Hypoiodite-mediated cyclopropanation of alkenes

Article abstract of DOI:10.1002/chem.201402372

An efficient, transition metal-free procedure for the cyclopropanation of alkenes using malononitrile and the LiI-tBuOCl combination under mild reaction conditions is described. The reaction mechanism most likely involves tBuOI generated in situ from LiI and tBuOCl. The utility of this new methodology has been demonstrated by the synthesis of a potential HIV-1 RT inhibitor. An efficient, transition-metal-free procedure for the cyclopropanation of alkenes using malononitrile and the LiI/tBuOCl combination under mild reaction conditions is described. The reaction mechanism most likely involves tBuOI generated in situ from LiI and tBuOCl. The utility of this new methodology has been demonstrated by the synthesis of a potential HIV-1 RT inhibitor (see scheme).

Full text of DOI:10.1002/chem.201402372

DOI: 10.1002/chem.201402372
Communication
&
Cyclopropanation
Hypoiodite-Mediated Cyclopropanation of Alkenes
Akira Yoshimura,*[a] Steven R. Koski,[a] Brent J. Kastern,[a] Jonathan M. Fuchs,[a]
T. Nicholas Jones,[b] Roza Y. Yusubova,[c] Victor N. Nemykin,[a] and Viktor V. Zhdankin*[a]
the oxidative dimerization of aromatic amines.[5g,h] Several
other research groups reported reactions using catalytic
Abstract: An efficient, transition metal-free procedure for
amounts of hypoiodite species generated in situ from iodine
the cyclopropanation of alkenes using malononitrile and
source as a precatalyst.[6] Very recently, our group has reported
the LiI-tBuOCl combination under mild reaction conditions
metal-free catalytic reactions using hypoiodite species generat-
is described. The reaction mechanism most likely involves
ed in situ from iodine sources and common oxidants.[7]
tBuOI generated in situ from LiI and tBuOCl. The utility of
In the initial study we investigated the cyclopropanation of
this new methodology has been demonstrated by the
styrene 1a (1 equiv) with malononitrile (1.2 equiv) screening
synthesis of a potential HIV-1 RT inhibitor.
several oxidants in the presence of iodine sources under a vari-
ety of reaction conditions in dichloromethane (see Table 1; for
Cyclopropanation of alkenes is an important chemical transfor-
mation that leads to a cyclic system commonly found in natu-
Table 1. Optimization of cyclopropanation of styrene.[a]
ral products, bioactive molecules, and intermediates of medici-
nal compounds.[1] Among the known procedures of cyclopro-
panation, particularly important methods are based on the use
of organoiodine(III) compounds,[2,3] such as iodonium
ylides,[3a–c] alkynyl-,[3d,e] and alkenyliodonium salts.[3f] In several
procedures, iodonium ylides generated in situ from a b-dicar-
bonyl compound or malononitrile and a hypervalent iodine re-
agent (iodosylbenzene[3g,h] or (diacetoxyiodo)benzene[3k–l]),
have been utilized as primary carbenoid sources. Most of these
organoiodine(III)-mediated cyclopropanations are performed at
elevated temperature or require environmentally unsafe transi-
tion-metal salts or complexes as catalysts.
Entry
t [h]
Oxidant [(equiv)]
Iodine source [(equiv)]
3a [%][b]
1
2
3
4
5
6
7
8
24
24
24
24
24
24
24
24
24
24
24
24
12
12
tBuOCl (2)
tBuOCl (2)
tBuOCl (2)
tBuOCl (2)
tBuOCl (2)
tBuOCl (2)
tBuOCl (1.5)
TBHP (1.5)
H2O2 (1.5)
mCPBA (1.5)
oxone (1.5)
tBuOCl (1.2)
tBuOCl (1.2)
tBuOCl (1.5)
none
NaI (2)
LiI (2)
KI (2)
TBAI (2)
I2 (2)
LiI (1.5)
LiI (1.5)
LiI (1.5)
LiI (1.5)
LiI (1.5)
LiI (1.2)
LiI (1.2)
LiI (0.5)
(0)
(65)
86 (86)
(<1)
(22)
(0)
86 (85)
(9)
(15)
(25)
(4)
Herein we report the first hypoiodite-mediated cyclopropa-
nation of alkenes with malononitrile. This reaction is promoted
by tert-butyl hypoiodite, which is generated in situ from the
LiI-tBuOCl combination at room temperature. Recently, the re-
actions using hypoiodite as active iodine species have attract-
ed significant attention.[4,5] In particular, Minakata and co-work-
ers reported the use of tBuOI generated in situ from the NaI-
tBuOCl combination for the aziridination of alkenes,[5a,b] the
cyclization of alkenes with aldoximes[5c] and amides,[5d,f] and
9
10
11
12
13
14
76 (78)
(57)
(7)
[a] Reaction conditions: styrene 1a (1 equiv), malononitrile 2 (1.2 equiv),
iodine source (0–2 equiv), and oxidant (1.2–2 equiv) in dichloromethane
at room temperature. [b] Yields of isolated product 3a (numbers in pa-
rentheses show yields determined from 1H NMR spectra of reaction mix-
tures).
[a] Dr. A. Yoshimura, S. R. Koski, B. J. Kastern, J. M. Fuchs,
Prof. Dr. V. N. Nemykin, Prof. Dr. V. V. Zhdankin
Department of Chemistry and Biochemistry
University of Minnesota Duluth
additional details see Table S1 in the Supporting Information).
In the absence of an iodine source, the reaction of styrene
with malononitrile 2 and tBuOCl failed to produce the desired
product 3a (Table 1, entry 1), while addition of iodide salts re-
sulted in the formation of 3a. Of the iodide salts examined, LiI
was found to be optimal for this reaction (entries 2–6). tBuOCl
was the most effective oxidant in this reaction (entries 7–11).
Decreasing the amounts of LiI and tBuOCl from 2 to 1.5 equiv-
alents did not affect the yield of the desired product 3a (en-
tries 3 and 7); however, lower amounts of LiI, tBuOCl and also
Duluth, MN 55812 (USA)
E-mail: vzhdanki@d.umn.edu
[b] Prof. Dr. T. N. Jones
Department of Chemistry
College of St. Benedict/St. John’s University
St. Joseph, MN 56374 (USA)
[c] Dr. R. Y. Yusubova
Tomsk Polytechnic University
634050 Tomsk (Russian Federation)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402372.
Chem. Eur. J. 2014, 20, 1 – 5
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
shorter reaction time led to reduced yields of 3a (entries 12–
14).
Table 2. (Continued)
Using the optimized reaction condition with LiI as the iodide
source, we have investigated the conversion of various substi-
tuted alkenes 1 to the respective cyclopropane derivatives 3
(Table 2). In general, all styrenes with either electron-donating
or electron-withdrawing substituents in the aromatic ring af-
Entry
9
Alkene 1
Product 3
Yield [%][b]
83
Table 2. Cyclopropanation of alkenes with malononitrile under optimized
1i
3i
3j
conditions.[a]
10
11
78
79
1j
Entry
1
Alkene 1
Product 3
Yield [%][b]
86
1k
1l
3k
3l
1a
3a
3b
12
13
57 (74)[c]
22 (71)[c]
2
3
4
5
6
7
8
92
96
74
91
88
77
87
1b
1m
3m
74
(93:7)[d]
14
15
16
1c
3c
1n
3n+3o
78
(92:8)[d]
1o
1p
3n+3o
1d
3d
23 (50)[c]
3p
1e
3e
17
18 (17)[c]
1q
3q
[a] Reactions of alkenes
1 (1 equiv), malononitrile 2 (1.2 equiv), LiI
1 f
3 f
(1.5 equiv) and tBuOCl (1.5 equiv) were performed in CH2Cl2 at room tem-
perature for 24 h. [b] Yields of isolated products 3. [c] Numbers in paren-
theses show yields of products when 3 equiv of LiI and tBuOCl were
1
used. [d] The product ratio was determined by H NMR spectroscopy.
1g
1h
3g
3h
forded corresponding cyclopropanes 3 in high yields (en-
tries 2–9). In the reactions of a- and b-substituted styrenes, the
products were obtained in good yields (entries 10–15). The re-
actions of a-substituted styrenes (a-methylstyrene and a-phe-
nylstyrene) and aliphatic alkene (1-octene) required 3 equiva-
lents of both LiI and tBuOCl in order to obtain products in
&
&
Chem. Eur. J. 2014, 20, 1 – 5
www.chemeurj.org
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
good yields (entries 12, 13, 16). It is noteworthy that the reac-
tions of cis- and trans-b-styrenes under these conditions gave
the trans-cyclopropane 3n as major product in good yield, and
cis-cyclopropane 3o was detected only as a minor product (en-
tries 14, 15). The reaction of a,b-unsaturated ketone 1q afford-
ed corresponding cyclopropanes in low yields, and these yields
were not improved upon using 3 equivalents of both LiI and
tBuOCl (entries 17). Our procedure was more efficient com-
pared to the previously reported methods of cyclopropanation
of alkenes with malononitrile using hypervalent iodine re-
agents.[3i,l] Moreover, the previously reported reactions of a- or
b-methylstyrenes did not give any products of cyclopropana-
tion, while our method afforded these products in good yields.
The structure of dicyanocyclopropane 3k (Table 2, entry 11)
was established by a single crystal X-ray analysis (see Support-
ing Information for details).
Scheme 1. Proposed mechanism of tBuOI-mediated cyclopropanation.
In order to gain additional information on the mechanism of
this reaction, we have performed several control experiments
(see the Supporting Information for details). Most likely, this re-
action involves tBuOI as active species generated from LiI and
tBuOCl. The intermediacy of tBuOI was examined by generat-
ing it in situ by different methods using either NaI-tBuOCl[5] or
I2-tBuOK[8] in place of LiI-tBuOCl. In both cases, the cyclopro-
pane 3a was isolated in about 50% yield, which suggests that
in situ generated tert-butoxy hypoiodite species, tBuOI 4 are
the active species in this reaction. However, the yields of 3a
using our optimized condition compared to the other tBuOI
generation methods were much better. We have found that
the presence of LiCl, which is produced from LiI-tBuOCl, is im-
portant for this reaction. When LiCl was used as the additive in
NaI-tBuOCl and I2-tBuOK conditions, cyclopropane 3a was ob-
tained in 74% and 73% yields, respectively. As expected, the
addition of NaCl instead of LiCl was not effective under NaI-
tBuOCl or I2-tBuOK conditions. This result suggests that LiCl
may act as a Lewis acid facilitating the formation of tBuOI or
the LiCl-tBuOI complex in this reaction. During our mechanistic
studies, we observed isomerization of cis-b-styrene to trans-b-
styrene when the combinations of LiI-tBuOCl and I2-tBuOK
were used in the absence of malononitrile 2.
From these control experiments, we propose the hypoio-
dite-mediated cyclopropanation mechanism outlined in
Scheme 1. The active species, tBuOI 4, and LiCl generated in
situ from LiI-tBuOCl combination, form the LiCl-tBuOI complex
that reacts with alkene 1 to give the iodonium ion 5, which is
then opened at the benzylic position to give the cationic inter-
mediate 6. The intermediate 6 rotates to the thermodynamical-
ly more stable trans isomer 7, which reacts with malononitrile
anion, formed from 2 in the presence of tert-butoxy anion. This
sequence of events gives b-iodo compound 8, which upon
anionic cyclization affords cyclopropane 3.
Scheme 2. Synthesis of potential HIV-1 RT inhibitor 10.
In summary, we have developed a new procedure for the cy-
clopropanation of alkenes using malononitrile and the LiI-
tBuOCl combination. The reaction mechanism most likely in-
volves tBuOI generated in situ from LiI and tBuOCl. The syn-
thetic usefulness of this new procedure was demonstrated by
the synthesis of potential HIV-1 RT inhibitor.
Experimental Section
Malononitrile
2 (0.150 mmol), LiI (0.1875 mmol), and tBuOCl
(0.1875 mmol) were added to a solution of alkene 1 (0.125 mmol)
in dichloromethane (1.5 mL). The resulting light-brown suspension
was stirred at room temperature for 24 h. After reaction comple-
tion, the mixture was washed with 5% aqueous Na2S2O3 (5 mL),
and the solution was extracted with dichloromethane. The organic
phase was dried over anhydrous Na2SO4 and concentrated. Purifi-
cation by preparative TLC (hexane/ethyl acetate=3:1) afforded an-
alytically pure dicyanocyclopropane 3.
Acknowledgements
This work was supported by a research grant from the National
Science Foundation (CHE-1262479).
Our new cyclopropanation procedure was applied in the
synthesis of potential HIV-1 RT inhibitor. The dicyanocyclopro-
pane 3a upon partial hydrolysis under mild basic condition af-
forded the cyanocarboxamide cyclopropane 9 in moderate
yield (Scheme 2). This cyclopropane 9 has been used as a pre-
cursor for the preparation of the potential HIV-1 RT inhibitor
10 as previously described.[9]
Keywords: cyclopropanation reactions · hypoiodous acid ·
iodine · oxidation · small ring systems
[1] a) The Chemistry of the Cyclopropyl Group (Eds.: S. Patai, Z. Rappoport),
Wiley, New York, 1987; b) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996,
Chem. Eur. J. 2014, 20, 1 – 5
www.chemeurj.org
3
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
96, 49–92; c) G. Boche, J. C. W. Lohrenz, Chem. Rev. 2001, 101, 697–756;
d) A. B. Charette, A. Beauchemin, Org. React. 2001, 58, 1–415; e) H.
Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev. 2003, 103,
977–1050; f) H.-U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151–1196;
g) M. Rubin, M. Rubina, V. Gevorgyan, Chem. Rev. 2007, 107, 3117–3179;
h) C. A. Carson, M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051–3060; i) D. Y.-K.
Chen, R. H. Pouwer, J.-A. Richard, Chem. Soc. Rev. 2012, 41, 4631–4642;
j) H. Y. Kim, P. J. Walsh, Acc. Chem. Res. 2012, 45, 1533–1547.
[5] a) S. Minakata, Y. Morino, Y. Oderaotoshi, M. Komatsu, Chem. Commun.
2006, 3337–3339; b) S. Minakata, Y. Morino, Y. Oderaotoshi, M. Komatsu,
Org. Lett. 2006, 8, 3335–3337; c) S. Minakata, S. Okumura, T. Nagamachi,
Y. Takeda, Org. Lett. 2011, 13, 2966–2969; d) S. Minakata, Y. Morino, T.
Ide, Y. Oderaotoshi, M. Komatsu, Chem. Commun. 2007, 3279–3281; e) Y.
Takeda, S. Enokijima, T. Nagamachi, K. Nakayama, S. Minakata, Asian J.
Org. Chem. 2013, 2, 91–97; f) Y. Takeda, S. Okumura, S. Minakata, Angew.
Chem. 2012, 124, 7924–7928; Angew. Chem. Int. Ed. 2012, 51, 7804–
7808; g) Y. Takeda, S. Okumura, S. Minakata, Synthesis 2013, 1029–1033.
[6] a) M. Kirihara, Y. Asai, S. Ogawa, T. Noguchi, A. Hatano, Y. Hirai, Synthesis
2007, 3286–3289; b) M. Uyanik, H. Okamoto, T. Yasui, K. Ishihara, Science
2010, 328, 1376–1379; c) M. Uyanik, D. Suzuki, T. Yasui, K. Ishihara,
Angew. Chem. 2011, 123, 5443–5446; Angew. Chem. Int. Ed. 2011, 50,
5331–5334; d) A. Rodrꢃguez, W. J. Moran, Org. Lett. 2011, 13, 2220–2223;
e) T. Froehr, C. P. Sindlinger, U. Kloeckner, P. Finkbeiner, B. J. Nachtsheim,
Org. Lett. 2011, 13, 3754–3757; f) J.-S. Tian, K. W. J. Ng, J.-R. Wong, T.-P.
Loh, Angew. Chem. 2012, 124, 9239–9243; Angew. Chem. Int. Ed. 2012,
51, 9105–9109; g) H. Li, J. Xie, Q. Xue, Y. Cheng, C. Zhu, Tetrahedron Lett.
2012, 53, 6479–6482; h) U. Kloeckner, N. M. Weckenmann, B. J. Nacht-
sheim, Synlett 2012, 97–100; i) J. Zhang, J. Jiang, Y. Li, Y. Zhao, X. Wan,
Org. Lett. 2013, 15, 3222–3225; j) T. Nobuta, N. Tada, A. Fujiya, A. Kariya,
T. Miura, A. Ito, Org. Lett. 2013, 15, 574–577.
[2] For books and selected reviews on hypervalent iodine chemistry, see:
a) V. V. Zhdankin, Hypervalent Iodine Chemistry: Preparation, Structure, and
Synthetic Applications of Polyvalent Iodine Compounds, Wiley, Chichester,
2013; b) Hypervalent Iodine Chemistry (Ed.: T. Wirth), Springer, Berlin,
2003; c) M. Brown, U. Farid, T. Wirth, Synlett 2013, 24, 424–431; d) M. S.
Yusubov, V. V. Zhdankin, Curr. Org. Synth. 2012, 9, 247–272; e) J. L. F. Sil-
va, Jr., B. Olofsson, Nat. Prod. Rep. 2011, 28, 1722–1754; f) R. M. Moriarty,
J. Org. Chem. 2005, 70, 2893–2903.
[3] a) R. Knorr, Chem. Rev. 2004, 104, 3795–3849; b) S. R. Goudreau, D. Mar-
coux, A. B. Charette, J. Org. Chem. 2009, 74, 470–473; c) C. Zhu, A. Yoshi-
mura, L. Ji, Y. Wei, V. N. Nemykin, V. V. Zhdankin, Org. Lett. 2012, 14,
3170–3173; d) K. S. Feldman, D. A. Mareska, J. Org. Chem. 1999, 64,
5650–5660; e) H.-Y. Lee, Y.-H. Lee, Synlett 2001, 1656–1658; f) M. Ochiai,
T. Sueda, K. Uemura, Y. Masaki, J. Org. Chem. 1995, 60, 2624–2626; g) P.
Mꢁller, A. Ghanem, Org. Lett. 2004, 6, 4347–4350; h) Y. Ye, C. Zheng, R.
Fan, Org. Lett. 2009, 11, 3156–3159; i) A. S. Biland, S. Altermann, T. Wirth,
ARKIVOC 2003, 2003, 164–169; j) R. P. Wurz, A. B. Charette, Org. Lett.
2003, 5, 2327–2329; k) L. L. Welbes, T. W. Lyons, K. A. Cychosz, M. S. San-
ford, J. Am. Chem. Soc. 2007, 129, 5836–5837; l) S. Lin, M. Li, Z. Dong, F.
Liang, J. Zhang, Org. Biomol. Chem. 2014, 12, 1341–1350.
[4] a) J. Madsen, C. Viuf, M. Bols, Chem. Eur. J. 2000, 6, 1140–1146; b) J. Bar-
luenga, F. Gonzꢂlez-Bobes, J. M. Gonzꢂlez, Angew. Chem. 2002, 114,
2668–2670; Angew. Chem. Int. Ed. 2002, 41, 2556–2558; c) J. Barluenga,
M. Marco-Arias, F. Gonzꢂlez-Bobes, A. Ballesteros, J. M. Gonzꢂlez, Chem.
Eur. J. 2004, 10, 1677–1682; d) J. Barluenga, M. Marco-Arias, F. Gonzꢂlez-
Bobes, A. Ballesteros, J. M. Gonzꢂlez, Chem. Commun. 2004, 2616–2617;
e) T. Hu, K. Liu, M. Shen, X. Yuan, Y. Tang, C. Li, J. Org. Chem. 2007, 72,
8555–8558; f) R. Fan, W. Li, D. Pu, L. Zhang, Org. Lett. 2009, 11, 1425–
1428; g) S. Minakata, Acc. Chem. Res. 2009, 42, 1172–1182; h) H. Kikui, K.
Moriyama, H. Togo, Synthesis 2013, 791–797.
[7] a) A. Yoshimura, K. R. Middleton, C. Zhu, V. N. Nemykin, V. V. Zhdankin,
Angew. Chem. 2012, 124, 8183–8186; Angew. Chem. Int. Ed. 2012, 51,
8059–8062; b) A. Yoshimura, C. Zhu, K. R. Middleton, A. D. Todora, B. J.
Kastern, A. V. Maskaev, V. V. Zhdankin, Chem. Commun. 2013, 49, 4800–
4802.
[8] a) R. Montoro, T. Wirth, Org. Lett. 2003, 5, 4729–4731; b) S. Ghosh, S. De,
B. N. Kakde, S. Bhunia, A. Adhikary, A. Bisai, Org. Lett. 2012, 14, 5864–
5867.
[9] a) P. Gopinath, S. Chandrasekaran, J. Org. Chem. 2011, 76, 700–703;
b) A. C. Gaudio, C. A. Montanari, J. Comput.-Aided Mol. Des. 2002, 16,
287–295.
Received: February 26, 2014
Published online on && &&, 0000
&
&
Chem. Eur. J. 2014, 20, 1 – 5
www.chemeurj.org
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
&
Cyclopropanation
A. Yoshimura,* S. R. Koski, B. J. Kastern,
J. M. Fuchs, T. N. Jones, R. Y. Yusubova,
V. N. Nemykin, V. V. Zhdankin*
&& – &&
Hypoiodite-Mediated
Cyclopropanation of Alkenes
An efficient, transition-metal-free proce-
dure for the cyclopropanation of al-
kenes using malononitrile and the LiI-
tBuOCl combination under mild reaction
conditions is described. The reaction
mechanism most likely involves tBuOI
generated in situ from LiI and tBuOCl.
The utility of this new methodology has
been demonstrated by the synthesis of
a potential HIV-1 RT inhibitor (see
scheme).
Chem. Eur. J. 2014, 20, 1 – 5
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ