols with NaI or NaBr and PhI(OAc)2 under visible light still highly desirable to develop mild and economical procedure for
irradiation is developed. In this protocol the concentration of I2 is this important transformation.
modulated through the generation of triiodide (I3-), thus
In 2016, Nagib and co-workers reported a -amination of
significantly avoiding the undesired side reactions. The reaction is secondary C-H bonds (Hofmann-Loffler-Freytag reaction) by using a
under mild conditions and has wide substrate scope, thus providing reaction system of NaI-PhI(OAc)2 under visible light irradiations.8
a pratically useful method for accessing -iodo or -bromoketones. Highlight of this method is the in situ requisition of I2, which isderived
from sodium iodide, and I- to yield a triiodide (I3 ). This procedure
-
The -scission of alkoxy radicals have been extensively studied as a
limits the concentration of I2 and reactive intermediate AcOI, thus
significantly preventing undesired side reactions. Inspired by Nagib’s
work, we have conceived that the same protocol may be applied to
ring-opening iodination and boromination of unstrained
cycloalkanols. Herein we report our study along this line (Scheme 1c).
unique strategy for C(sp3)-C(sp3) bond cleavage, among which the
ring-opening halogenation of cycloalkanols provides
a
straightforward approach toward distally halo-substituted ketones.1
In this context, the ring-opening halogenation of strained
cycloalkanols (3- and 4-membered rings) through -scission of alkoxy
radicals is well studied,2 but the corresponding reaction of
unstrained cycloalkanols has attracted recent attentions (Scheme
1a).3 The traditional methods for generating alkoxy radicals involve
the conversion of the alcohols into the corresponding hypoiodites
with I2/PhI(OAc)2 (Suárez reagent), I2/Pb(OAc)2 or I2/HgO, followed
by photolysis or thermolysis.4,5 However, these methods suffer from
some drawbacks. In particular, the iodine (I2) and the in situ
generated reactive species acetyl hypoiodite (AcOI) are prone to
homolysis to generate radical species which may lead to undesired
side reactions. Besides, the substrates containing electron-rich
aromatic ring or reactive C-H bonds are not tolerated under these
conditions.
Recently, new methods for generating alkoxy radicals based on
photoredox catalytic processes have emerged.3c,6,7 In particular, Zhu
and co-workers explored a [Ir(ppy)2(dtbbpy)]PF6, NBS and PhI(OAc)2
system for visible light-promoted ring-opening functionalization of
unstrained cycloalkanols (Scheme 1b).3c Regardless of the significant
improvement of the reaction conditions, expensive transition-metal
Scheme 1 The ring-opening halogenation of cycloalkanols
At the out of the study, 1-phenylcyclohexan-1-ol (0.2 mmol) in 1
mL MeCN was irradiated by 10 W white LED in the presence of NaI
(4.0 equiv) and PhI(OAc)2 (4.0 equiv) at room temperature for 16 h
(Table 1, entry 1). The expected ring-opening iodization product 1
could be generated in 34% yield. Optimization experiments indicated
that the loading of NaI and PhI(OAc)2 could be reduced, while the
yield of 1 was significantly increased (entries 2 and 3 ). We reasoned
that this might be attributed to the decreased concentration of the
a. Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China. E-mail:
wangjb@pku.edu.cn
† Electronic supplementary information (ESI) available: Experimental details,
Characterization data. See DOI: 10.1039/x0xx00000x
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in situ generated reactive AcOI species, thus minimizing the side
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The reaction also worked with the substrVaiteewsArticbleeOarnilninge
reactions. Thus, we further optimized the reaction concentration and heteroaromatic ring (21) and active C-H boDnOdsI: 1(02.210a3n9d/D203C)C.0In172th0Ee
found that MeCN (2.0 mL) was optimal, affording 1 in 98% isolated case when the tether bearing a carbonyl group, the ring-opening was
yield (entry 4). Subsequently, we examined the reaction time and followed by dehydroiodination to give an unsaturated 1,4-diketone
found this transformation took 10 h to complete (entries 5-9). Next, product (24). We also examined the ring-opening iodination of
-
to verify the hypothesis that I- requisition of I2 as I3 prevents the seven-, eight- and twelve-membered cycloalkanols, the reaction
undesired byproduct pathways, control experiments were carried afforded the corresponding products 25-27 in 86%, 36% and 95%
out. Using the traditional Suárez reagent (I2/PhI(OAc)2), the reaction yield, respectively. The reaction also worked with alkyl-substituted
gave 1 in 81% yield (entry 10). When NaI was introduced, the yield of cyclohexanols (28 and 29). Finally, the substrates bearing
1 could be increased to 95% (entry 11). Finally, control experiment disubstituted aromatic ring also tolerated the reaction (30-31).
indicated that the reaction did not occur when carried out in dark
(entry 12).
Table 1 Optimization of the Reaction Conditionsa
Entry
NaI
(equiv)
PhI(OAc)2
(equiv)
Time (h)
Yield (%)a
1b
2b
3b
4
4
1
2
2
2
2
2
2
2
0
1
2
4
1
2
2
2
2
2
2
2
2
2
2
16
16
16
16
1
34
83
88
98c
18
70
80
98c
97
81
95
0
5
6
3
7
6
8
10
12
10
10
10
9
10d
11e
12f
aIf not otherwise noted, the yield was determined by 1H NMR (400 MHz) using
dibromomethane as the internal standard. bMeCN (1.0 mL). cIsolated yield. dI2
(1 equiv) was used in the reaction. eI2 (1 equiv) was used in the reaction. fThe
reaction was carried out in dark.
With the optimized reaction conditions in hand, we set out to
investigate the substrates scope (Scheme 2). Firstly, the scope of
various cyclopentanols were tested. The substrates bearing para
substituents such as -OMe, -Me, -F, and -Cl (2-6) on the aromatic ring
were all tolerated, giving the corresponding ring-opening products in
92-98% isolated yields. Change of position (meta-, and ortho-) of
substituents such as -OMe, -F, did not affect the reaction, giving the
corresponding products in comparable yields (7-10). Then, the
substrates of cyclohexanols were examined. Similarly, the reaction
with substrates bearing substituents on the aromatic ring gave the
corresponding products in good to excellent yields (1, 11-20). To
demonstrate the synthetic potential of the reaction, a gram scale
experiment was carried out, which afforded the corresponding
product 1 in comparable yield. It is worth mentioning that for the
substrates bearing electron-rich aromatic ring, such as the
cyclohexanols that leads to the formation of 11, 15, 18, the
traditional Suárez condition (I2/PhI(OAc)2) failed to afford the
corresponding products (See Electronic Supplementary Information
for the details).
Scheme 2 Substrates scope of the ring-opening iodination: cycloalkanol
derivatives (0.2 mmol), NaI (0.4 mmol), PhI(OAc)2 (0.4 mmol), MeCN (2.0 mL),
10 W white LED, rt, N2, 10 h. All the yields refer to isolated products. aThe
reaction was carried out in 6 mmol scale.
Subsequently, we proceeded to explore the corresponding ring-
opening bromination by replacing NaI with NaBr.9 To our delight,
under the otherwise identical conditions, the ring-opening
bromination occurred smoothly and afforded the distally bromo-
substituted alkyl ketones (Scheme 3). First, the reaction of
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possible ring-opening chlorination, but to our disappointment,
DOI: 10.1039/D0CC01720E
almost all the starting cyclohexanol substrate was recovered when
cycloalkanols of various ring size was examined and the
corresponding -bromoketones were obtained in moderate to good
yields (33-37). We further examined the scope of the substrate by
using a series of cyclohexanol derivatives. The reaction with the
substrates bearing para and meta substituted aromatic ring all
worked well and gave the corresponding -bromoketones in
moderate to good yields (38-41).
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NaBr was replaced by NaCl, which may be attributed to the
decomposition of AcOCl. Besides, when cyclohexanol, a secondary
cyclic alcohol, was subjected to the standard conditions, the alcohol
substrate was recovered. Neither ring-opening nor cyclohexanone
could be detected.
For the substrates bearing ortho-substituted aromatic rings, the
reaction with F-substituted substrate afforded the ring-opening
product 42 in 83%, while the reaction with Me-substituted substrate
gave a mixture of ring-opening product 43 together with 1,5-
hydrogen atom transfer product. In contrast to the ring-opening
iodination, the substrates bearing MeO-substituted aromatic ring
were found not tolerable for the bromination due to the side
reaction of direct bromination of the electron-rich aromatic ring.
However, when the MeO-substituted aromatic ring is substituted by
additional electron-withdrawing fluoro substituent, the ring-opening
reaction occurred smoothly to give the corresponding products in
good yields (44 and 45). The reaction tolerated substrates of active
C-H bonds (46 and 47). The bromination also worked with the alkyl-
substituted cyclohexanols (48 and 49). Finally, we have examined the
Based on previous reports,8 a plausible reaction pathway is
proposed in Scheme 4. First, I2 is generated in situ from NaI and
PhI(OAc)2. The in situ generated I2 can be captured by I- to generate
triiodide (I3 ). The equilibrium between I- and I3 modulate the
concentration of the reactive AcOI. The reaction between the
substrate 1-phenylcyclohexan-1-ol and AcOI gives hypoiodite A, from
which alkoxyl radical B is generated upon visible light irradiation.
Subsequently, alkoxy radical B undergoes -scission to generate alkyl
radical C, which is captured by I2 or I· to afford the final product 1.10
-
-
Scheme 4 Proposed reaction mechanism
In summary, we have reported a mild and convenient method
to realize ring-opening iodination and bromination of unstrained
cycloalkanols with NaI or NaBr and PhI(OAc)2 under visible light
irradiation. The reaction is operationally simple and shows wide
substrate scope. Particularly in the case of ring-opening iodination
the substrates can include those bearing electron-rich aromatic ring
substituents, which are not compatible with the classic Suárez
reagent.
The project is supported by NSFC (Grant 21871010).
Conflicts of interest
There are no conflicts to declare.
Scheme 3 Substrates scope of the ring-opening bromination. Reaction
conditions: cycloalkanol derivatives (0.2 mmol), NaBr (0.4 mmol), PhI(OAc)2
(0.4 mmol), MeCN (2.0 mL), 10 W white LED, rt, N2, 10 h. All the yields are
isolated yields. aThe reaction gave a complex mixture.
Notes and references
1
For selected reviews, see: (a) E. Suárez and M. Rodriguez, in Radicals in
Organic Synthesis: Applications, ed. by P. Renaud, M. Sibi, Wiley-VCH,
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DOI: 10.1039/D0CC01720E
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6
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9
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For a related ring-opening boromination, see: W.-C. Zhang and C.-J. Li, J.
Org. Chem., 2000, 65, 5831-5833.
10 An alternative pathway as proposed by one of the reviewers, the
reaction of ROH with PIDA to generate (RO)2-IPh intermediate which is
homolyzed to generate RO· radical under light irradiation, can be ruled
out by the following control experiment. In Table 1, when the reaction
was carried out in the absence of NaI under the otherwise identical
conditions, ring-opening product was not detected.
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DOI: 10.1039/D0CC01720E
Graphical Abstract
R
O
R
R OH
NaI or NaBr (2.0 equiv)
PhI(OAc)2 (2.0 equiv)
O
or
I
Br
MeCN (2.0 mL), rt, N2
10 W white LED
( )n
X
( )
X
( )
X
n
n
32 examples
up to 99%
gram scale
16 examples
up to 90%
X = CH2, O, CO
n = 0-3, 7
A ring-opening iodination and bromination of unstrained cycloalkanols with NaI or
NaBr and PhI(OAc)2 under visible light irradiation is developed. In this protocol the
concentration of I2 is modulated through the generation of triiodide (I3-), thus
significantly preventing the undesired side reactions.