Reductive radical-initiated 1,2-C migration assisted by an azidyl group

Article abstract of DOI:10.1039/d0sc02559c

We report here a novel reductive radical-polar crossover reaction that is a reductive radical-initiated 1,2-C migration of 2-azido allyl alcohols enabled by an azidyl group. The reaction tolerates diverse migrating groups, such as alkyl, alkenyl, and aryl groups, allowing access to n+1 ring expansion of small to large rings. The possibility of directly using propargyl alcohols in one-pot is also described. Mechanistic studies indicated that an azidyl group is a good leaving group and provides a driving force for the 1,2-C migration. This journal is

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COMMUNICATION
Reductive radical-initiated 1,2-C migration assisted by azidyl
group
Xueying Zhang,†a Zhansong Zhang,†a Jin-Na Song,*b and Zikun Wang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We here report a novel reductive radical-polar crossover reaction infancy, and the development of novel RRPCO reaction is of
that is a reductive radical-initiated 1,2-C migration of 2-azido allyl great importance.
alcohols enabled by an azidyl group. The reaction tolerates diverse
(A) Reductive radical-polar crossover reactions
migrating groups, such as alkyl, alkenyl, and aryl groups, allowing
Y
E
Y
Y
Path 1
Path 3
R
X
access to n+1 ring expansion of small to large rings. Possibility to
directly use the propargyl alcohols in one-pot is also described.
Mechanistic studies indicated that an azidyl group, as a good
leaving group and providing a driving force for the 1,2-C migration.
-X
n
+E
R
R
R
X
X
n
n
n
Y
Nucleophilic
substitution
Nucleophilic
addition
HO
Y
Since the groups of Ryu and Sonoda described the reductive
radical-polar crossover (RRPCO) concept in the 1990s,1 which
attracts considerable attention in modern organic synthesis.2
By using this concept, a variety of complex molecules could be
assembled in a fast step-economic fashion that is not possible
using either radical or polar chemistry alone. However, only
two RRPCO reaction modes are known to date: nucleophilic
addition, and nucleophilic substitution (Figure 1A). The first
RRPCO reaction is the nucleophilic addition of the
organometallic species, which is generated in situ from the
reduction of strong reducing metal with carbon-centered
radical intermediate and cations (E+ = H+, I+, Br+, path 1).3
However, due to the necessity of a large amount of harmful
and strongly reducing metals has greatly limited the scope and
functional group tolerance of the reaction. Recently,
photoredox catalysis has not only successfully overcome the
shortcomings of using toxic strong reducing metals in RRPCO
reaction,4 but also enabling the development of several new
RRPCO reaction types, including the nucleophilic addition with
carbonyl compounds or carbon dioxide (path 2),5 the
cyclization of alkyl halides/tosylates (path 3),6 and β-fluorine
elimination (path 4).7 Although RRPCO reaction has been
greatly advanced by the photoredox catalysis, it is still in its
R1
n
CF2
Path 4
Path 2
R
X
Carbonyls
Y = CF3, -F
R
X
n
(B) This work: reductive radical-initiated 1,2-C migration assisted by azidyl group
O
N3
N
3 As leaving group
HO
R1 RM
Ts
R1
Ts
RM = Alkyl, Alkenyl, Aryl
RM
N3
O
R1 RM
N3
N3
SET
1,3-H shift
HO
R1 RM
Ts
HO
R1 RM
Ts
Ts
Figure 1 | (A) Reductive radical-polar crossover reactions; (B) This
work: reductive radical-initiated 1,2-C migration assisted by azidyl
group.
Herein, we wish to report a new type of reductive radical-
polar crossover cascade reaction that is the reductive radical-
initiated 1,2-C migration under metal-free conditions (Figure
1B). The development of this approach is not only further
expand the application of RRPCO reaction, but also solve the
problems associated with the oxidative radical-initiated 1,2-C
migration, such as the necessity of an oxidant and/or
transition metal for the oxidative termination of the radicals,
and also required sufficient ring strain to avoid the generation
of epoxy byproducts.8 To realize this reaction, a driving force
must be needed to drive the 1,2-C migration after reductive
termination, to avoid the otherwise inevitable protonation of
the generated anion.9 Inspired by the leaving group-induced
semipinacol rearrangement,10 we envisaged that 2-azidoallyl
alcohols11 might be the ideal substrates for the reductive
radical-initiated 1,2-C migration. Because, these compounds
contain both an allylic alcohol motif, which is vital for the
radical-initiated 1,2-C migration, and an azidyl group, a good
a. Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis,
Department of Chemistry, Northeast Normal University, Changchun 130024,
China.
b. School of Life Science, Jilin University, Changchun 130012, China.
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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leaving group,12 which may facilitate the 1,2-C migration after might be attributed to the aryl group possessing greater steric
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DOI: 10.1039/D0SC02559C
resistance. The structure of 3an was further verified by single-
the reductive termination of the radicals.
With the optimal conditions established (Supporting crystal diffraction. Interestingly, the vinyl azide derived from a
Information, Table S1), we then explored the scope of this pharmaceutical ethisterone was also a viable substrate,
radical-initiated 1,2-migration. As shown in Table 1, a series of affording the migration product 3aq in 57% yield, highlighting
naphthenic allylic alcohols could undergo n+1 ring expansion the applicability of this strategy in the late-stage modification
with minimal impact on the product yield (Table 1, 3aa-aq). of pharmaceuticals. Moreover, the acyclic allylic alcohol with
Notably, only the alkyl groups were migrated when using an alkyl chain was also successfully delivered the migration
benzonaphthenic allylic alcohols in the reaction. These results product 3ar in 64% yield.
Table 1 | Substrate scope of 2-azidoallyl alcoholsa
O
N3
O
S
TMSN3
HO
R1
R1
Ts
+
DMSO:H2O = 2:1
50 oC, 48 h
Tol
ONa
R2
R2
1
2a
3
Alkyl migration (3a)
O
6
O
6
O
6
O
6
O
6
O
5
Ts
Ts
Ts
Ts
Ts
Ts
Cl
F
3aa
, 68%
3ab
, 70%
3ac
, 64%
3ad
, 71%
3ae
, 54%
3af
, 59%
O
O
O
O
7
O
O
Ts
Ts
Ts
Ts
Ts
Ts
7
7
7
7
7
Cl
O
O
3ag
, 65%
3ah
, 61%
3ai
, 58%
3aj
, 66%
3ak
, 53%
3al
, 52%
O
O
O
Ts
Ts
O
O
Ts
Ts
O
Ts
H
Ts
9
8
8
13
H
H
O
3am
3an
3ao
3ap
3aq
3ar
, 71%
, 54%
, 52%
, 55%
, 57%
, 64%
O
CCDC 1897875
Aryl migration (3b)
O
O
O
O
O
F3C
MeO
Cl
Ts
Ts
Ts
Ts
Ts
Ts
CF3
OMe
Cl
3ba
, 84%
CCDC 1897779
3bb
3bc
3bd
3be
3bf
, 86%
, 91%
, 82%
, 69%
, 81%
O
O
O
O
O
O
Ts
MeO
Ts
Ts
Ts
Ts
Ts
Br
MeO
F
Cl
MeO
MeO
OMe
Br
, 78%
OMe
F
Cl
, 77%
3bg
3bh
3bi
3bj
3bk
, 87%
3bl
, 70%
, 89%
, 75%
Alkenyl migration (3c)
N3
OH
OH
HO
Ts
OH
R1
R2
Ph
Ph
HO
R1
O
S
TMSN3
Ts
Ts
R4
R3
+
Ts
DMSO:H2O = 2:1
50 oC, 48 h
R4
Ph
Tol
ONa
R2
R3
3c
Ph
3ca
1c
2a
3cb
, 71%
3cc
, 74%
, 63%
a Standard reaction conditions: 1 (0.5 mmol), TMSN3 (2.0 mmol), 2a (3.0 mmol), in H2O (0.7 mL) and DMSO (1.4 mL) at 50 oC under air for 48 h. b Isolated
yields.
Next, we extend the reaction scope to a range of aryl allylic afforded the corresponding products in moderate to high
alcohols. In comparison with alkyl allylic alcohols, the aryl yields (67-89%). Unsurprisingly, the substrates containing
allylic alcohols gave the migration products in higher yields. electron-donating groups afforded higher yields than those
The structure of 3ba was unambiguously confirmed by X-ray containing electron-withdrawing groups.
single crystal diffraction (CCDC 1897779). As demonstrated by
Phenols and their derivatives are important structural
the arene scope (Table 1, 3ba-bl), a variety of aryl allylic constituents of numerous pharmaceuticals, agrochemicals,
alcohols, including electron-withdrawing phenyl, electron- polymers, and natural products.13 The most common method
donating phenyl, polysubstituted phenyl, and fused rings, for constructing phenols is the hydroxylation of aryl halides.14
2 | J. Name., 2012, 00, 1-3
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However, the method usually requires transition metals and
harsh reaction conditions. Interestingly, by using this current derived from propargylic alcohols through a silver-catalyzed
strategy, the inexpensive and abundant cyclopentadiene hydroazidation of alkynes.15 Consequently, we hypothesized
moieties can also be easily converted into phenols (Table 1, that the radical-initiated 1,2-carbon migration could be directly
3ca-cc) in moderate to good yield. Thus, this strategy provides achieved from the propargylic alcohols in a one pot process.
COMMUNICATION
In this work, the 2-azidoallyl alcohols substrates were
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DOI: 10.1039/D0SC02559C
metal-free and mild conditions for accessing phenols.
With a slight modification of the reaction conditions, we
realized the one-pot preparation of the desired products from
propargylic alcohols (Table 4). Propargylic alcohols containing
cyclic alkyl (3ag and 3ah), heterocyclic alkyl (3ak and 3al),
acyclic alkyl (3ar), and aryl (3ba) groups all gave the desired
migration products, although the yields were slightly lower
than those from the reactions of the 2-azidoallyl alcohols. Note
that the ring expansion products could be directly generated
from a bioactive compound, ethisterone (3aq). Performing
such a reaction in a single step could greatly reduce the cost of
pharmaceutical modification. The fused phenol (3cd) could
also be obtained in moderate yield via the one-step reaction.
In addition, the migration order of the different substituted
groups (3db) was nearly identical to those observed in vinyl
azide-based protocol. Furthermore, alkyl sodium sulfinates
(3ea) were also well tolerated.
Table 2 | Investigation of the migration efficiency
O
O
N3
TMSN3
HO
R1 R2
+
TolSO2Na
+
R1
Ts
R2
Ts
DMSO:H2O = 2:1
R2
R1
50 o
C
1
2a
3d
3d'
Yield(%)a
3d’
42
entry
1
R1
R2
3d
15
53
56
42
42
46
41
36
1
2
3
4
5
6
7
8
1da
1db
1dc
1dd
1de
1df
Me
t-Bu
Me
C6H5
26
Me
4-MeOC6H5
4-CF3C6H5
4-MeC6H5
4-MeOC6H5
4-ClC6H5
4-CF3C6H5
14
Me
32
C6H5
C6H5
C6H5
C6H5
40
39
1dg
1dh
44
48
Table 4 | Substrate scope of propargyl alcoholsa,b
a Isolated yields.
TMSN3
O
R2
Ag2CO3 (10 mol %)
O
R1
Next, we investigated the migration capabilities of different
groups (Table 2). When using a substrate that contains two
different alkyl groups (1da), the product with less sterically
hindered alkyl group obtained in a higher migration ratio. A
comparison of aryl groups and alkyl groups in the same allylic
alcohols showed that the migration of aryl groups was more
facile, and the migration ratio ranged from 1:4 to 1:1.3 (3db-
dd). The results of the migration ratio of different aryl groups
(3de-dh) revealed that aryl moieties with electron-donating
groups possessed higher migration ratios than aryl moieties
with electron-withdrawing groups.
R1
S
+
RSO2Na
DMSO:H2O = 2:1
R
R2
OH
O
50 o
C
4
2
O
3
O
O
O
Ts
Ts
Ts
Ts
7
7
7
7
O
O
3ag
, 54%
3ah
, 43%
3ak
, 42%
3al
, 41%
OH
O
O
Ts
H
H
Ts
H
H
H
H
O
O
Ethisterone
3aq
, 38%
3ar
, 51%
Table 3 | Substrate scope of sodium sulfinatesa
O
N3
HO
Ts
O
O
O
O
TMSN3
Ph
HO
O
S
+
RSO2Na
Ph
S
DMSO:H2O = 2:1
R
Ph
Ts
Ts
Ph
O
Ph
Ph
1ba
50 o
C
O
Ph
Ph
3db
Ph
2
3e
3ba
, 72%
3cd
, 46%
3ea
, 82%
, 61%
O
O
O
O
O
S
O
S
3db'
, 24%
Ph
O
S
Ph
Ph
O
a
O
O
Ph
Ph
3eb
Ph
Standard reaction conditions: 4 (0.5 mmol), TMSN3 (2.0 mmol), 2 (3.0
3ea
3ec
, 87%
, 91%
, 90%
mmol), Ag2CO3 (0.05 mmol) in H2O (0.7 mL) and DMSO (1.4 mL) at 50 oC
under air for 48 h. b Isolated yields.
O
O
O
S
O
O
Ph
Ph
S
O
Ph
S
O
To gain more insight into the mechanism of radical-initiated
1,2-carbon migration, we conducted various experiments to
confirm the presence or absence of radical and carbanion
intermediates (Scheme 1). When the reaction of 1ba was
O
Ph
Ph
Ph
3ef
Cl
3ed
3ee
, 76%
, 82%
, 71%
a Isolated yields.
After the evaluation of our allylic alcohols scope, we turned performed in the presence of TEMPO (6.0 equiv), the reaction
our attention to the sulfonyl radical precursors (Table 3). We was suppressed under the standard conditions (Scheme 1, Eq
carried out various sodium sulfinates with allylic alcohol 1ba 1), supporting the involvement of a radical intermediate. To
under standard conditions. Pleasingly, the sodium sulfinates prove the formation of carbanion intermediate, we carried out
with chain alkyl (3ea), cyclic alkyl (3eb), and aryl (3ec-ef) two deuterium labeling experiments (Scheme 1, Eqs 2 and 3).
groups were all suitable for this radical-initiated 1,2-carbon The resulting products [D]-3ba and MA-1 contains the
migration, and afforded corresponding products in 71-91% deuterium atom α to the carbonyl group, confirming the
yield.
formation of a carbanion intermediate. To identify the key
intermediate of the 1,2-migration, we prepared a potential
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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intermediate M1 and was subjected to the standard conditions exchange of TolSO2Na with TMSN3. Such intermediates are
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(Scheme 1, Eq 4). But, the product 3ba was not observed and known to be somewhat unstable,16 as similar to the analogous
DOI: 10.1039/D0SC02559C
almost all of the M1 was recovered, which indicates that M1 is compounds, such as TolSO2I,17 and TMSTePh18 thus undergo
not a key intermediate. Whereas, the product 3ba was homolysis. Therefore, we anticipated that TolSO2TMS (I)
obtained in a yield of 41% while M2 was subjected to the should also yield sulfonyl and trimethylsilyl radicals.19 Then the
standard conditions (Eq. 5). If the hydroxyl group on the 2- 2-azidoallyl alcohol 1ba is readily attacked by the sulfonyl
azidoallyl alcohols was protected (M3), the reaction would not radical, leading to carbon-centered radical II. Subsequently,
give the corresponding migration product (3ga), but generate the carbon-centered radical II undergoes the single electron
product 5 with a yield of 51% (Eq. 6).11c This results proved transfer by the oxidation of sulfinate to the sulfonyl radical
that the reaction involved a 1,3-H migration process thereby yields the carbanion III.20 A 1,3-H shift of carbanion III affords
enabling an oxygen anion intermediate IV. (Other mechanistic the intermediate IV21 which rapidly undergoes a 1,2-migration
studies are discussed in Supporting Information Figure S1.)
with the assistance of the azidyl leaving group, generating the
desired product. It is worth noting that the present work is a
novel radical reaction mode for vinyl azides to the existing
reports that involving N-N bond breaking in the presence of
radical. Moreover, the development of this strategy is of great
significance for the application of vinyl azides in the
reconstruction of C-C bonds.
On the other hand, the coupling of sulfonyl radicals
produces intermediate V.22 The azidyl anion that is generated
in the reaction, is more prone to attack intermediate V to
afford tosyl azide.23 Subsequently, tosyl azide is reduced to p-
toluenesulfonamide by the trimethylsilyl radical.24 The side
products tosyl azide, and p-toluenesulfonamide were isolated
by column chromatography, and the associated TMSOH and
TMS2O have been detected by GC-MS.25
TEMPO (6 eq)
O
N3
TMSN3, (4 eq)
HO
Ph Ph
1ba
(1)
TolSO2Na
+
Ph
Ts
DMSO:H2O = 2:1
50 oC, 48 h
Ph
2a
, (6 eq)
3ba
, trace
1ba
was recovered in 81%
O
D
N3
TMSN3, (4 eq)
DMSO:D2O = 2:1
50 oC, 48 h
HO
TolSO2Na
(2)
(3)
+
+
Ph
Ts
Ph Ph
Ph
3ba
1ba
2a
, (6 eq)
[D]-
, 79%
>99% -deuterated
O
O
TMSN3, (4 eq)
DMSO:D2O = 2:1
50 oC, 48 h
TolSO2Na
Ts
OMe
OMe
D
MA
2a
, (6 eq)
MA-1
, 92%
>99% -deuterated
O
N3
TMSN3, (4 eq)
HO
Ts
(4)
(5)
TolSO2Na
+
Ph
Ts
DMSO:H2O = 2:1
50 oC, 48h
Ph Ph
Ph
3ba
M1
2a
, (6 eq)
, 0%
M1
was recovered in 87%
Conclusions
O
N3
TMSN3, (4 eq)
TMSO
Ph Ph
M2
Ts
+
TolSO2Na
In conclusion, we report a novel RRPCO reaction: reductive
radical-initiated 1,2-C migration under transition-metal free
conditions. The key driving force for this procedure was the
presence of azidyl group as a good leaving group. This reaction
features broad substrate scope, good functional group
tolerance, and the facile generation of diverse ketones and
phenols. Moreover, the direct use of propargyl alcohols in one-
pot process was also established, providing a high step
economy. Mechanistic studies reveal that the combination of
sodium sulfinate and TMSN3 play a vital role in the generation
of sulfonyl radical and the reduction of carbon radicals. Further
efforts to develop an asymmetrical version of this novel
reductive radical-initiated 1,2-C migration are underway in our
laboratory.
Ph
Ts
DMSO:H2O = 2:1
50 oC, 48h
Ph
2a
, (6 eq)
3ba
, 41%
N3
MeO
TMSN3, (4 eq)
TolSO2Na
+
(6)
NC
Ts
DMSO:H2O = 2:1
50 oC, 48h
5
, 51%
M3
2a
, (6 eq)
Scheme 1 | Mechanistic investigations
N3
O
Ph
+
TolSO2Na
TMSN3
NaN3
+
Ph
Ts
HO
Ph
3ba
Ph
1ba
TMS Ts
I
O
S
NH2
O
N3
TMSOH
or
TMS
Ts
TMS2O
Conflicts of interest
Tol
S
There are no conflicts to declare.
O
S
N3
O
O
O
O
Tol
N3
S
O
Tol
V
Ts
N3
Acknowledgements
N3
N3
Ph
HO
Ts
Ph
HO
Ts
Ph
O
Ts
1,3-H Shift
SET
The authors thanks the National Natural Science Foundation of
China (Grant #. 21604082), Department of Science and Technology
of Jilin Province (Grant #.s 20190201076JC and 20190701012GH),
and the Fundamental Research Funds for the Central Universities
(Grant #. 2412019FZ006).
Ph
Ph
II
Ph
IV
III
TolSO2
Figure 2 | Proposed mechanism.
Based on the above experimental results and relevant
literature, a possible reaction pathway was proposed as shown
in Figure 2. First, TolSO2TMS (I) is generated by the anion
4 | J. Name., 2012, 00, 1-3
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9752-9755. (f) E. E. Touney, N. J. Foy, S. V. Pronin, J. Am.
Notes and references
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Chem. Soc. 2018, 140, 16982-16987.
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DOI: 10.1039/D0SC02559C
Table of Contents Entry
O
N3
RSO2Na + TMSN3
HO
R1
SO2R
DMSO:H2O = 2:1, 50 o
C
R1 RM
RM
Reductive radical-initiated
1,2-C migration
-
Ts
-N3
N3
N3
N3
HO
SO2R
HO
R1 RM
SO2R
O
R1 RM
SO2R
R1 RM
Transition metal-free
Suitable for the n+1 ring expansion of small to large rings
Broad scope of migrating groups: Alkyl, Alkenyl, and Aryl