Iodohydroxylation of alkylidenecyclopropanes. An efficient synthesis of iodocyclopropylmethanol and 3-iodobut-3-en-1-ol derivatives

Article abstract of DOI:10.1021/jo800123m

(Chemical Equation Presented) A variety of iodocyclopropylmethanol and 3-iodobut-3-en-1-ol derivatives were readily prepared in good to excellent yields via the simple iodohydroxylation reaction of alkylidenecyclopropanes with I₂ and H₂

Full text of DOI:10.1021/jo800123m

of methylenecyclopropanes is their multiform reactivities that
may lead to formation of a variety of products through addition
to a CdC double bond and cleavage of proximal or distal bonds
of the three-membered ring. Moreover, for the reactions with
unsymmetrical ACPs, the regiochemistry generally affords
different possible products. Thus, the regio- and stereoselectivity
of the insertion and ring-opening methods have been the
highlight of methylenecyclopropane chemistry.5
We have found that ACPs 1 can be opened by using
electrophiles and nucleophiles to give the corresponding diha-
logenation or Ritter-type derivatives in good yields under mild
conditions.6 These interesting results encouraged us to inves-
tigate further unique addition reactions with different electro-
phile/nucleophile systems to give novel products. Although
halohydroxylations of CdC of olefins7 are conventional meth-
ods, reports on the halohydroxylation of ACPs are limited,8,9
probably because the regiochemistry makes the reaction com-
plicated. In this paper, we wish to disclose our recent results of
addition reactions of ACPs 1 with iodine and water to give ring-
opening or ring-keeping products and that, in most of the cases
studied, the reactions are clean and efficient.
Iodohydroxylation of Alkylidenecyclopropanes.
An Efficient Synthesis of
Iodocyclopropylmethanol and 3-Iodobut-3-en-1-ol
Derivatives
Yewei Yang† and Xian Huang*,†,‡
Department of Chemistry, Zhejiang UniVersity (Xixi
Campus), Hangzhou 310028, People’s Republic of China,
and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, People’s Republic of China
huangx@mail.hz.zj.cn
ReceiVed January 18, 2008
First, we carried out the iodohydroxylation of various ACPs
1 with 2.0 equiv of iodine in aqueous acetone at room
temperature. We found that (1-iodocyclopropyl)methanol 2 was
obtained as the major product efficiently. The results are
summarized in Table 1. Starting from 1a-h, the corresponding
2a-h were obtained in moderate to excellent yields (Table 1,
entries 1-8). On the other hand, reaction of 1a and 1j with
bromine under similar conditions also successfully provided the
corresponding bromohydroxylation adducts 3a and 3j in 88%
and 92% yields within 0.5 h (Table 1, entries 9 and 10,
respectively).
However, for ACPs 1e-g and 1k having a hydrogen atom,
we observed that the reaction proceeded smoothly to afford
useful product 4 using 5.0 equiv of I2. The results are
summarized in Table 2.
Furthermore, for unsymmetric aliphatic ACP 1h, we observed
that iodine cation can easily add to the CdC bond without
cleavage of the cyclopropane ring to give the vinylcyclopropane
derivative 5a as a single product in good yield (eq 1).
A variety of iodocyclopropylmethanol and 3-iodobut-3-en-
1-ol derivatives were readily prepared in good to excellent
yields via the simple iodohydroxylation reaction of alky-
lidenecyclopropanes with I2 and H2O. An unexpected rear-
rangement to give 4-hydroxy-1,2-diphenyl-butan-1-one de-
rivatives was observed compared to the halohydroxylation
products.
Alkylidenecyclopropanes (ACPs) are highly strained but
readily available molecules that have served as useful building
blocks in organic synthesis.1 So far, increasing attention has
been paid to the transition metal-catalyzed reactions of unsub-
stituted methylenecyclopropanes, which have been employed
for the construction of complex organic molecules.2,3 Examples
of Lewis acid or Brønsted acid mediated reactions of ACPs have
also been disclosed.4 An attractive but often troublesome feature
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45, 2903. (b) Patient, L.; Berry, M. B.; Kiburn, J. D. Tetrahedron Lett. 2003,
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Huang, J.-W. Org. Lett. 2004, 6, 1175. (e) Shi, M.; Liu, L.-P.; Tang, J. Org.
Lett. 2006, 8, 4043.
† Zhejiang University (Xixi Campus).
‡ Chinese Academy of Sciences.
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Cordero, F. M.; Goti, A. Chem. ReV. 2003, 103, 1213. (d) Rubin, M.; Rubina,
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Int. Ed. 2001, 40, 1298. (h) Oh, B. H.; Nakamura, I.; Saito, S.; Yamamoto, Y.
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4702 J. Org. Chem. 2008, 73, 4702–4704
10.1021/jo800123m CCC: $40.75 2008 American Chemical Society
Published on Web 05/24/2008

TABLE 1. Iodohydroxylation and Bromohydroxylation of ACPs
1a
Controlled experiments with varying solvents revealed an
interesting reactivity pattern, leading to entirely different
products. In the presence of 2.0 equiv of I2 in DMSO/H2O, 1a
was consumed after 72 h at higher reaction temperature to afford
7a as a major product in 86% yield (eq 2). To confirm the
formation route, we carried out the reaction of 1 equiv of iodine
with a solution of 2a in DMSO at 100 °C, which resulted in
the smooth conversion of 2a into the same compound 7a (91%).
And we also examined the reaction in anhydrous DMSO, which
gave 7a in 61% yield,13 suggesting that the OH group has to
come from starting material 2a.
entry
ACP 1 (R1/R2)
C6H5/C6H5(1a)
p-ClC6H4/p-ClC6H4(1b)
p-FC6H4/p-FC6H4(1c)
p-MeC6H4/p-MeC6H4(1d)
C6H5/H(1e)
p-MeC6H4/H (1f)
o-MeOC6H4/H (1g)
p-MeOC6H4/CH3 (1h)
1a
X2 time/h yield of 2 or 3 (%)b
1
2
3
4
5
6
7
8
9
10
I2
1
2a, 95
2b, 84
2c, 96
2d, 65
2e, 75
2f, 85
2g, 87
2 h, 36c
3a, 88
3j, 92
I2
5
I2
I2
I2
I2
12
18
20
5
I2
6
I2
5
Br2
0.5
0.5
p-MeOC6H4/ p- ClC6H4 (1j) Br2
This reaction also appears to be general and the results are
summarized in Table 3. When a solution of 1 in DMSO/H2O
was treated with 2 equiv of iodine, the substrate was converted
cleanly into the 3-iodobut-3-en-1-ol 7. Using unsymmetric ACP
1e, we obtained only the Z isomer.
a Unless otherwise specified, the reaction was carried out with 1 (1.0
mmol) and X2 (2.0 mmol) in acetone aqueous. b Isolated yields and the
reaction time are determined by TLC on the basis of consuming the
starting materials 1. c 8% of 5a was isolated as byproduct.
TABLE 3. Iodohydroxylation of ACPs in Aqueous DMSOa
TABLE 2. Iodohydroxylation of Monosubstituted ACPs
entry
ACP 1 (R)
1e
1f
time/h
yield of 4 (%)a
entry
ACP 1 (R1/R2)
time/h
yield of 7 (%)b
1
2
3
4
72
72
72
48
4e, 78
4f, 60
4g, 75
4k, 81
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1i
72
72
72
24
24
72
24
7a, 86
7b, 80
7c, 90
7d, 95
(Z)-7e, 46
7i, 71
1g
p-BrC6H4 (1k)
a Isolated yields.
p-i-BuOC6H4/ p-i-BuOC6H4 (1m)
7m, 75
a Unless otherwise specified, the reaction was carried out with 1 (1.0
mmol) and I2 (2.0 mmol) in DMSO/H2O and then quenched by the
addition of a saturated aqueous solution of Na2S2O3. b Isolated yields.
SCHEME 2. Proposed Mechanistic Pathway for the
Reaction in Table 3
A possible mechanistic pathway for the formation of 2-5 is
shown in Scheme 1. First, electrophilic addition of I+ to the
C-1 position of the electron-rich double bond provides cyclo-
propylcarbinyl cation 6. Subsequent water attacks the C-2
positon of 6 affording the product 2. Previously, the iodination
of 1 in aprotic solvents (CH2Cl2, DCE) has been reported to
yield the regular diiodide addition adduct in the presence of an
excess of the reagent.8d,e The fact indicates that in acetone/water
the cation 6 may be stabilized by solvation and therefore has
no tendency to stabilize itself by rearrangement.10 Product 4
must arise via oxidation of 2 (R1 ) Ar, R2 ) H) by excessive
I2.11 If the R1 group is methyl, the carbonium ion intermediate
gives product 5 via ꢀ-proton elimination.12
Apparently, products 7 are derived from the cation 6 (Scheme
2). 14 In this case, strain release is more favorably accomplished
by ring opening of the intermediate and bond migration. The
observed selectivity was assigned based on the mechanism.
Nucleophilic attack of the H2O competitive with its iodine
trapping produces the stereospecific ring-opened Z isomer.
Iodohydroxylation of the ACP 1i with an electron-donating
substituent on the benzene ring in aqueous DMSO gave the
single product 2i (Scheme 3). Furthermore, a big different
product 8i was obtained when the reaction was carry out in
aqueous acetone, instead of DMSO, albeit in low yield. Besides
the products 8i and 8n, a number of side products were
SCHEME 1. Proposed Mechanistic Pathway for the
Reaction in Tables 1 and 2 and Eq 1
(10) Kozhushkov, S.; Spa¨th, T.; Fiebig, T.; Galland, B.; Ruasse, M.-F.;
Xavier, P.; Apeloig, Y.; de Meijere, A. J. Org. Chem. 2002, 67, 4100.
(11) Mori, N.; Togo, H. Tetrahedron 2005, 61, 5915.
(12) Liu, L.-P.; Shi, M. J. Org. Chem. 2004, 69, 2805.
(13) See the Supporting Information for experimental details.
(14) Siriwardana, A. I.; Nakamura, I.; Yamamoto, Y. Tetrahedron Lett. 2003,
44, 985.
J. Org. Chem. Vol. 73, No. 12, 2008 4703

SCHEME 3. Iodohydroxylation of ACPs with an
Electron-Donating Substituent on the Benzene Ring
in 8 mL of acetone was added H2O (2 mL). Then I2 (508 mg, 2.0
mmol) was subsequently added. The progress of the reaction was
monitored by TLC, and the mixture was stirred until the starting
material disappeared (1 h). Then a saturated aqueous solution of
Na2S2O3 was added. The mixture was extracted with ether (2 × 25
mL) and dried over MgSO4. Evaporation and column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate ) 10:1) afforded
2a (332 mg, 95%) as a solid. 2a: white solid; mp 80-81 °C; IR
(ATR) νmax 3539, 3054, 1779, 1658, 1489, 1444, 1323, 1227, 1141,
1079, 917, 754, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.52 (d,
J ) 7.6 Hz, 4H), 7.29-7.21 (m, 6H), 2.95 (s, 1H), 1.22 (t, J ) 6.6
Hz, 2H), 0.92 (t, J ) 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
127.8, 127.6, 127.5, 82.0, 20.7, 15.4; MS (EI) m/z (%) 350 (M+,
2.5), 223 (16.0), 183 (100), 105 (83.1), 77 (50.2); HRMS m/z (ESI)
calcd for C16H15OI (M+) 350.0168, found 350.0179.
SCHEME 4. Proposed Mechanism for the Reaction in
Scheme 3
Preparation of 3-Iodo-4,4-diphenylbut-3-en-1-ol (7a): Typi-
cal Procedure 2. To a solution of ACP 1a (206 mg, 1.0 mmol) in
8 mL of DMSO was added H2O (2 mL). Then I2 (508 mg, 2.0
mmol) was subsequently added. The reaction was then heated to
100 °C for 3 days. The course of the reaction was monitored by
TLC. Then a saturated aqueous solution of Na2S2O3 was added.
The mixture was extracted with ether (2 × 25 mL) and dried over
MgSO4. Evaporation and column chromatography on silica gel
(petroleum ether/ethyl acetate ) 4:1) afforded 7a (301 mg, 86%)
as a solid. 7a: white solid; mp 112-114 °C; IR (ATR) νmax 3407,
3053, 2882, 1592, 1491, 1438, 1263, 1185, 1073, 1030, 1006, 802
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m, 10 H), 3.89
(t, J ) 6.2 Hz, 2H), 2.87 (t, J ) 6.4 Hz, 2H), 1.66 (b, 1H); 13C
NMR (100 MHz, CDCl3) δ 150.8, 146.6, 140.1, 128.6, 128.4, 128.2,
127.3, 127.2, 104.0, 62.4, 44.4; MS (EI) m/z (%) 350 (M+, 26.1),
319 (4.5), 191 (56.4), 165 (36.2), 115 (45.5), 61 (100); HRMS m/z
(ESI) calcd for C16H15OI (M+) 350.0168, found 350.0157.
produced. It is noteworthy that substitutent and solvation did
significantly affect the reaction.
Although the mechanistic underpinnings of the reaction are not
clearly known, the following rationalization may be advanced to
explain the product formation (Scheme 4). Presumably, I+ first add
to ACPs bearing an electron-donationg substituent (methoxyl or
ethoxyl group) on the aromatic ring to give the intermediate A.
Consequently, rapid interconversion occurred between A and ions
B, which attacked by the H2O to give C. 15 The addition of H+ to
D produces the intermediate E, which undergoes the cyclopropane
ring-opening reaction to form the intermediate F. Finally isomer-
ization of F furnishes the derivative 8.
In conclusion, we have developed the novel reactions of ACPs
with the I2/H2O system leading to two different products with or
without ring opening under mild conditions. In one case, the
bifunctional cyclopropane derivatives 2-5 can be obtained in good
to excellent yields. In the other case, the ACPs are converted to
3-iodobut-3-en-1-ol derivatives efficiently with ring opening. These
clean/convenient available products bearing two functional groups
-X and -OH may be converted to other interesting and useful
structural units in organic synthesis.16 In addition, different solvents
can lead to selective synthesis of diverse products. For example,
in contrast to 2 and 7, rearrangement product 8 can also be obtained
from the same starting material. Further studies to expand the scope
and synthetic utility of this method are currently underway.
Preparation of 4-Hydroxy-1,2-bis(4-methoxyphenyl)-butan-
1-one (8i): Typical Procedure 3. To a solution of ACP 1i (266
mg, 1.0 mmol) in 8 mL of acetone was added H2O (2 mL). Then
I2 (508 mg, 2.0 mmol) was subsequently added. The reaction was
then heated to 40 °C for 3 days. Then a saturated aqueous solution
of Na2S2O3 was added. The mixture was extracted with ether (2 ×
25 mL) and dried over MgSO4. The mixture was concentrated under
reduced pressure, and residue was subjected to chromatography
eluting with petroleum ether/ethyl acetate ) 3:1 to give 8i (144
mg, 48%) as an oil. 8i: colorless oil; IR (ATR) νmax 3436, 2933,
1
2837, 1666, 1598, 1508, 1245, 1168, 1028, 826 cm-1; H NMR
(400 MHz, CDCl3) δ 7.95 (d, J ) 8.8 Hz, 2H), 7.21 (d, J ) 8.4
Hz, 2H), 6.85-6.80 (m, 4H), 4.76 (t, J ) 7.2 Hz, 1H), 3.80 (s,
3H), 3.73 (s, 3H), 3.67-3.61 (m, 1H), 3.59-3.54 (m, 1H),
2.41-2.34 (m, 1H), 2.01-1.99 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 198.8, 163.2, 158.5, 131.4, 131.0, 129.5, 129.2, 114.3,
113.6, 60.4, 55.3, 55.1, 48.7, 36.3; MS (EI) m/z (%) 300 (M+, 2.5),
282 (15.6), 165 (14.1), 148 (24.2), 135 (100); HRMS m/z (ESI)
calcd for C18H20O4 (M+) 300.1362, found 300.1370.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Project Nos. 20672095 and
20732005) and CAS Academician Foundation of Zhejiang
Province for financial support.
Experimental Section
Note Added after ASAP Publication. Due to a production
error, the equation in Table 2 was incorrect and the equation in
Table 3 was missing some bonds. The corrected version was
published ASAP on May 31, 2008.
Preparation of (1-Iodocyclopropyl)diphenylmethanol (2a):
Typical Procedure 1. To a solution of ACP 1a (206 mg, 1.0 mmol)
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(b) Wichmann, J.; Adam, G. Eur. J. Org. Chem. 1999, 3131. (c) Chappell, M. D.;
Harris, C. R.; Kuduk, S. D.; Balog, A.; Wu, Z.; Zhang, F.; Lee, C. B.; Stachel,
S. J.; Danishefsky, S. J.; Chou, T.-C.; Guan, Y. J. Org. Chem. 2002, 67, 7730.
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Supporting Information Available: General experimental
procedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO800123M
4704 J. Org. Chem. Vol. 73, No. 12, 2008