Converting gem-dimethyl groups into cyclopropanes via Pd-catalyzed sequential C-H activation and radical cyclization

Article abstract of DOI:10.1021/ol0618858

(Diagram presented) A novel route to the synthesis of cyclopropane derivatives is described. 1,1-Dimethyls in 2-(1,1-dimethylalkyl) dimethyloxazolines are first converted into 1,3-diiodide derivatives via Pd-catalyzed sequential C-H activation and then radically cyclized to provide 2-(1-alkylcylclopropyl)-dimethyloxazolines. The use of EtOAc as a solvent is crucial for the diiodination of the functionalized substrates.

Full text of DOI:10.1021/ol0618858

ORGANIC
LETTERS
2
006
Vol. 8, No. 25
685-5688
Converting gem-Dimethyl Groups into
Cyclopropanes via Pd-Catalyzed
5
Sequential C−H Activation and Radical
Cyclization
Ramesh Giri, Masayuki Wasa, Steven P. Breazzano, and Jin-Quan Yu*
Department of Chemistry MS015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
yu200@brandeis.edu
Received July 30, 2006
ABSTRACT
A novel route to the synthesis of cyclopropane derivatives is described. 1,1-Dimethyls in 2-(1,1-dimethylalkyl)dimethyloxazolines are first
converted into 1,3-diiodide derivatives via Pd-catalyzed sequential C H activation and then radically cyclized to provide 2-(1-alkylcylclopropyl)-
dimethyloxazolines. The use of EtOAc as a solvent is crucial for the diiodination of the functionalized substrates.
−
Cyclopropanes serve as versatile building blocks in organic
synthesis because of their ability to undergo various trans-
formations. The rigid carbocyclic system has been of great
has warranted increasing research interests. Therefore, novel
approaches to construct them in a variety of molecular
backbones would be of considerable significance. Cyclo-
propanes are commonly synthesized from alkenes by Sim-
1
value to alter the activity of biologically active compounds
2
5
by restricting their conformation. Their widespread occur-
mons-Smith and related reactions, transition metal-
3
4
6
rence in natural products and biologically active analogues
catalyzed carbene transfer, and Michael-initiated ring closure
7
(
MIRC). Recently, more diverse approaches have been
(
1) For recent reviews, see: (a) Kulinkovich, O. G. Chem. ReV. 2003,
sought to synthesize variously functionalized cyclopropane
derivatives. However, less attention has been paid to the
formation of cyclopropane derivatives from 1,3-dihalides via
a radical cyclization. 1,3-Dihalogen derivatives can be
reductively cyclized to cyclopropanes by using metal reduc-
1
1
03, 2597-2632. (b) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103,
8
151-1196.
(
2) (a) Kazuta, Y.; Matsuda, A.; Shuto, S. J. Org. Chem. 2002, 67, 1669-
1
677. (b) Reddy, V. K.; Valasinas, A.; Sarkar, A.; Basu, H. S.; Marton, L.
J.; Frydman, B. J. Med. Chem. 1998, 41, 4723-4732. (c) Shuto, S.; Ono,
S.; Imoto, H.; Yoshii, K.; Matsuda, A. J. Med. Chem. 1998, 41, 3507-
3
514. (d) Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.; Takada, H.;
Yamasihita, K.; Matsuda, A. J. Org. Chem. 1996, 61, 915-923.
(5) For reviews, see: (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.;
Charette, A. B. Chem. ReV. 2003, 103, 977-1050. (b) Lautens, M.; Klute,
W.; Tam, W. Chem. ReV. 1996, 96, 49-92. (c) Hoveyda, A. H.; Evans, D.
A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.
(6) For reviews, see: (a) Maas, G. Chem. Soc. ReV. 2004, 33, 183-190.
(b) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911-935. (c) Doyle,
M. P.; Protopopova, M. N. Tetrahedron, 1998, 54, 7919-7946.
(7) Little, R. D; Dawson, J. R. Tetrahedron Lett. 1980, 21, 2609-2612.
(8) (a) Azin Quntar, A. A.; Srebnik, M. J. Org. Chem. 2006, 71, 730-
733. (b) Okamoto, N.; Sasaki, M.; Kawahata, M.; Yamaguchi, K.; Takeda,
K. Org. Lett. 2006, 8, 1889-1891. (c) Ma, S.; Jiao, N.; Yang, Q.; Zheng,
Z. J. Org. Chem. 2004, 69, 6463-6466.
(
3) (a) Beaulieu, P. L.; Gillard, J.; Bailey, M. D.; Boucher, C.; Duceppe,
J.-S.; Simoneau, B.; Wang, X.-J.; Zhang, L.; Grozinger, K.; Houpis, I.;
Farina, V.; Heimroth, H.; Krueger, T.; Schnaubelt, J. J. Org. Chem. 2005,
7
0, 5869-5879. (b) Wipf, P.; Reeves, J. T.; Balachandran, R.; Day, B. W.
J. Med. Chem. 2002, 45, 1901-1917. (c) Salaun, J. Top. Curr. Chem. 2000,
07, 1-67. (d) Wipf, P.; Xu, W. J. Org. Chem. 1996, 61, 6556-6562.
4) (a) Devreux, V.; Wiesner, J.; Goeman, J. L.; Van der Eycken, J.;
2
(
Jomaa, H.; Van Calenbergh, S. J. Med. Chem. 2006, 49, 2656-2660. (b)
Frydman, B.; Blokhin, A. V.; Brummel, S.; Wilding, G.; Maxuitenko, Y.;
Sarkar, A.; Bhattacharya, S.; Church, D.; Reddy, V. K.; Kink, J. A.; Marton,
L. J.; Valasinas, A.; Basu, H. S. J. Med. Chem. 2003, 46, 4586-4600.
1
0.1021/ol0618858 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/09/2006

9
9b,c,10
tion, metal-hydride reduction,
metal-halogen inter-
attempted to convert oxazoline 1 to a 1,3-diiodide derivative.
Despite the use of high reaction temperature (120 °C) and a
surplus amount of the oxidant (3 equiv), the reaction in
different solvents such as CH Cl , DCE, and EtOAc provided
the monoiodide as the predominant product. We anticipated
that sequential C-H activation could be achieved if a
sterically less demanding nonchiral oxazoline was used. We
were delighted to find that the diiodide can be obtained as a
11
12
change reactions, and metal complexes. Leonard reported
a single case of cyclopropanation of 1,3-diiodopropane in
quantitative yield using benzoyl peroxide via radical-induced
γ-elimination.13 Although these methods produce excellent
yields of cyclopropane derivatives, they have found limited
utility in synthesis because of the lack of a general procedure
to access the required 1,3-dihalides.10,14 Herein, we report a
novel route to prepare 2,2-disubstituted 1,3-diiodide deriva-
tives from 2-(1,1-dimethylalkyl)dimethyloxazolines via Pd-
2
2
main product by using 1 equiv of the oxidant (PhI(OAc)
). Thus, stirring substrate 2 with 10 mol % Pd(OAc) , 1
equiv of PhI(OAc) , and 1 equiv of I in CH Cl for 2.5 h at
5 °C gave mono- and diiodinated products 2a and 2b in
0% and 70% yields, respectively (Table 1). The triiodinated
2
/
I
2
2
3
catalyzed sequential sp C-H activation and subsequent
2
2
2
2
conversion to cyclopropane derivatives by radical cyclization.
This protocol provides an unusual conversion of gem-
dimethyl into cyclopropyl groups in good yields. Remark-
ably, the diiodination reaction can be carried out in gram-
scale quantity and also the catalytic system allows the reuse
of the Pd catalyst for at least five times by simply decanting
the reaction solution.
6
1
Table 1. Pd-Catalyzed Di- and Triiodination of
2
-(tert-Butyl)dimethyloxazolinea
We have recently reported the use of oxazoline as the
directing group for Pd-catalyzed room temperature monoio-
3
2
15
dination of sp and sp C-H bonds using IOAc as the
terminal oxidant. IOAc generated from the reaction of I with
or AgOAc is a superior oxidant for mild
2
16
17
either PhI(OAc)
2
condition C-H functionalization (eqs 1-2). A highly
selective monoiodination was achieved by using a sterically
bulky chiral group in the oxazoline ring (Scheme 1).
a
Isolated yields (NMR yields).
Scheme 1. Pd-Catalyzed Selective Monoiodination
product can also be obtained in excellent yield, albeit
requiring much longer reaction time (24 h). Both di- and
triiodinated products are easily separable by column chro-
matography.
The requisite 2-(1,1-dimethylalkyl)dimethyloxazolines were
prepared from 2-amino-2-methyl-1-propanol and the corre-
sponding carboxylic acids. Sterically crowded substrates such
as tert-butyloxazoline 5 and adamantyloxazoline 6 reacted
very well to provide diiodides 5a and 6a in good yields
AgOAc + I f AgI + IOAc
(1)
(2)
2
PhI(OAc) + I f PhI + IOAc
2
2
(
Table 2). The diiodination reaction also tolerated primary
The multistep C-H activation process using a single
directing group represents one way of enhancing the practical
efficiency of directed C-H activation reactions. In our effort
to carry out multistep C-H activation, we rigorously
halogens such as in substrates 7 and 8 giving good yields of
diiodides 7a and 8a.
However, the reaction ceased to proceed after monoiodi-
nation in oxygen- and nitrogen-containing substrates such
as 9 and 10. Very low yield (30%) of diiodinated product
(9) (a) Sakuma, D.; Togo, H. Tetrahedron 2005, 61, 10138-10145. (b)
Newman, M. S.; Cohen, G. S.; Cunico, R. F.; Dauernheim, L. W. J. Org.
Chem. 1973, 38, 2760-2763. ( c) Newman, M. S.; LeBlanc, J. R.; Karnes,
H. A.; Axelrad, G. J. Am. Chem. Soc. 1964, 86, 868-872. (d) Wiberg, K.
B.; Lampman, G. M. Tetrahedron Lett. 1963, 4, 2173-2175. (e) Kelso, R.
G.; Greenlee, K. W.; Derfer, J. M.; Boord, C. E. J. Am. Chem. Soc. 1955,
9
b was obtained in methylene chloride even after prolonged
reaction time (72 h) at elevated temperature (100 °C) with
a surplus amount of PhI(OAc)/I (4 equiv each) (Table 3,
2
7
7, 1751-1755. (f) Kelso, R. G.; Greenlee, K. W.; Derfer, J. M.; Boord,
entry 1). No diiodinated product was formed in DCE.
Reactions carried out in benzene and HOAc at 100 °C for
48 h provided low yields of the diiodinated product 9b.
C. E. J. Am. Chem. Soc. 1952, 74, 287-292.
(
10) Curran, D. P.; Gabarda, A. E. Tetrahedron 1999, 55, 3327-3336.
(11) Bailey, W. F.; Gagnier, R. P.; Patricia, J. J. J. Org. Chem. 1984,
4
9, 2098-2107.
12) Takeda, T.; Shimane, K.; Fujiwara, T.; Tsubouchi, A. Chem. Lett.
(
2
002, 31, 290-291.
(16) For the generation of IOAc in situ from I2 and PhI(OAc)2, see: (a)
Reference 15. (b) Wang, D.-H.; Hao, X.-S.; Wu, D.-F.; Yu, J.-Q. Org. Lett.
2006, 8, 3387-3390. ( b) Courtneidge, J. L.; Lusztyk, J.; Pag e´ , D.
Tetrahedron Lett. 1994, 35, 1003-1006.
(17) For the generation of IOAc in situ from I2 and AgOAc, see: (a)
Cambie, R. C.; Chambers, D.; Rutledge, P. S.; Woodgate, P. D. J. Chem.
Soc., Perkin Trans. I 1978, 12, 1483-1485. (b) Rubottom, G. M.; Mott, R.
C. J. Org. Chem. 1979, 44, 1731-1734.
(
13) Leonard, K. J. Am. Chem. Soc. 1967, 89, 1753.
(14) (a) Kabalka, G. W.; Wu, Z.; Ju, Y.; Yao, M.-L. J. Org. Chem. 2005,
7
2
0, 10285-10291. (b) Kabalka, G. W.; Wu, Z.; Ju, Y. Tetrahedron Lett.
001, 42, 5793-5796.
(15) (a) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44,
2
112-2115. (b) Giri, R.; Chen, X.; Hao, X.-S.; Li, J.-J.; Liang, J.; Fan,
Z.-P.; Yu, J.-Q. Tetrahedron: Asymmetry 2005, 16, 3502-3505.
5686
Org. Lett., Vol. 8, No. 25, 2006

stirring a mixture of substrate 9, 10 mol % Pd(OAc)
2
, and
PhI(OAc) /I (2 equiv each at 0 h, 1 equiv each at 24 h) in
2
2
Table 2. Pd-Catalyzed Diiodination of
a
EtOAc at 100 °C for 48 h gave the diiodinated product 9b
in 83% isolated yield. This new iodination procedure
displayed a better functional group tolerance. Substrates such
as phthalimide-protected R-amino- and TBS-protected R-hy-
droxy oxazolines 10 and 11 respectively could be diiodinated
in good yields (Table 4). Interestingly, nonfunctionalized
2
-(1,1-Dimethylalkyl)dimethyloxazolines
Table 4. Pd-Catalyzed Diiodination of
2
-(1,1-Dimethylalkyl)dimethyloxazolines Containing Ether and
a
Imide Functionalities
a
Reagents and conditions: 10 mol % Pd(OAc)2, 1-3 equiv of PhI(OAc)2
and I2, CH2Cl2, 65 °C, 24-48 h. Isolated yields (NMR yields). c 30 mmol
scale reaction.
b
a
Reagents and conditions: 10 mol % Pd(OAc)2, 3 equiv of PhI(OAc)2
and I2, EtOAc, 100 °C, 48 h. b Isolated yields (NMR yields). 115 °C, 72
h. Contains ca. 10% monoiodide as an impurity and the given NMR and
isolated yields refer to diiodide 10a only.
c
Reactions attempted in other solvents such as toluene, DMF,
MeCN, and NMP proved futile as no iodinated product was
observed.
substrates 2-6 and halogen-containing substrates 7 and 8
gave lower yields of the corresponding diiodinated products
Table 3. Solvent Screening for Diiodination Reactiona
in EtOAc in comparison to the reactions carried out in CH
Cl (see the Supporting Information).
A clear advantage of this catalytic system is that the
reaction can be carried out in gram-scale quantity (5.08 g,
0 mmol, substrate 3) and the palladium catalyst can be easily
recycled (Table 5). As PdI precipitates from the solution
2
-
2
3
2
Table 5. Recycling Experiment with Substrate 3a
run
yield (%)
1
80
2
76
3
78
4
75
5
76
b
a
Reagents and conditions: 10 mol % Pd(OAc)2, 2 equiv of PhI(OAc)2
and I2, CH2Cl2, 65 °C, 24 h. b Isolated yields.
toward the completion of reaction, it can be isolated by
centrifugation and reused for the next run using the same
amount of oxidant. With substrate 3, five runs of diiodination
reaction (10 mmol each run) starting with only 0.224 g (10
a
Reagents and conditions: 2 equiv of PhI(OAc)2/I2 at 0 h and 1 equiv
b
c
d
at 24 h. Isolated yields. 72 h, 4 equiv of PhI(OAc)2/I2. 5 mmol scale
reaction.
2
mol %) of Pd(OAc) produced 16.2 g (38.5 mmol) of the
diiodinated product 3a.
With variously functionalized 2,2-disubstituted 1,3-diio-
dide derivatives in hand, we proceeded to test the feasibility
of using Leonard’s procedure to radically carbocyclize the
t
Remarkably, the reaction carried out in EtOAc or BuOAc
produced the diiodinated product in good yields. Thus,
Org. Lett., Vol. 8, No. 25, 2006
5687

diiodides into cycloproanes.18 Heating a stirred solution of
diiodide 2b and benzoyl peroxide (2 equiv) in benzene at
substituents. It is interesting to note that the iodide substituent
in the triiodide substrate 2c remained intact as neither a
benzoylated nor hydroxylated cyclopropane derivative was
detected. The procedure was also compatible with an ester
substrate 9b, TBS-protected hydroxy substrates 11a and 12a,
and phthalimide-protected R-amino substrate 10a.19 The
facile hydrolysis of nonfunctionalized and functionalized
cyclopropane oxazolines 3b, 9c, and 12b to the correspond-
ing cyclopropanecarboxylic acids (Table 7) in high yields
115 °C for 2 h produced 1-methylcyclopropane oxazoline
2d in quantitative yield by NMR (Table 6).
Table 6. Radical Cyclization of 2,2-Disubstituted
1
,3-Diiodidesa
Table 7. Hydrolysis of Cyclopropapane Oxazolinesa
a
Reagents and conditions: 4 N H2SO4:dioxane (1:1), 100 °C, 15 h.
b
Isolated yields.
demonstrates the practicality of the current cyclopropanation
protocol.
In summary, we have developed a novel protocol to access
1
,3-diiodide and cyclopropane carboxylic acid derivatives
3
via Pd-catalyzed sequential sp C-H activation and radical
cyclization. The newly developed protocol provides an
efficient route to prepare variously functionalized 2,2-
disubstituted 1,3-diiodides and a unique procedure to con-
struct cyclopropane building blocks from readily available
R,R-dimethylcarboxylic acids. Moreover, the diiodination
reaction can be carried out in gram-scale quantity and the
catalyst can be readily recycled.
Acknowledgment. We thank Brandeis University and the
U.S. National Science Foundation (NSF CHE-0615716) for
financial support and the Camille and Henry Dreyfus
Foundation for a New Faculty Award. We also thank the
NSF for a REU Fellowship to S.P.B.
Supporting Information Available: Experimental pro-
cedure and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a
Reagents and conditions: 2 equiv of benzoyl peroxide, C6H6, 115 °C,
b
2
h. Isolated yields. Substrates are quantitatively converted into the
1
c
cyclopropane products as measured by H NMR. Contains ca. 8% benzoyl
peroxide as an impurity and the given NMR and isolated yields refer to
diiodide 2e only.
OL0618858
(19) For recent publications to prepare aminocyclopropanecarboxylic acid
derivatives, see: (a)Adams, L. A.; Aggarwal, V. K.; Bonnert, R. V.; Bressel,
B.; Cox, R. J.; Shepherd, J.; de Vicente, J.; Walter, M.; Whittingham, W.
G.; Winn, C. L. J. Org. Chem. 2003, 68, 9433-9440. (b) Barluenga, J.;
Aznar, F.; Guti e´ rrez, I.; Garc ´ı a-Granda, S.; Llorca-Baraga n˜ o, M. A. Org.
Lett. 2002, 4, 4273-4276. (c) Zhao, Z.; Liu, H.-w. J. Org. Chem. 2002,
67, 2509-2514.
Halogen (Cl, Br)-containing substrates 7a and 8a were
selectively cyclized only at the carbons containing iodide
(18) Reactions of substrates 6a, 9b, and 11a with Zn powder in refluxing
ethanol did not produce the corresponding cyclopropanes (see ref 9a).
5688
Org. Lett., Vol. 8, No. 25, 2006