Metal-free intermolecular cyclopropanation between alkenes and iodonium ylides mediated by PhI(OAc)2·Bu4NI

Article abstract of DOI:10.1039/c7cc04859a

A rapid, mild and metal-free intermolecular cyclopropanation between iodonium ylides and alkene-containing substrates mediated by PhI(OAc)₂·Bu₄NI is reported. Iodonium ylides of cyclic and acyclic 1,3-dicarbonyls were reacted with a variety of mono-, di-, tri- and tetra-substituted alkenes of various structural types to give 29 cyclopropanes in up to 97% yield.

Full text of DOI:10.1039/c7cc04859a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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DOI: 10.1039/C7CC04859A
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Metal-Free Intermolecular Cyclopropanation Between Alkenes
and Iodonium Ylides Mediated by PhI(OAc)2•Bu4NI
Jason Tao,a Carl D. Estradaa and Graham K. Murphya
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A rapid, mild and metal-free intermolecular cyclopropanation
between iodonium ylides and alkene-containing substrates
mediated by PhI(OAc)2•Bu4NI is reported. Iodonium ylides of cyclic
and acyclic 1,3-dicarbonyls were reacted with a variety of mono-,
di-, tri- and tetra-substituted alkenes of various structural types to
give 29 cyclopropanes in up to 97% yield.
a) intramolecular:
O
O
O
O
CH2Cl2
rt
Moriarty
6 examples
55% to 95% yield
OMe
OMe
IPh
tBuO2C
b) intermolecular:
Synthetic applications of hypervalent iodine (HVI) compounds
have undergone tremendous growth in the last few decades,
with their rise in popularity stemming from their broad reactiv-
ity, their ease of handling, and their ready accessibility.1 HVI
compounds have attracted much attention because their reac-
tivity is reminiscent of toxic and costly transition metals, but
they are much less toxic and the aryl iodide reaction by-prod-
ucts are considered to be environmentally benign. Iodonium
ylides are commonly employed as reagents2 or synthetic inter-
mediates3 that undergo rearrangements, cycloadditions, and
reactions with nucleophiles or electrophiles.4 In addition, an io-
donium ylide’s ability to generate free carbene or metallocarbe-
noid intermediates through thermal, photochemical, or metal-
catalyzed decomposition has led to the discovery of trifluoro-
methylthiolation or difluoromethylthiolation,5 C-H insertion,6
ylide formation,7 and cyclopropanation8 reactions, where they
serve as surrogates for diazo compounds.3b, 3c, 4, 6, 8-9
tBuO2C
O
CO2Et
CO2Et
O
O
N
Boc
MeO
O
OMe
O
CH2Cl2/Et2O
rt, 24 h
Feng
IPh
N
40% yield
Boc
Ph
CHO
O
IPh
CHO
Mayr
up to 72% yield
up to 70:30 er
O
Ph
O
chiral iminium (cat.)
rt, 24 h
PhICl2 (1.1 equiv)
styrene (5.0 equiv)
O
O
O
O
Ph
1a
OMe
Ph
2a
OMe
CH3CN, 0 °C
5 min
Murphy
46% NMR yield
8.6 : 1 trans:cis
IPh
Ph
Scheme 1 Metal-free cyclopropanations of iodonium ylides.
free, HVI-promoted intermolecular cyclopropanation of alkenes
by iodonium ylides offers a direct, convergent means for their
synthesis.15 To gain more insight into this novel reactivity be-
tween iodonium ylides and aryl-l3-iodanes, we decided to fur-
ther investigate this reaction.
Iodonium ylides also provide carbenoid-type reactivity under
metal-free conditions, such as the intramolecular cyclopropana-
tion of phenyliodonium ylides with alkenes (Scheme 1, a).10 In-
termolecular variants consist of the thermal reaction between
a malonate-derived phenyliodonium ylide and a 3-alkylidene-2-
oxidole,11 or the cyclopropanation using chiral iminium catalysis
reported by Mayr (Scheme 1, b).12 Recently we also reported an
intermolecular cyclopropanation, observed upon addition of
Optimizing the cyclopropanation of 1a using PhICl2 or other (di-
chloroiodo)arenes failed due to the competing dichlorination
reaction. 16 We next screened several related iodanes that were
less likely to transfer their ligands to the ylides. Koser’s reagent,
TolIF2, PhI(OAc)2 and PhI(OTFA)2 were unsuccessful, but we
eventually discovered PhI(OAc)2•
Bu4NI17 to be effective, gener-
styrene to a gem-dichlorination reaction of ylide 1a 13,14
Donor-
.
ating 2a in modest 30% yield (eq 1).
acceptor cyclopropanes that can be furnished by these reac-
tions are of great synthetic value, and the potential for a metal-
5 equiv styrene
1 equiv PhI(OAc)2
O
O
O
O
(1)
Ph
OMe
Ph
Ph
OMe
0.3 equiv Bu4NI
CD3CN, rt, 30 min
IPh
1a
2a
30% yield (NMR)
2:1 trans:cis
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Further optimization was unsuccessful, however, we believed
these conditions would be tolerant to a larger alkene scope than
PhICl2. To minimize the potential for competing processes (i.e.,
dimerization or oxidation), a large excess of styrene (5 equiv)
View Article Online
Ar
Ar
DOI: 10.1039/C7CC04859A
IPh
2 equiv
Ar
O
O
O
O
O
O
1 equiv PhI(OAc)2
0.3 equiv Bu4NI
CH3CN, rt, 2 h
and/
or
1i
2
3
was used to test phenyliodonium ylides
in the cyclopropanation reaction (Scheme 2). Ylides of benzoyl
acetate esters gave cyclopropanes 2a 2d in low yield, and the
1 and PhI(OAc)2•Bu4NI
Ar
Ar
O
O
O
-
O
ylides of acetoacetate (1e) and malonate (1f) gave cyclopro-
panes 2e and 2f in moderate 56% and 52% yield. The ylide of
acetylacetone (1g) failed, but the ylides of cyclic 1,3-diketones
fared better, generating cyclopropanes 2h and 2i in 58% and
89% (75% isolated) yield. Increasing the scale for the cyclopro-
panation of 1i five-fold resulted in a higher isolated yield
(82%)of 2i. Finally, the ylides of Meldrum’s acid (1j) and N,N-
dimethylbarbituric acid (1k) reacted poorly, failing to give cyclo-
propane 2j, and giving 2k in only 20% yield.
2i, Ar=Ph, 55% yield
2l, Ar=C6F5, 0% yield
2m, Ar=m-NO2-Ph, 60% yield
2n, Ar=p-Cl-Ph, 64% yield
2o, Ar=p-tolyl, 44% yield
3p, Ar=p-tBu-Ph, 57% yield
3q, Ar=3,4-diOMe-Ph, 82% yield
3r, Ar=p-anisyl, 93% yield
Scheme 3 Styrene scope for cyclopropanations.a
aGeneral Conditions: 1i (0.2 or 0.3 mmol, 1.0 equiv), styrene (2.0 equiv), PhI(OAc)2
(1.0 equiv), Bu4NI (0.3 equiv) in 0.1M CH3CN at rt for 2 h under N2. Isolated yields.
We next investigated the cyclopropanation of poly-substituted
alkenes (Scheme 4). Optimization with iodonium ylide 1f per-
5 equiv styrene
1 equiv PhI(OAc)2
O
O
O
O
mitted us to decrease the loading of alkene
4 to 1 equiv, elimi-
R
R'
nating the need for excess alkene. Under these conditions, the
reaction proceeded with 4a to give 5a in 71% yield (see Scheme
1, b).11 Other electron poor N-substituents (-CBZ (4b), -Ac (4c) -
Ts (4d)) also resulted in good to excellent yields of cyclopro-
R
R'
0.3 equiv Bu4NI
CH3CN, rt, 1-2 h
IPh
Ph
1
2
O
O
O
O
O
O
O
O
Ph
Ph
OMe Ph
Ph
OiPr Ph
OBn Ph
Ph
O
Ph
panes 5b-d. The N-Me and N-Bn derivatives 5e
in good yield, as was N-allyl substrate (5g, 59%). Changing the
alkene substituent from CO2Me to Bz was well tolerated (5h
,f were recovered
Ph
Ph
2b
2c
29% yield
4:1 dr
2a
2d
25% (42%)c yield
2 :1 dr
30% yieldb
2:1 dr
17% yield
5:1 dr
,
83%), however substitution with an electronically neutral phe-
nyl group was not (5i, 28%). The yield for a disubstituted alkyli-
dene was moderate (5j, 50%), as was the yield for tetra-substit-
O
O
O
O
O
O
Me
OMe MeO
Ph
OMe Me
Ph
Me
Ph
2e
2f
2g
<5% yield
56% yield
0.7:1 dr
52% yield
1 equiv alkene
MeO2C CO2Me
MeO2C
CO2Me
IPh
R2
R3
1 equiv PhI(OAc)2
0.3 equiv Bu4NI
CH3CN
Ph
O
R
Ph
Ph
1f
Ph
O
R1
5a-q
1 equiv
O
O
O
O
O
O
N
N
O
O
O
5a R=Boc 71% yield
5b R=CBZ 79% yield
5c R=Ac 92% yieldb
5d R=Ts 97% yield
5e R=Me 62% yield
5f R=Bn 75% yield
5g R=allyl 59% yield
O
EtO
Ph
O
CO2Me
CO2Me
CO2Me
CO2Me
2h
58% yield
2i
89% (75%)c[82%]d
2j
<5% yield
2k
20% yield
O
O
Scheme 2 Ylide (
aGeneral:
1
) scope for cyclopropanation of styrenea
N
N
5a-g
Ph
R
Ac
5h
83% yield
1
(0.1 mmol, 1.0 equiv), styrene (5.0 equiv), PhI(OAc)2 (1.0 equiv), Bu4NI
(0.3 equiv), in CH3CN (1 mL) at rt for 1 h (for acyclic 1,3-dicarbonyls) or 2 h (for
cyclic 1,3-dicarbonyls) under N2. 1H NMR yields, unless otherwise stated. b CD3CN
used as solvent. c0.3 mmol of 1d or 0.2 mmol of 1i used; isolated yield. dReaction
performed at 5x scale, using 1.0 mmol of 3i; isolated yield.
CO2Me
CO2Me
CN
CO2Me
CO2Me
CO2Me
CO2Me
NC
O
N
O
N
N
We used iodonium ylide 1i to explore the scope of styrenes and
discovered that both cyclopropane (2) and/or dihydrofuran (3)
5i
28% yield
5jc
Me
Ac
5k
Ac
51% yield
50% yield
O
O
products were possible (Scheme 3). Decreasing the styrene
loading from 5 equiv to 2 equiv resulted in a decrease from 75%
to 55% yield of 2i. Cyclopropanations on styrenes bearing m-
NO2 (2m) or p-Cl (2n) groups occurred in 60% and 64% yields,
but cyclopropanation with the extremely electron-deficient
pentafluorostyrene (2l) failed. The moderately electron-rich p-
methylstyrene gave 2o in 44% yield, whereas p-(tert-butyl)sty-
O
CN
CN
EtO
EtO
CO2Me
CO2Me
CO2Me
CO2Me
O
F
CO2Me
CO2Me
O
O
5n
35% yield
N
O
5m
83% yield
5l
Ac
96% yield
O
O
O
O
CO2Me
CO2Me
OTs
CO2Me
CO2Me
CO2Me
Ph
N
rene gave a mixture of cyclopropane 2p and dihydrofuran 3p
.
CO2Me
O
Ph
O
O
Complete isomerization occurred upon standing overnight,
from which 3p was recovered in 57% yield.18 More electron rich
p-OMe and 3,4-diOMe styrenes furnished the dihydrofuran
O
5o
74% yield
5p
79% yield
5q
27% yield
Scheme 4 Intermolecular cyclopropanation of heterocycle-derived poly-substi-
tuted alkenes.a
aGeneral Conditions: 1f (0.3 mmol, 1.0 equiv), alkene (1.0 equiv), PhI(OAc)2
(1.0 equiv), Bu4NI (0.3 equiv), in CH3CN (0.1 M) at rt for 1 h under N2. Isolated
yields. Major diasteromer shown. b2 equiv of 4c. cTwo-step yield.
products 3q,r directly, in excellent yield. The stilbenes, E-methyl
cinnamate and a- or b-methylstyrene all failed to produce any
cyclopropanes in quantities observable by 1H NMR.
2 | J. Name., 2012, 00, 1-3
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uted alkene 4k, which gave the fully-substituted cyclorpopane zoquinone only partially inhibited the formation of 2i (entry 8,
View Article Online
DOI: 10.1039/C7CC04859A
5k in 51% yield. As expected, substitution at C5 of the oxindole 42% yield), while BHT and TEMPO completely suppressed the
was not problematic (5l, 96%), and the related 3-alkylidene-2- reaction (entries 9,10). In the absence of ambient light, cyclo-
benzofuranone scaffold gave 5m in 83% yield. Alkylidene-1,1- propanations were equally viable using PhI(OAc)2 with either
dicarbonyls derived from ninhydrin (4n) and Meldrum’s acid Bu4NI or Bu4NI3 (entries 11,12), indicating that radicals are pos-
(
(
4o), and enediones derived from lawsone (4p) and maleimide sible intermediates in this metal-free cyclopropanation, how-
4q) generated 5n
-
q
in varying yields. Thus, this reaction offers ever, they are unlikely to be photogenerated.22
an efficient strategy for the synthesis of poly-functionalized, spi-
rocyclic donor-acceptor cyclopropanes.
Table 2. Control experiments probing iodine and additives.a
Ph
O
We investigated the roles of PhI(OAc)2 and Bu4NI in the reac-
tion, and found that both were essential (Table 1, entries 1-3).
N-methylpyridinium iodide (NMPI) or KI and could be used in
place of Bu4NI, resulting in a decreased yield (82% and 50%, re-
spectively) of 2i (entries 4,5), but the iodide could not be re-
placed with Bu4NBr or Bu4NCl (entries 6,7). When only 10 mol%
PhI(OAc)2 was used, the reaction gave 2i in 71% yield (entry 8),
suggesting it to either be a catalyst19 or an initiator.20
IPh
PhI(OAc)2
"iodine", additive
O
O
O
5 equiv styrene
CH3CN, rt, 2 h
1i
2i
PhI(OAc)2
(equiv)
0
“iodine”
(0.3 equiv)
NBu4I
additive
(equiv)
yield
(%)
27
entry
1
2
3
4
5
6
7
8
Oxone® (1.0)
None
To gain further insight into the role of the PhI(OAc)2•Bu4NI rea-
gent combination, we performed a series of control experi-
ments (Table 2). Since HVI reagents are oxidizers, it is plausible
that the reaction initiates once PhI(OAc)2 oxidizes the iodide in
situ to an electrophilic “I+” species such as AcOI.20 To test this
hypothesis, we attempted the cyclopropanation of 1i using
Bu4NI and Oxone®, but only 27% yield 2i was observed (entry 1).
Substituting Bu4NI for I2, in which iodine is present in a higher
oxidation state, gave 2i in 55% yield, but I2 alone gave dihydro-
furan (3i) in 44% yield (entries 2,3). The anionic iodate
Bu4N[I(OAc)2] is a reported adduct of PhI(OAc)2 + Bu4NI,17 and
we found that 0.3 equiv of this iodate, either with or without
PhI(OAc)2, generate 2i in 86% and 55% yield (entries 4,5). Simi-
lar results were found when using Bu4NI3 (entries 6,7), suggest-
ing that if anionic iodates are participating in the reaction, the
role PhI(OAc)2 may not be limited to only oxidizing I– to
[I(AcO)2]–. As photoexcitation of I3– by visible light can generate
1.0
0
0
1.0
0
1.0
1.0
1.0
1.0
1.0
1.0
I2
I2
55
None
None
None
None
44b
55
Bu4N[I(OAc)2]
Bu4N[I(OAc)2]
Bu4NI3
86
77
88
42
Bu4NI3
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI3
None
PBQc (1.0)
BHTd (1.0)
TEMPOe (1.0)
None
9
<5
10
11
12
<5
80f
80f
None
aGeneral conditions: 1i (0.1 mmol, 1.0 equiv), styrene (5 equiv), CH3CN (1 mL); 1H
NMR yields. bYield of dihydrofuran 3i. cp-benzoquinone. d2,6-di-tert-butyl-4-
methylphenol. e2,2,6,6-tetramethylpyrrolidine-N-oxide. fReactions were per-
formed in the dark.
Guided by the control experiments in Tables 1 and 2, we offer
the following radical-mediated reaction mechanism (Scheme
4).23 As both PhI(OAc)2 and Bu4NI are required (Table 1, entries
2,3), and since the reaction works equally well with [I(OAc)2]– or
– *
–
21
•
a diiodine radical anion and atomic iodine ([I3 ]
→
I2 + I•),
we added radical scavengers to the reactions of 1i . Using p-ben-
Table 1. Investigating effect of iodide and PhI(OAc)2 on cyclopropanation of 1i.a
–
I3 , we propose that such iodates are acting as redox mediators.
Upon its formation (Figure 1, inset), [I(OAc)2]– might transfer an
Ph
IPh
PhI(OAc)2
additive
O
O
electron to the ylide (1i), generating a carbonyl-stabilized radi-
O
O
cal anion (
stabilized radical (
to regenerate the iodate and give biradical
nation would lead to iodocycle , which could undergo reduc-
tive elimination to give cyclopropane 2i. Oxidation of to may
A
) that styrene can intercept. The resulting benzylic
) could undergo a single electron oxidation
. Radical recombi-
5 equiv styrene
CH3CN, rt, 2 h
B
1i
2i
C
E
PhI(OAc)2
additive
(equiv)
B
C
entry
(equiv)
yield (%)b
1
2
3
4
5
6
7
8
1
1
0
1
1
1
1
0.1
Bu4NI (0.3)
None
Bu4NI (0.3)
KI (0.3)
89
<5
<5
82
50
<5
<5
71
Ph
Ph
Ph
Ph
I
I
I
[I(OAc)2]
[I(OAc)2]•
Ph
O
O
O
O
O
O
[I(OAc)2]•
1i
A
B
NMPI (0.3)b
Bu4NBr (0.3)
Bu4NCl (0.3)
Bu4NI (0.3)
PhI(OAc)2 + Bu4NI
O
Bu4N[I(OAc)2] + PhI
[I(OAc)2]
Ph
Ph
O
Ph
O
I
Ph
O
I
Ph
O
O
aGeneral conditions: 1i (0.1 mmol, 1.0 equiv), styrene (5 equiv), additive (30 mol%).
bYield was determined by 1H NMR analysis of the crude reaction mixture. bN-
methylpyridinium iodide
PhI
2i
E
C
Figure 1. Mechanistic proposal.
This journal is © The Royal Society of Chemistry 20xx
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and Y. Tang, Angew. Chem., Int. Ed. 2012, 51, 11620; (e) A. E.
Bosnidou, D. Kalpogiannaki, S. KaraneDstOoIr:a1,0.J1.0A3V9.ie/NCwi7xACratCisc0lea4On8nd5l9inLAe.
P. Hadjiarapoglou, J. Org. Chem. 2015, 80, 1279.
be facilitated by PhI(OAc)2, which explains the improved yields
observed when it is used with Bu4N[I(OAc)2] (Table 2, entry 4 vs.
5). To support this proposal, we are working to elucidate fur-
ther mechanistic details for this transformation.
10 R. M. Moriarty, S. Tyagi and M. Kinch, Tetrahedron 2010, 66
,
5801.
11 J. Guo, Y. Liu, X. Li, X. Liu, L. Lin and X. Feng, Chem. Sci. 2016,
7
, 2717.
In summary, we investigated the ylide and alkene scope of a re-
cently discovered metal-free, intermolecular cyclopropanation
reaction, which proceeded under very mild conditions with the
12 S. Chelli, K. Troshin, P. Mayer, S. Lakhdar, A. R. Ofial and H.
Mayr, J. Am. Chem. Soc. 2016, 138, 10304.
13 J. Tao, T. N. Tuck and G. K. Murphy, Synthesis 2016, 48, 772.
14 We observed the opposite diastereoselectivity (8.6:1
trans:cis) to that obtained using rhodium carbenoids (1:14
trans:cis). See D. Marcoux and A. B. Charette, Angew. Chem.,
Int. Ed. 2008, 47, 10155.
15 For a review of synthetic uses of cyclopropanes see (a) T. F.
Schneider, J. Kaschel and D. B. Werz, Angew. Chem., Int. Ed.
2014, 53, 5504. For recent examples of metal-free intermo-
lecular cyclopropanation see (b) Y.-N. Duan, Z. Zhang and C.
Zhang, Org. Lett. 2016, 18, 6176; (c) K. Usami, Y. Nagasawa, E.
Yamaguchi, N. Tada and A. Itoh, Org. Lett. 2016, 18, 8; (d) P.
Qian, B. Du, R. Song, X. Wu, H. Mei, J. Han and Y. Pan, J. Org.
Chem. 2016, 81, 6546.
16 We have found that when styrene is omitted from the
reaction conditions of Scheme 1d, dichlorination of the ylidic
carbon of 1a occurs within 5 minutes as well.
17 (a) G. Doleschall and G. Tóth, Tetrahedron 1980, 36, 1649; (b)
P. De Armas, J. I. Concepción, C. G. Francisco, R. Hernández, J.
A. Salazar and E. Suárez, J. Chem. Soc., Perkin Trans. 1 1989,
405; (c) A. Kirschning, C. Plumeier and L. Rose, Chem.
Commun., 1998, 33; (d) A. Kirschning, M. Jesberger and H.
Monenschein, Tetrahedron Lett., 1999, 40, 8999; (e) K. Muñiz,
PhI(OAc)2•NBu4I reagent mixture. Styrenes were moderately ef-
fective as alkenes, but poly-substituted 3-alkylidene-2-oxin-
doles, 3-alkylidene-2-benzofuranone and various other dicar-
bonyl alkenes found success in moderate to excellent yields.
Control experiments showed various iodine sources (NBu4I, I2,
Bu4NI3, Bu4N[(OAc)2I]) could be used in conjunction with
PhI(OAc)2 to provide cyclopropanation products. Mechanistic
investigations suggested that, though rare with iodonium
ylides, radical intermediates are likely participating. 24 The cur-
rent work has demonstrated hypervalent iodine reagents react-
ing via novel pathways, and has further shown iodonium ylides
are capable of cyclopropanating alkenes based on a variety of
carbon skeletons. Investigations of other metal-free intermolec-
ular cyclopropanations are underway, as well as mechanistic
studies which will help guide us towards more advanced syn-
thetic applications.
B. García, C. Martínez and A. Piccinelli, Chem. Eur. J., 2017, 23
1539.
,
Notes and references
1
For review see: (a) V. V. Zhdankin and P. J. Stang Chem. Rev.
2008, 108, 5299; (b) V. Zhdankin, Arkivoc 2009, 2009, 1; (c) A.
Yoshimura and V. V. Zhdankin, Chem. Rev. 2016, 116, 3328;
(d) T. Wirth, Hypervalent Iodine Chemistry: Modern
Developments in Organic Synthesis. Springer Berlin
Heidelberg: Berlin, 2003; (e) V. V. Zhdankin, Hypervalent
iodine chemistry: preparation, structure, and synthetic
applications of polyvalent iodine compounds, John Wiley &
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7CC04859A
TOC graphic and text:
A simple and highly effective synthesis of poly-substituted cyclopropanes was developed. This
metal-free intermolecular reaction between iodonium ylides and alkenes is mediated by
PhI(OAc)2 and Bu4NI.
O
O
O
O
alkene
R1
R3
R2
R5
R1
R2
PhI(OAc)2, Bu4NI
17-97% yield
IPh
R4
R6
29 examples
up to 97% yield
Metal free!