Synthesis of cyclopropanes by Pd-catalyzed activation of alkyl C-H bonds

Article abstract of DOI:10.1016/j.tetlet.2009.10.013

A novel synthesis of cyclopropanes has been developed via palladium-catalyzed C-H activation in which two new carbon-carbon bonds are formed in a single step. This method involves palladium-catalyzed activation of normally unreactive secondary alkyl C-H b

Full text of DOI:10.1016/j.tetlet.2009.10.013

Tetrahedron Letters 50 (2009) 7235–7238
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Synthesis of cyclopropanes by Pd-catalyzed activation of alkyl C–H bonds
*
Qinhua Huang, Richard C. Larock
Department of Chemistry, Iowa state University, Ames, IA 50011, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthesis of cyclopropanes has been developed via palladium-catalyzed C–H activation in which
two new carbon–carbon bonds are formed in a single step. This method involves palladium-catalyzed
activation of normally unreactive secondary alkyl C–H bonds and provides an efficient way to access
cyclopropapyrrolo[1,2-a]indoles, analogues of mitomycin and cyclopropamitosenes.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 22 July 2009
Revised 30 September 2009
Accepted 2 October 2009
Available online 8 October 2009
The ability of palladium to activate C–H bonds has been used
extensively in organic synthesis.1 In recent years, palladium-cata-
lyzed C–H activation has received considerable attention due to a
wide variety of reactions this metal will catalyze. For instance, cata-
lytic amounts of Pd salts have been used to effect the addition of C–H
bonds of electron-rich arenes to alkenes and alkynes, and to effect
the carbonylation.2 We3 and others4 have reported that intramolec-
ular C–H activation in organopalladium intermediates derived from
o-halobiaryls leads to 1,4-palladium migration (Scheme 1). These
migration reactions provide an alternate way to introduce a palla-
dium moiety into organic molecules and have been found to be quite
general. Recently, aryl to aryl,3,4 vinylic to aryl,5 alkyl to aryl,6 aryl to
alkyl,7 vinylic to aryl to allylic,8 benzylic to aryl,9 aryl to benzylic,10
aryl to imidoyl,11 and aryl to acyl12 migrations have been reported
to be a useful tool for the synthesis of a variety of carbocyclic and
heterocyclic ring systems. Herein, we wish to report a novel C–H
activation using palladium chemistry to synthesize cyclopro-
panes,13 especially cyclopropapyrrolo[1,2-a]indoles, analogues of
the mitomycin antibiotics14 and anticancer cyclopropamitosenes.15
During our investigation of Pd-catalyzed aryl to aryl migration
chemistry,3c iodoindole 1 was allowed to react under our standard
palladium migration conditions [5 mol % Pd(OAc)2, 5 mol %
bis(diphenylphosphino)methane (dppm), 2 equiv of CsO2CCMe3
(CsPiv) and DMF as the solvent], and only trace amounts of the de-
sired migration/arylation product 2 were detected (Scheme 2). Sur-
prisingly, compound 3 was isolated in a 42% yield. As shown in
Scheme 2, the indolylpalladium iodide A, formed by palladium
migration from the 2 position of the phenyl group to the 2 position
of the indole ring, apparently reacts with the carbon–carbon double
bond to generate an alkyl intermediate B. Instead of forming a new
carbon–carbon bond at the 2 position of the phenyl group to form
pentacyclic compound 2, the alkylpalladium iodide apparently acti-
vates a normally unreactive alkyl C–H bond through a four-mem-
bered palladacycle C intermediate to generate cyclopropane 3. Due
to our interest in Pd-catalyzed activation of unreactive alkyl C–H
bonds and the substantial biological activities of cyclopropapyrrol-
o[1,2-a]indoles,15 we have investigated this novel Pd-catalyzed
C–H activation and examined its scope by employing various
substrates.
Our initial studies focused on achieving optimal reaction condi-
tions for this novel palladium-catalyzed C–H activation process
employing the isomeric iodoindole 4 (Table 1).
While the reaction of compound 1 generated a 42% yield of the
desired cyclopropane 3 (Scheme 2), the reaction of compound 4
under the same reaction conditions afforded cyclopropane 3 in a
62% yield and compound 2 in a 15% yield (Table 1, entry 1). Omit-
ting dppm as the ligand, the yield dropped from 62% (entry 1) to
37% (entry 2). When the organic base Bu3N was used, cyclopropane
3 was isolated in only a 15% yield (entry 3). When the reaction was
carried out at 100 oC, the yield dropped to 55% and a longer reac-
tion time was required to reach completion (entry 4). Compared
to the reaction using dppm as the ligand (entry 1), when bis(dicy-
clohexylphosphino)methane (dcpm), a more electron-donating li-
gand, was employed, the C–H activation process was much faster
and reached completion in 1.5 h (entry 5). However, the yield de-
creased to 47% from 62% (entry 1). The bases NaOAc, Na2CO3,
Cs2CO3, and KO-t-Bu have also been employed and the desired
cyclopropane 3 has been obtained in yields of 36%, 26%, 52%, and
a trace amount, respectively (entries 6–9). When Pd(PPh3)4 was
employed as the catalyst with and without the addition of dppm,
the reactions were very sluggish and compound 3 was produced
in 30% and 27% yields, respectively (entries 10 and 11). Thus, we
chose the following conditions as our ‘optimal’ reaction conditions:
0.50 mmol of the substrate, 5 mol % Pd(OAc)2, 5 mol % dppm,
2 equiv of CsPiv in DMF (4 mL), stirred at 110 °C under an Ar
atmosphere.
Using our optimal reaction conditions,16 the scope of this novel
Pd-catalyzed C–H activation process has been explored using a
variety of substrates carefully selected in order to establish the
generality of the process and its applicability to commonly
encountered synthetic problems (Table 2). While the reaction of
* Corresponding author. Tel.: +1 515 294 4660; fax: +1 515 294 0105.
E-mail address: larock@iastate.edu (R.C. Larock).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.013

7236
Q. Huang, R. C. Larock / Tetrahedron Letters 50 (2009) 7235–7238
X
X
X
X
X
CO2Et
1,4-Pd
shift
CO2Et
PdI
+
cat. Pd(0)
I
PdI
CO2Et
Scheme 1.
Ph
5 mol % Pd(OAc)2
+
I
N
5 mol % dppm
2 equiv CsPiv
110 oC, DMF
N
N
3
2
trace
42%
1
PdI
PdI
N
PdI
N
N
N
Pd
C
B
A
Scheme 2.
of the indole ring circumventing cyclopropane formation, although
we failed to isolate any recognizable products (Scheme 3).17 This
type of alkyl to aryl palladium migration has been observed previ-
ously in our research group under the same reaction conditions.6
To test if the C–H activation process occurs when forming a new
six-membered ring, we have prepared compounds 9 and 11 and
carried out the corresponding reactions under our optimal reaction
conditions (entries 5 and 6). Although the yields are a little lower,
the anticipated new fused six-membered ring systems can be gen-
erated by this Pd-catalyzed alkyl C–H activation chemistry.
Is the indole nitrogen essential to this C–H activation process?
To answer this question, compounds 13 and 15 were employed un-
der our optimal reaction conditions. Unfortunately, only trace
amounts of the desired cyclopropane products 14 and 16 were de-
tected by GC analysis (entries 7 and 8). It appears that the indole
ring system is critical to formation of the cyclopropanes by this
Pd-catalyzed C–H activation process. Consistent with this observa-
tion is the fact that the reaction of compound 17 afforded none of
the desired cyclopropane product. It is quite possible that com-
Table 1
Optimization reactions for the synthesis of compound 3a,b
Ph
5 mol % Pd
Ph
5 mol % ligand
I
+
N
2 equiv base, DMF
N
N
4
3
2
Entry
Catalyst
Ligand
Base
T (°C)
Time (h)
Yield of 3 (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
dppm
—
—
CsPiv
CsPiv
Bu3N
CsPiv
110
110
110
100
110
115
110
115
115
110
110
6
62c,d
37c
12
72
24
1.5
24
72
48
0.5
72
72
15c
dppm
dcpm
dppm
dppm
dppm
dppm
dppm
—
55e
47e
36e
26e
52e
Trace
30e
27e
CsPiv
NaOAc
Na2CO3
Cs2CO3
KOtBu
Na2CO3
Na2CO3
10
11
Pd(PPh3)4
Pd(PPh3)4
a
pound 17 under our reaction conditions may generate a p-allylpal-
All reactions were carried out under the following reaction conditions:
0.25 mmol of compound 4, 5 mol % Pd catalyst, 5 mol % ligand, 2 equiv of base in
ladium intermediate, which circumvents cyclopropane formation.
When compound 19 was employed, the reaction again failed to
produce any cyclopropane product. However, 2-iodo-3-phenylin-
dole was isolated in a 72% yield (entry 10). This product probably
arises by simple decomposition of the N-(alkoxycarbonyl)indole.
When, aryl bromide 21 was allowed to react under our optimal
reaction conditions, none of the desired cyclopropane product
was detected (entry 11).
4 mL of DMF at the indicated temperature under an Ar atmosphere.
b
Along with cyclopropane 3, another cyclopropane product, generated by having
the palladium intermediate close onto the methyl group, has been obtained in a 5–
10% yield.
c
Isolated yield.
Compound 2 was isolated in a 15% yield.
The yield is based on gas chromatographic analysis.
d
e
In conclusion, a novel palladium-catalyzed activation of simple
alkyl C–H bonds has been investigated as a unique new way to
form polycyclic cyclopropanes. Our experiments indicate that the
indole ring is apparently critical to this activation process,
although the reason for this is not clear. This method provides a
facile method to access cyclopropapyrrolo[1,2-a]indoles and cyclo-
propapiperido[1,2-a]indoles.
compound 4 afforded cyclopropane 3 in a 62% yield (entry 2), the
reaction of iodoindole 5 generated cyclopropane 6 in a 46% yield
(entry 3). Iodoindole 7, with no substituent in the 3 position of
the indole ring, has been allowed to react under our optimal reac-
tion conditions, but only a trace amount of the desired product was
detected. It is quite possible that the alkylpalladium intermediate
first produced undergoes palladium migration to the 3 position

Q. Huang, R. C. Larock / Tetrahedron Letters 50 (2009) 7235–7238
7237
Table 2
Table 2 (continued)
Pd-catalyzed cyclopropanation through C–H activationa,b
Entry
Aryl iodide
Time (h)
12
Product
% Yieldc
Entry
Aryl iodide
Time (h)
Product
% Yieldc
O
O
9
0
I
18
I
17
1
8
42
N
N
3
1
Ph
N
Ph
I
I
N
10
12
72
H
O
20
O
2
6
3
62
I
N
19
4
Br
CH3
I
CH3
11
24
Trace
22
3
12
40 (46d)
N
N
21
6
a
All reactions were carried out under the following reaction conditions, unless
5
otherwise specified: 0.5 mmol of the substrate, 5 mol % Pd(OAc)2, 5 mol % dppm,
2 equiv of CsPiv in 4 mL of DMF at 110 °C under an Ar atmosphere.
b
For entries 1–3, 5, and 6, along with the desired cyclopropane derivative,
another cyclopropane product has been detected in 5–10% yields, in which the
palladium closes onto the methyl group.
c
Isolated yield.
I
d
The yield was determined by gas chromatographic analysis.
N
N
4
5
6
12
16
18
Trace
31d
42
8
7
PdI
I
Pd0
PdI Pd migration
N
CH3
I
CH3
N
N
N
N
7
10
9
Scheme 3.
Acknowledgments
Ph
I
Ph
We thank the National Science Foundation for the financial sup-
port of this research and Johnson Matthey, Inc., and Kawaken Fine
Chemicals Co., Ltd, for donations of palladium catalysts.
N
N
12
11
References and notes
1. For recent reviews on metal-catalyzed C–H activation see: (a) Ma, S.; Gu, Z.
Angew. Chem., Int. Ed. 2005, 44, 7512–7517; (b) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. Rev. 2002, 102, 1731–1770; (c) Li, C.-J. Acc. Chem. Res. 2002, 35, 533–538.
2. (a) Fujiwara, Y.; Jia, C. Handbook of Organopalladium Chemistry for Organic
Synthesis 2002, 2, 2859–2862; (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem.
Res. 2001, 34, 633–639.
3. (a) Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2002, 124, 14326–14327; (b)
Campo, M. A.; Zhang, H.; Yao, T.; Ibdah, A.; McCulla, R. D.; Huang, Q.; Zhao, J.;
Jenks, W. S.; Larock, R. C. J. Am. Chem. Soc. 2007, 129, 6298–6307; (c) Campo, M.
A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 11506–
11507.
4. Karig, G.; Moon, M.-T.; Thasana, N.; Gallagher, T. Org. Lett. 2002, 4, 3115–3118.
5. (a) Larock, R. C.; Tian, Q. J. Org. Chem. 2001, 66, 7372–7379; (b) Tian, Q.; Larock,
R. C. Org. Lett. 2000, 2, 3329–3332; (c) Zhao, J.; Larock, R. C. J. Org. Chem. 2006,
71, 5340–5348; (d) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 701–704; (e) Bour,
C.; Suffert, J. Org. Lett. 2005, 7, 653–656; (f) Mota, A. J.; Dedieu, A.; Bour, C.;
Suffert, J. J. Am. Chem. Soc. 2005, 127, 7171–7182.
7
3
<5%
14
I
13
I
CO2Et
CO2Et
CO2Et
CO2Et
8
12
Trace
15
16

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Q. Huang, R. C. Larock / Tetrahedron Letters 50 (2009) 7235–7238
6. Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004,
126, 7460–7461.
7. Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem., Int. Ed. 2003, 42, 5736–
5740.
R. J.; Norton, C. L.; O’ Sullivan, N.; Stephens, M. A.; Stradiotto, N. R.; Swann, E.;
Stratford, I. J. J. Med. Chem. 1994, 37, 3834–3843; (c) Naylor, M. A.; Jaffar, M.;
Nolan, J.; Stephens, M. A.; Butler, S.; Patel, K. B.; Everett, S. A.; Adams, G. E.;
Stratford, I. J. J. Med. Chem. 1997, 40, 2335–2346.
8. Zhao, J.; Campo, M. A.; Larock, R. C. Angew. Chem., Int. Ed. 2005, 44, 1873–1875.
9. Wang, L.; Pan, Y.; Jiang, X.; Hu, H. Tetrahedron Lett. 2000, 41, 725–727.
10. Kesharwani, T.; Larock, R. C. Tetrahedron 2008, 64, 6090–6102.
11. (a) Zhang, X.; Larock, R. C. In Handbook of CÀH Transformations; Dyker, G., Ed.;
Wiley-VCH: Weinheim, 2005; p 309; (b) Zhao, J.; Yue, D.; Campo, M. A.; Larock,
R. C. J. Am. Chem. Soc. 2007, 129, 5288–5295.
12. Kesharwani, T.; Verma, A. K.; Emrich, D.; Ward, J. A.; Larock, R. C. Org. Lett.
2009, 11, 2591–2593.
13. For recent reviews regarding cyclopropanes, see: (a) Donaldson, W. A.
Tetrahedron 2001, 57, 8589–8627; (b) Kulinkovich, O. G. Chem. Rev. 2003,
103, 2597–2632; (c) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151–
1196.
14. For recent reviews on mitomycin, see: (a) Colucci, M. A.; Couch, G. D.; Moody,
C. J. Org. Biomol. Chem. 2008, 6, 637–656; (b) Abraham, L. M.; Selva, D.; Casson,
R.; Leibovitch, I. Drugs 2006, 66, 321–340.
15. For leading references on cyclopropamitosenes, see: (a) Moody, C. J.; O’
Sullivan, N.; Stratford, I. J.; Stephens, M. A.; Workman, P.; Bailey, S. M.; Lewis, A.
Anti-Cancer Drugs 1994, 5, 367–372; (b) Cotterill, A. S.; Moody, C. J.; Mortimer,
16. Representive Pd-catalyzed cyclopropanation procedure (entry 2, Table 2): To a 6
dram vial were added Pd(OAc)2 (6.0 mg, 0.025 mmol), dppm (9.2 mg,
0.025 mmol), CsPiv (234 mg, 1.0 mmol), compound 4 (0.50 mmol), and dry
DMF (4 mL). The reaction mixture was stirred at 25 °C under an Ar atmosphere
for 5 min, and was then stirred at 110 °C for 6 h to reach completion. The
reaction mixture was allowed to cool to 25 °C, diluted with Et2O (20 mL), and
washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was subjected to
purification by chromatography to afford 80 mg of the desired cyclopropane 3
in a 62% yield as a white solid; mp 158–160 °C; 1H NMR (CDCl3) d 1.01–1.03
(m, 1H), 1.28 (dd, J = 4.8, 8.0 Hz, 1H), 1.46 (s, 3H), 2.08–2.10 (m, 1H), 4.05 (d,
J = 6.4 Hz, 1H), 4.24 (dd, J = 5.6, 10.4 Hz, 1H), 7.06–7.17 (m, 3H), 7.25–7.29 (m,
1H), 7.42–7.46 (m, 2H), 7.61 (dd, J = 0.8, 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H); 13C
NMR (CDCl3) d 17.5, 23.6, 24.2, 28.8, 46.5, 108.4, 109.2, 119.3, 119.7, 121.2,
125.6, 128.4, 129.5, 131.3, 132.8, 135.2, 145.7; IR (CHCl3, cmÀ1) 3018, 2930,
1602, 1478, 1460, 1216; HRMS calcd for C19H17N: 259.1361. Found: 259.1365.
17. For compounds 4 (entry 2) and 5 (entry 3), the 3-position of the indole ring is
blocked; therefore, 1,4 alkyl to aryl migration is prohibited.