Asymmetric radical cyclopropanation of alkenes with in situ-generated donor-substituted diazo reagents via Co(II)-based metalloradical catalysis

Article abstract of DOI:10.1021/jacs.6b11336

Donor-substituted diazo reagents, generated in situ from sulfonyl hydrazones in the presence of base, can serve as suitable radical precursors for Co(II)-based metalloradical catalysis (MRC). The cobalt(II) complex of D2-symmetric chiral porphyrin [Co(3,5-DuBu-Xu(2'-Naph)Phyrin)] is an efficient metalloradical catalyst that is capable of activating different N-arylsulfonyl hydrazones for asymmetric radical cyclopropanation of a broad range of alkenes, affording the corresponding cyclopropanes in high yields with effective control of both diastereo- and enantioselectivity. This Co(II)-based metalloradical system represents the first catalytic protocol that can effectively utilize donor-type diazo reagents for asymmetric olefin cyclopropanation.

Full text of DOI:10.1021/jacs.6b11336

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Communication
Asymmetric Radical Cyclopropanation of Alkenes with In Situ-Generated
Donor-Substituted Diazo Reagents via Co(II)-Based Metalloradical Catalysis
Yong Wang, Xin Wen, Xin Cui, Lukasz Wojtas, and Peter Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11336 • Publication Date (Web): 04 Jan 2017
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Asymmetric Radical Cyclopropanation of Alkenes with In
Situ-Generated Donor-Substituted Diazo Reagents via
Co(II)-Based Metalloradical Catalysis
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Yong Wang,§ Xin Wen,§ Xin Cui,† Lukasz Wojtas† and X. Peter Zhang*§†
§Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
†Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States
Supporting Information Placeholder
tive? Additional questions arose from the intrinsic instability of do-
nor-substituted diazomethanes, which are typically generated in
situ from stable sulfonyl hydrazone precursors.8 Would Co(II)-
MRC system be compatible with the basic conditions required for
the in-situ generation protocol? If these questions could be an-
swered positively, it would further expand the application of
Co(II)-based radical cyclopropanation for the catalytic synthesis of
enantioenriched 1,2-bisaryl and related cyclopropane compound 3.
ABSTRACT: Donor-substituted diazo reagents, generated in situ
from sulfonyl hydrazones in the presence of base, can serve as suit-
able radical precursors for Co(II)-based metalloradical catalysis
(MRC). The cobalt(II) complex of D2-symmetric chiral porphyrin
[Co(3,5-DitBu-Xu(2’-Naph)Phyrin)] is an efficient metalloradical
catalyst that is capable of activating different N-arylsulfonyl hydra-
zones for asymmetric radical cyclopropanation of a broad range of
alkenes, affording the corresponding cyclopropanes in high yields
with effective control of both diastereoselectivity and enantioselec-
tivity. This Co(II)-based metalloradical system represents the first
catalytic protocol that can effectively utilize donor-type diazo rea-
gents for asymmetric olefin cyclopropanation.
Scheme 1. Proposed Pathway for Asymmetric Radical Cy-
clopropanation with Donor-Substituted Diazo Reagents
There has been lasting interest in devising strategies to control
stereoselectivity, especially enantioselectivity, of radical reactions
for applications in organic synthesis.1 Among recent advances,1,2
metalloradical catalysis (MRC), which aims at the development of
metalloradical-based systems for both catalytic initiation and selec-
tive control of radical processes, has led to the discovery of new
catalytic pathways for stereoselective radical reactions.3,4 As stable
metalloradicals, cobalt(II) complexes of D2-symmetric chiral ami-
doporphyrins [Co(D2-Por*)] have emerged as effective catalysts
for asymmetric radical transformations through catalytic genera-
tion of metal-stabilized organic radicals, such as the fundamentally
new α-metalloalkyl radicals and α-metalloaminyl radicals, as the
key intermediates.5 To date, Co(II)-based metalloradical catalysis
(Co(II)-MRC) has exhibited capability of activating both acceptor-
and acceptor/acceptor-substituted diazo reagents to generate corre-
sponding α-Co(III)-alkyl radicals (also known as Co(III)-carbene
radicals) as key intermediates for various C-centered radical pro-
cesses, including radical cyclopropanation of alkenes.6,7 Studies
suggest that potential hydrogen-bonding interactions between car-
bonyl groups of these types of diazo reagents and the amide units
of the porphyrin ligands in the resulting α-Co(III)-alkyl radicals
play an important role in enhancing reactivity and controlling ste-
reoselectivity. It was unclear if Co(II)-MRC could also be applica-
ble to other types of diazo reagents that lack a carbonyl group, such
as donor-substituted diazo reagents. Specifically, we wondered
whether [Co(D2-Por*)] metalloradical catalysts were able to acti-
vate aryldiazomethanes to generate the corresponding α-Co(III)-
benzyl radical intermediate I (Scheme 1). In the absence of car-
bonyl functionalities, what element of interaction could be explored
for the effective control of enantioselectivity in the subsequent rad-
ical addition of the α-Co(III)-benzyl radical I to the olefin sub-
strate? Furthermore, would the final step, 3-exo-tet radical cycliza-
tion of the resulting g-Co(III)-alkyl radicals II, be diastereoselec-
Asymmetric olefin cyclopropanation with diazo reagents repre-
sents one of the most general methods for the construction of opti-
cally active three-membered carbocycles.9 While tremendous pro-
gress has been made with the use of several types of diazo reagents,
asymmetric cyclopropanation with donor-substituted diazo rea-
gents has been much less developed.10 As a novel alternative in-
volving the further transfer of the initially formed electrophilic Rh2-
carbenes into nucleophilic chiral sulfur ylides, Aggarwal and
coworkers developed an indirect approach for asymmetric cyclo-
propanation with sulfonyl hydrazones as diazo precursors using the
combination of dirhodium carboxylates and chiral sulfides as the
catalyst that works specifically for electron-deficient olefins.8c,10c
Nevertheless, it would be desirable to develop new catalytic sys-
tems that are capable of direct asymmetric cyclopropanation of di-
verse alkenes with donor-substituted diazo reagents.11 In view of
the radical pathway of MRC (Scheme 1), we hypothesized that the
radical cyclopropanation approach could potentially address the
aforementioned issues with donor-substituted diazo reagents be-
cause a neutral radical process is generally less sensitive to elec-
tronic effects. Herein, we wish to report the development of the first
asymmetric catalytic system that is highly effective for direct cy-
clopropanation of alkenes with α-aryl diazomethanes. Under mild
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conditions, the Co(II)-based metalloradical system is suitable for
(1b). Considering MeO group is known as good hydrogen bond ac-
ceptors,12 we postulated that the potential formation of N–H⋯O
hydrogen bond between the amido group of the chiral ligand and
the MeO group of tosylhydrazone 1b (Figure S1 in SI) might rigid-
ify the resulting intermediate I, leading to improved stereoselectiv-
ity. Indeed, the corresponding cyclopropane 3ba was obtained in
good yield (78%) with high diastereoselectivity (95:5 dr) and ex-
cellent enantioselectivity (99% ee) (entry 5; see Table S2 in SI for
detailed solvent effect). Conversely, asymmetric induction of the
cyclopropanation process was significantly reduced when the MeO
group in 1b was replaced by a sterically comparable Et group de-
spite the high reactivity (entry 6). Moreover, low enantioselectivity
was observed when the MeO group in 1b was moved from ortho-
to either meta- or para- positions of the phenyl ring although with
similarly high diastereoselectivity (entries 7 and 8). These results
seem support the hypothesized hydrogen-bonding interaction.
1
2
3
4
5
6
7
8
various alkenes, allowing for the efficient construction of cyclopro-
pane rings with excellent control of both diastereoselectivity and
enantioselectivity. The Co(II)-catalyzed cyclopropanation is fur-
ther highlighted by its functional group tolerance, a feature that is
closely related to the underlying radical mechanism.
Table 1. Asymmetric Cyclopropanation of Styrene with To-
sylhydrazones by Metalloradical Catalysts [Co(D2-Por*)]a
9
10
11
12
13
14
15
16
17
18
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22
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25
26
27
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Table 2. Asymmetric Cyclopropanation of Different Olefins
with Tosylhydrazone 1b Catalyzed by [Co(P3)]a
NHTs
R2
R1
[Co(P3)] (2 mol %)
N
H
+
Ar =
Cs2CO3; MeOH; 40 oC; 24 h
Ar
1R
R2
Ar
H
OMe
3bx
1b
2x
Ar
Ar
Ar
Ar
OMe
CF3
Br
Cl
3bb
entry 2: 88%
3bc
entry 3: 81%
dr: 96:4, ee: 93%
3bd
3ba
entry 1b: 83%
dr: 95:5, ee: 99%
entry 4c: 85%
dr: 95:5, ee: 94%
dr: 94:6, ee: 94%
Br
Br
Ar
Ar
Ar
Ar
3be
3bf
3bh
entry 8: 90%
3bg
entry 7d: 61%
entry 5: 85%
dr: 94:6, ee: 94%
entry 6: 89%
dr: 95:5, ee: 96%
dr: 83:17, ee: 93%
dr: 90:10, ee: 96%
Br
NH2
Ar
Ar
Ar
Ar
3bj
3bk
3bi
entry 9: 42%
dr: 83:17, ee: 92%
3bl
entry 10: 71%
dr: 75:25, ee: 95%
entry 11: 69%
dr: 92:8, ee: 97%
entry 12: 68%
dr: 93:7, ee: 99%
a Carried out with 1x (0.1 mmol) and 2a (1.5 equiv.) in the presence of Cs2CO3
d
b
c
1
NH2
nPr
Ar
(2 equiv.) in methanol (0.6 mL). Isolated yields. Determined by H NMR.
Ar
Ar
Ar
Ph
Ar
O
Determined by chiral HPLC for the major trans diastereomer.
O
O
3bq
3bp
entry 16: 41%
3bm
entry 13: 77%
3bo
3bn
entry 17e: 42%
entry 15: 49%
entry 14: 50%
dr: 71:29, ee: 77% dr: 75:25, ee: 82%
dr: 81:19, ee: 81%
dr: 83:17, ee: 91%
dr: 78:22, ee: 89%
Our study began with cyclopropanation of styrene (2a) with ben-
zaldehyde tosylhydrazone (1a), which is known to generate α-phe-
nyldiazomethane under basic conditions (Table 1). Even simple
a Carried out with 1b (0.1 mmol) and 2x (1.5 equiv.) in the presence of Cs2CO3
(2 equiv.) in methanol (0.6 mL); isolated yields; dr was determined by 1H NMR;
ee of the major trans diastereomer was determined by chiral HPLC. b Performed
metalloradical catalyst [Co(TPP)] (TPP
= 5,10,15,20-tetra-
c
on 1.0 mmol scale. Absolute configuration was determined by X-ray as (1S,
2S). d 5 mol % [Co(P3)]. e 5.0 equiv. 2q.
phenylporphyrin) could catalyze the reaction in the presence of
Cs2CO3 in methanol, forming the desired 1,2-diphenyl cyclopro-
pane 3aa in 46% yield (entry 1). This result signifies the compati-
bility of Co(II)-based metalloradical system with the use of both
bases and polar solvents. The stereoselectivity of the reaction was
then evaluated by using Co(II) complexes of D2-symmetric chiral
amidoporphyrins [Co(D2-Por*)]. When the first-generation catalyst
[Co(P1)] (P1 = 3,5-DitBu-ChenPhyrin) was used,6f 3aa could form
in higher yield with significant level of both enantioselectivity and
diastereoselectivity (entry 2). To further improve the catalytic re-
action, we then turned our attention to the second-generation
Co(II)-based metalloradical catalysts.6b While the phenyl-substi-
tuted [Co(P2)] (P2 = 3,5-DitBu-QingPhyrin) was less selective, the
Under the optimized conditions, the scope of [Co(P3)]/1b-based
catalytic system was then evaluated by employing different alkenes
(Table 2). Like styrene, its derivatives bearing substituents with dif-
ferent electronic properties, including electron-donating MeO and
electron-withdrawing CF3 groups, could be cyclopropanated in
high yields with excellent diastereoselectivity and enantioselectiv-
ity (entries 1–3). Halogenated styrenes such as those with a Br atom
at various positions were also shown to be suitable substrates for
the catalytic process (entries 4–6). The relative and absolute con-
figurations of cyclopropane 3bd (entry 4) were established as trans
and (1S,2S), respectively (see Figure S2 in SI). As demonstrated for
2-bromostyrene (2f) together with 2,4,6-trimethylstyrene (2g), ste-
rically hindered styrene derivatives could also undergo productive
cyclopropanation (entries 6 and 7). Furthermore, this system was
also applicable for 1,1-disubstituted olefins as demonstrated with
a-substituted styrene derivatives 2h, 2i and 2j, affording the de-
sired cyclopropanes with enantioselective control of the newly-
formed quaternary stereogenic centers, albeit with moderate dia-
stereoselectivity (entries 8–10). Distinctly, the Co(II)-based radical
process could tolerate functional groups as exemplified by the
highly enantioselective cyclopropanation of 3-aminostyrene (entry
11). In addition to the expanded aromatic olefins such as 2-vi-
nylnaphthalene (entry 12), conjugated dienes, including both aro-
matic diene 2m and aliphatic diene 2n, could also be employed as
naphthyl-substituted [Co(P3)] (P3
=
3,5-DitBu-Xu(2’-
Naph)Phyrin)) could effectively catalyze the formation of 3aa with
excellent diastereoselectivity but lower enantioselectivity (entry 4).
It should be noted that comparable reactivity was observed with the
use of preformed α-phenyldiazomethane (see Table S1 in SI). The
ineffective asymmetric induction is likely attributed to the low-bar-
rier rotation of the α-benzyl radical unit around the Co(III)–C σ
bond in intermediate I (Scheme 1) that diminishes its approaching
preference to the prochiral styrene substrate between the re and si
faces. To restrict the rotation, we decided to use benzaldehyde to-
sylhydrazone derivative that contains an ortho-methoxy group
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substrates but with relatively lower stereoselectivities (entries 13
5). Likewise, the reactions with related (2,4,6-triiso-
1
2
3
4
5
6
7
8
and 14). It was notable that both electron-rich and -deficient non-
aromatic olefins, such as vinyl ether 2o, acrylamide 2p and vinyl
ketone 2q could be enantioselectively cyclopropanated as well (en-
tries 15–17) with moderate control of stereoselectivities. The ob-
served substrate scope and reactivity profile of [Co(P3)]-catalyzed
cyclopropanation is in agreement with the underlying radical mech-
anism (Scheme 1). It was also noteworthy to mention that the one-
pot protocol of the Co(II)-catalyzed cyclopropanation could be
scaled up ten-fold as demonstrated with the high-yielding synthesis
of cyclopropane 3ba on 1.0 mmol scale without affecting the ex-
cellent stereoselectivity (entry 1).
propylphenyl)sulfonyl hydrazones 1h’–1j’ could also be produc-
tively conducted at 0 oC, affording the cyclopropanes 3ha–3ja with
significantly improved diastereoselectivity and enantioselectivity
(entries 7, 9 and 11). Under the same conditions, while o-Cl-ben-
zaldehyde-derived sulfonylhydrazone gave a similar result to o-F-
benzaldehyde-derived sulfonylhydrazone, o-Br- and o-I-benzalde-
hyde-derived sulfonylhydrazones proved to be less effective radi-
cal precursors for the catalytic process (see Scheme S1 in SI).
Scheme 2. Cyclopropanation of (E)- and (Z)-β-Deuterosty-
9
renes to Probe Radical Reaction Mechanism
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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35
36
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40
41
42
43
44
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46
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48
49
50
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52
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57
58
59
60
NHTs
H
D
D
H
N
[Co(D2-Por)] (2 mol %)
H
H
D
H
H
Table 3. Asymmetric Cyclopropanation of Styrene with
+
+
Ph
Various Sulfonyl Hydrazones Catalyzed by [Co(P3)]a
Ph
Ar
H
Cs2CO3; MeOH; RT
24 h
Ar
Ar
Ph
1g
NHR
trans-3ga
trans-3ga
N
β-D-2a
[Co(P3)] (2 mol %)
Ar = 2,6-F2C6H3
A
B
+
Ph
Ar
drd
trans-3ga
/ cis-3ga
trans-3ga
A / B
Ar
H
Cs2CO3; MeOH; temp.; 24 h
Ph
[Co(D2-Por)]
β-D-2a
1x
2a
3xa
O
O
temp.
(oC)
yield
(%)c
ee
(%)e
N H
H N
entry
1
Ar
Rb
product
[Co(P3)]
[Co(P3)]
[Co(P4)]
[Co(P4)]
E
Z
E
Z
94 / 06
94 / 06
67 / 33
67 / 33
93 / 07
07 / 93
80 / 20
20 / 80
N
Co
N
N
N
H N
N H
O
3ba
Ts (1b)
O
40
40
78
95:5
95:5
99
94
OMe
OMe
[Co(P4)]
MeO
1f
3fa
Ts (
)
2
91
To probe the underlying stepwise radical mechanism of the
Co(II)-catalyzed cyclopropanation, both (E)- and (Z)-β-deuterosty-
renes were employed as substrates (Scheme 2). While a concerted
mechanism is usually stereospecific, a stepwise radical mechanism
(Scheme 1) would result in the formation of four possible diastere-
omers from either (E)- or (Z)-β-deuterostyrene: two trans-isoto-
pomers A & B and two cis-isotopomers C & D due to the rotation
of β-C–C bond in the g-Co(III)-alkyl radical intermediate II before
ring closure (Schemes S2 and S3 in SI). Using catalyst [Co(P3)],
cyclopropanation of (E)-β-deuterostyrene with tosylhydrazone 1g
gave trans-3ga as the dominant product with a 93:7 ratio of isoto-
pomers A and B. Under the same conditions, the reaction of (Z)-β-
deuterostyrene resulted in the identical 93:7 ratio of isotopomeric
distribution but in favoring B over A. The observation of trans-
isotopomer B from (E)-β-deuterostyrene as well as trans-isoto-
pomer A from (Z)-β-deuterostyrene is evidently a result of the ro-
tation of β-C–C bond in intermediate II. When sterically less-hin-
dered [Co(P4)] (P4 = 3,5-DitBu-IbuPhyrin) was used as the cata-
lyst,15 a significantly different isotopomeric ratio of trans-isoto-
pomers A & B (from 93:7 to 80:20) was observed, suggesting eas-
ier rotation of the β-C–C bond in a less-crowded ligand environ-
ment (Schemes S4 and S5 in SI). Together, these observations con-
vincingly support the proposed stepwise radical mechanism of the
Co(II)-based cyclopropanation with N-arylsulfonyl hydrazones.
Furthermore experiments were performed for direct detection of
the α-Co(III)-benzyl radical species I (Scheme 1) by high-resolu-
tion mass spectrometry (HRMS).16 The exposure of [Co(P4)] to 1g
(10 equiv.) with base in methanol resulted in a mixture that was
filtrated and analyzed by HRMS in the absence of any additives
such as formic acids that commonly act as electron carriers for ESI
ionization. As shown in Scheme S6 in SI, the obtained spectrum
F
1g
1g
3
4
5
Ts (
)
)
3ga
3ga
3g'a
RT
0
90
<10
83
94:6
-
86
-
Ts (
1g'
TPS (
F
F
)
)
0
>99:1
93
1h
Ts (
3ha
6
7
)
RT
0
58
75
96:4
71
76
1h'
TPS (
3h'a
>99:1
F
3ia
1i
8
9
Ts (
)
RT
0
85
85
96:4
88
93
3i'a
1i'
TPS (
)
>99:1
F
F
F
F
F
F
1j
3ja
10
11
Ts (
)
RT
0
82
81
95:5
68
89
1j'
3j'a
TPS (
)
>99:1
F
a Carried out with 1x (0.1 mmol) and 2a (1.5 equiv.) in the presence of Cs2CO3
b
(2 equiv.) in methanol (0.6 mL). Ts = 4-toluenesulfonyl; TPS = (2,4,6-triiso-
c
d
e
propyl)phenyl sulfonyl. Isolated yields. Determined by 1H NMR. Deter-
mined by chiral HPLC for the major trans diastereomer.
Guided by the postulated hydrogen-bonding interaction in the
key intermediates I, we then sought to identify other benzaldehyde
sulfonylhydrazone derivatives as effective radical precursors for
asymmetric cyclopropanation (Table 3). Like arylhydrazone 1b
(entry 1), 2,5-dimethoxybenzaldehyde-derived tosylhydrazone (1f)
could be also effectively activated by [Co(P3)] for cyclopropana-
tion of styrene, affording cyclopropane 3fa in 91% yield with 90%
de and 94% ee (entry 2). Considering that fluorine atoms in organic
fluorides have been demonstrated as a potential hydrogen bond ac-
ceptor,13 we explored the use of fluorine-containing arylhydrazones
as diazo precursors. Remarkably, fluoroarene-based tosylhydra-
zones such as 1g–1j were found to be even more active than 1b,
enabling the catalytic process even at room temperature (entries 3,
6, 8 and 10). The desired fluorine-containing bisaryl cyclopropanes
3ga–3ja were obtained in up to 90% yield with 88–92% de and 68–
88% ee. Attempts to further improve enantioselectivity with 1g at
lower temperature were unsuccessful due to ineffective generation
of 2,6-difluorophenyl diazomethane at 0 oC (entry 4). Since the de-
composition of the sterically bulky (2,4,6-triisopropylphenyl)sul-
fonyl hydrazone salt was shown to be considerably faster than to-
sylhydrazone salt,14 the low temperature asymmetric cyclopropa-
nation was reexamined with the use of 2,6-difluorobenzaldehyde-
derived (2,4,6-triisopropylphenyl)sulfonyl hydrazone 1g’. As ex-
pected, the reaction could proceed effectively at 0 oC, affording 3ga
in 83% yield with considerably enhanced stereoselectivities (entry
clearly revealed
a
signal corresponding to [Co(P4)(2,6-
F2C6H3CH)]+ (m/z = 1361.6515), which resulted from the neutral
α-Co(III)-benzyl radical I by the loss of one electron.
In summary, Co(II)-based metalloradical catalysis (MRC) has,
for the first time, been successfully applied to donor-substituted di-
azo reagents, generated from N-arylsulfonyl hydrazones in the
presence of base, for olefin cyclopropanation. Chiral metalloradical
complex [Co(P3)] has been shown to be an effective catalyst for
asymmetric radical cyclopropanation with α-aryldiazomethane pre-
cursors. The Co(II)-based cyclopropanation is applicable to a broad
combination of N-arylsulfonyl hydrazones and alkenes, affording
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X.; de Mesa, S. L.; Wojtas, L.; Zhang, X. P. J. Am. Chem. Soc. 2011, 133,
the cyclopropane derivatives in high yields with excellent diastere-
oselectivity and enantioselectivity. In view of the underdevelop-
ment of donor-substituted diazo reagents in asymmetric cyclopro-
panation, the successful development of this catalytic radical pro-
cess will encourage further efforts in applying sulfonyl hydrazones
as stable precursors for various asymmetric catalytic processes.
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ASSOCIATED CONTENT
Supporting Information
Experimental details and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.”
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AUTHOR INFORMATION
Corresponding Author
* peter.zhang@bc.edu
ACKNOWLEDGMENT
We are grateful for financial support by NIH (R01-GM102554).
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NHSO2R
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[Co(P3)]
(2 mol %)
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up to 91% yield
up to 99:1 dr
up to 99% ee
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Donor-Type Diazo
Precursors
α-Co(III)-Benzyl Radical
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