Metal-free oxidative cyclization of urea-tethered alkenes with hypervalent iodine

Article abstract of DOI:10.1021/ol8022165

(Chemical Equation Presented) A metal-free oxidative cyclization of ureas onto unactivated alkenes using iodosylbenzene and an acid promoter is described. The products isolated are predominantly bicyclic isoureas resulting from an intramolecular oxyamination reaction. The acid type and urea substitution have a strong effect on the product formed. A variety of substrates form the isourea with high diastereoselectivity via syn addition including di- and trisubstituted alkenes. Hydrolysis of the isourea gives access to new diastereomerically pure prolinol derivatives.

Full text of DOI:10.1021/ol8022165

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5039-5042
Metal-Free Oxidative Cyclization of
Urea-Tethered Alkenes with Hypervalent
Iodine
Brian M. Cochran and Forrest E. Michael*
Department of Chemistry, UniVersity of Washington, Box 351700,
Seattle, Washington 98195-1770
fmichael@chem.washington.edu
Received September 22, 2008
ABSTRACT
A metal-free oxidative cyclization of ureas onto unactivated alkenes using iodosylbenzene and an acid promoter is described. The products
isolated are predominantly bicyclic isoureas resulting from an intramolecular oxyamination reaction. The acid type and urea substitution have
a strong effect on the product formed. A variety of substrates form the isourea with high diastereoselectivity via syn addition including di- and
trisubstituted alkenes. Hydrolysis of the isourea gives access to new diastereomerically pure prolinol derivatives.
Transition-metal-catalyzed oxidative amination reactions of
alkenes are powerful methods for the selective formation of
new carbon-nitrogen bonds. In many of these transforma-
tions, a hypervalent iodine(III) reagent, such as PhI(OAc)2
or PhIdNTs, serves as the oxidant. Common examples of
such reactions include aziridinations,1 oxyaminations,2 and
diaminations.3 For example, PhI(OAc)2 has been used as an
oxidant in Pd-catalyzed intramolecular aminoacetoxylation2b
and diamination reactions of sulfonamides and ureas.3
Given the toxicity and cost issues associated with transi-
tion-metal catalysts, the development of metal-free alterna-
tives is of significant interest. In the absence of metal
catalysts, hypervalent iodine reagents can be effective in
oxidizing a variety of electron-rich functional groups,4
including sulfides, amines, aromatic and heteroaromatic
rings,5a-d and alkynes.5e-g The direct oxidation of unacti-
(4) For reviews, see: (a) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002,
102, 2523–2584. (b) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96,
1123–1178. (c) Kitamura, T.; Fujiwara, Y. Org. Prep. Proc. Int. 1997, 29,
409–458. (d) Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem. 1996, 68,
627. (e) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893–2903. (f) Varvoglis,
A. Synthesis 1984, 709–726. (g) Wirth, T. Angew. Chem., Int. Ed. 2005,
44, 3656–3665.
(1) (a) Review: Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905–2919.
(b) Guthikonda, K.; Wehn, P. M.; Caliando, B. J.; DuBois, J. Tetrahedron
2006, 62, 11331–11342. (c) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J.
Org. Chem. 1991, 56, 6744–6746.
(2) (a) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179–7181.
(b) Alexanian, E. J.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690–
7691. (c) Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46,
5737–5740.
(5) (a) Lee, K.; Kim, D. Y.; Oh, D. Y. Tetrahedron Lett. 1988, 29, 667–
668. (b) Dohi, T.; Ito, M.; Morimoto, K.; Iwata, M.; Kita, Y. Angew. Chem.,
Int. Ed. 2008, 47, 1301–1304. (c) Nicolaou, K. C.; Baran, P. S.; Zhong,
Y.-L.; Sugita, K. J. Am. Chem. Soc. 2002, 124, 2212–2220. (d) Dohi, T.;
Morimoto, K.; Kiyono, Y.; Tohma, H.; Kita, Y. Org. Lett. 2005, 7, 537–
540. (e) Kitamura, T.; Furuki, R.; Taniguchi, H.; Stang, P. J. Tetrahedron
1992, 48, 7149–7156. (f) Kitamura, T.; Furuki, R.; Taniguchi, H.; Stang,
P. J. Tetrahedron Lett. 1990, 31, 703–704. (g) Serna, S.; Tellitu, I.;
Domingues, E.; Moreno, I; SanMartin, R. Org. Lett. 2005, 7, 3073–3076.
(3) (a) Mun˜iz, K.; Streuff, J.; Ho¨velmann, C. H.; Nu´n˜ez, A. Angew.
Chem., Int. Ed. 2007, 46, 7125–7127. (b) Steuff, J.; Ho¨velmann, C. H.;
Nieger, M.; Mun˜iz, K. J. Am. Chem. Soc. 2005, 125, 14586–14587. (c)
Mun˜iz, K.; Ho¨velmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130,
763–773.
10.1021/ol8022165 CCC: $40.75
Published on Web 10/09/2008
2008 American Chemical Society

Table 1. Acid-Promoted Oxidative Cyclization
entry
acid
TMSOTf
TIPSOTf
TfOH
Tf2O
Tf2NH
HBF4·Et2O
BF3·Et2O
(R)-CSAc
rac-(BINOL)PO2H
Sc(OTf)3
Zn(OTf)2
TFA
% conversionb
ratio2:3b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
100
100
95
100
100
100
100
100
100
84
10:1
8:1
>20:1
7:1
6:1
>20:1
9:1
>20:1
1.5:1
1.3:1
1.3:1
1:1.3
1:>20
1:>20
80
77
20
10
Figure 1
probability.
. ORTEP of 2 with thermal ellipsoids shown at 50%
BzOH
AcOH
a 1.2 equiv of acid, 1.2 equiv of PhIdO, CH2Cl2 (0.1 M), -78 °C to rt,
vated alkenes with iodine(III) reagents, however, is generally
limited to the vicinal disubstitution of the double bond with
2 equiv of the counterion to form dihalides or bis(sul-
fonates).6,7 There have been few reports of unactivated
alkenes undergoing oxidative intramolecular cyclizations with
these iodine reagents.8 Herein, we report a metal-free
oxidative cyclization of unactivated alkenes promoted by
simple Brønsted and Lewis acids to directly generate vicinal
amino alcohol derivatives from alkenes.9
b
1 d. Determined by H NMR. c Product was racemic by chiral HPLC.
1
strong acids (entries 1-8) resulted in complete consumption
of 1 and predominant or exclusive formation of isourea 2.
(R)-Camphorsulfonic acid ((R)-CSA) was also competent in
generating 2; however, no enantioselectivity was observed.
Weaker acids also promoted oxidative cyclization, albeit
more slowly and with a change in chemoselectivity (entries
9-14). Interestingly, a clear trend of reactivity vs chemose-
lectivity was seen: as the strength of the acid decreased, the
reaction favored formation of diamination product 3 at the
cost of conversion.
The effects of substitution at the distal urea nitrogen were
then examined (Table 2). When the tosyl substituent was
replaced with 3-trifluoromethylphenyl (4) or hydrogen (5),
the only products isolated were isoureas 9 and 10, respec-
tively. Substituting a benzoyl group (6) on the urea also led
to the formation of isourea 11 as the major product, though
the diamination product 12 was isolated in moderate yield.
Treatment of alkyl-substituted ureas 7 and 8 under the same
conditions, however, generated a new class of products.
These were identified as seven-membered ring isoureas 13
and 14, where 1 equiv of the triflate counterion had been
incorporated. From these limited examples, it appears that
subtle electronic effects of the urea substituent control the
mode of reactivity, namely, electron-withdrawing groups
favor the formation of bicyclization products (2, 9-12),
whereas electron-donating groups promote formation of the
monocyclic isourea (13 and 14).
In the above-mentioned diamination report,3b oxidative
cyclization of urea-tethered alkene 1 to cyclic urea 3 using
PhI(OAc)2 required catalytic Pd(OAc)2. In contrast, when
substrate 1 was treated with PhIdO and TMSOTf under metal-
free conditions (eq 1), complete consumption of the starting
material was observed, but only trace amounts of the expected
diamination product 3 were formed. The major product proved
to be isourea 2, which was isolated by column chromatography
in 89% yield and its identity confirmed spectroscopically and
by X-ray crystallography (Figure 1). Commercially available
PhI(OAc)2 also facilitated the reaction in the presence of
TMSOTf. When the reaction was performed in the absence of
acid, only starting material was observed. Toluene, MeCN, and
Et2O were also competent solvents.
A wide variety of Brønsted and Lewis acids were effective
at promoting oxidative cyclization (Table 1). The use of
(6) (a) Zefirov, N. S.; Zhdankin, V. V.; Dan’kov, Y. V.; Sorokin, V. D.;
Semerikov, V. N.; Koz’min, A. S.; Caple, R.; Berglund, B. A. Tetrahedron
Lett. 1986, 27, 3971–3974. (b) Rieke, R. D.; Li, P. T-J.; Burns, T. P.; Uhm,
S. T. J. Org. Chem. 1981, 46, 4324–4326. (c) Hembre, R. T.; Scott, C. P.;
Norton, J. R. J. Org. Chem. 1987, 52, 3650–3654.
(8) (a) Kim, H-J.; Schlecht, M. F. Tetrahedron Lett. 1987, 28, 5229–
5232. (b) Serna, S.; Tellitu, I.; Domingues, E.; Moreno, I; SanMartin, R.
Tetrahedron 2004, 60, 6533–6539.
(9) In the course of preparing this manuscript, the following publication
using IPy2BF4 to oxidatively cyclize tosylurea substrates appeared. Though
the isourea products were isolated as byproducts from their reactions, in
all cases the imidazolidinone (e.g., 3) was the major product. Mun˜iz, K.;
Ho¨velmann, C. H.; Campos-Go´mez, E.; Barluenga, J.; Gonza´lez, J. M.;
Streuff, J.; Nieger, M. Chem. Asian J. 2008, 3, 776–788.
(7) NaN3 or TMSN3 can be used in with iodine(III) reagents to generate
the 1,2-diazide. (a) Moriarty, R. M.; Khosrowshahi, J. S. Tetrahedron Lett.
1986, 27, 2809–2812. (b) Magnus, P.; Roe, M. B.; Hulme, C. J. Chem.
Soc., Chem. Commun. 1995, 263–265.
5040
Org. Lett., Vol. 10, No. 21, 2008

Table 2. Effect of Urea Substitution
Table 3. Oxidative Cyclization of Tosyl-Substituted Ureas
R
products (yield, %)b
Ts
1
4
5
6
7
8
2 (89)
9 (74)
10 (78)
11 (61)
trace
trace
trace
12 (20)
trace
trace
trace
trace
13 (53)
14 (85)
3-CF3Ph
Hc
Bz
Bn
tBu
a 1.2 equiv of TMSOTf, 1.2 equiv of PhIdO, CH2Cl2 (0.1 M), -78 °C
to rt. b Isolated yields. c 1.5 equiv of TMSOTf, 1.5 equiv of PhIdO, CH2Cl2
(0.1 M), 0 °C to rt.
The reactivities of a variety of alkene tethers were
examined using the tosyl-substituted urea (Table 3). When
the gem-dimethyl substituent was replaced with a spiro-
cyclohexyl (15) or gem-diphenyl group (17), or removed
completely (19), isoureas 16, 18, and 20 were isolated in
good yields. Substrates containing a single substituent on
the backbone also led to the formation of isoureas 22 and
24 in good yields and good diastereoselectivity for the cis
product. The cis-1,2-disubstituted cyclohexane 25 also af-
forded tricyclic isourea 26 in good yield, but modest
diastereoselectivity.
More highly substituted alkenes were also reactive under
these conditions. The 1,1- and 1,2-disubstituted alkenes 27,
29, and 32 were all converted to the expected isoureas (28,
30, 33) in good yields. The formation of trans product 30
from trans alkene 29 and cis product 33 from cis substrate
32 reveals that the cyclization takes place by selective syn
addition of the urea. In the former case, a small amount of
7-membered ring byproduct 31 was also formed as a single
diastereomer. Trisubstituted alkene 34 gave the expected
isourea 35 as well as allylic oxidation product 36. The
formation of the 6-membered ring isourea 38 was also
successful albeit in modest yield.
The isourea functionality can be further transformed in
several ways (Scheme 1). When isourea 2 was treated with
KOH/EtOH at room temperature, partial hydrolysis to the
ꢀ-hydroxyurea 40 was observed. Conversion to product 40
can also be accomplished from alkene 1 in a one-pot
procedure in 86% yield. Complete deprotection of the isourea
to give prolinol 39 could be accomplished by heating 2 in
H2SO4/H2O. Surprisingly, at room temperature the tosyl
group can be selectively removed to give the unsubstituted
isourea 10 in 72% yield.
a Isolated yields. Diastereoselectivity was determined by 1H NMR. b 1.2
equiv of TMSOTf, 1.2 equiv of PhIdO, CH2Cl2 (0.1 M), -78 °C to rt.
absence of other reagents, this complex rapidly decomposes
to form MeOTf and PhI. However, in the presence of
compound 1, the reagent can coordinate to the alkene to give
iodonium ion A. This intermediate normally undergoes a
5-exo cyclization through the nitrogen of the urea to give
intermediate B. The iodine of intermediate B is displaced
Scheme 1. Further Transformations of Isourea 2
Based on the products isolated from the reaction of the
urea-tethered alkenes and some initial NMR studies, a
plausible reaction mechanism is depicted in Scheme 2.
TMSOTf reacts with PhIdO to give the highly electrophilic
1
PhI(OTf)(OTMS). Support for this complex is based by H
NMR on newly formed aryl peaks downfield of PhI. In the
Org. Lett., Vol. 10, No. 21, 2008
5041

and 14. This double-displacement mechanism also explains
the selective syn addition observed in compounds 30 and
33.6
Scheme 2. Proposed Reaction Mechanism
In summary, urea-tethered alkenes undergo oxidative
cyclization reactions with PhIdO in the absence of metal
catalysts to generate a variety of new oxidative amination
products. Activation of the iodine reagent with strong acids
leads to the oxyamination product while weaker acids favor
the diamination product. The substitution pattern of the urea
and the alkene influences the product selection in subtle
ways. A variety of substrates, including di- and trisubstituted
alkenes, can be cyclized in good diastereoslectivity to form
isoureas and/or ꢀ-amino alcohols.
Acknowledgment. Werner Kaminsky and John Freudenthal
(University of Washington) are acknowledged for X-ray
crystallography, and the University of Washington and the
American Chemical Society Petroleum Research Fund are
acknowledged for financial support.
intramolecularly by the oxygen of the urea to give oxyami-
nation product 2, or through the nitrogen to give diamination
product 3, with the former being preferred under strongly
acidic conditions due to greater nucleophilicity of the oxygen
atom. Alternatively, alkyl ureas seem to prefer 7-exo
cyclization to form intermediate C. Since further intramo-
lecular attack is impossible, the iodine of intermediate C is
instead displaced with a triflate anion to give products 13
Supporting Information Available: Detailed reaction
conditions and experimental data for synthesis of all new
starting materials, cyclization products, and details of the
X-ray crystal structures of compounds 2 and 40. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL8022165
5042
Org. Lett., Vol. 10, No. 21, 2008