Rhodium carbenoid induced intermolecular C-H functionalization at tertiary C-H bonds

Article abstract of DOI:10.1055/s-0028-1087388

Rhodium carbenoid induced intermolecular C-H functionalization can occur at either primary, secondary, or tertiary C-H bonds. This study illustrates the investigation for the optimum systems for reaction at tertiary C-H bonds. Georg Thieme Verlag Stuttgar

Full text of DOI:10.1055/s-0028-1087388

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151
Rhodium Carbenoid Induced Intermolecular C–H Functionalization at
Tertiary C–H Bonds
Selective C–H
F
t
unctio
i
nalizat
e
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30097, USA
E-mail: hmdavie@emory.edu
Received 6 October 2008
asymmetric fashion. Selective C–H functionalization at
primary C–H bonds requires that the primary C–H bond is
electronically activated, while more highly functionalized
sites are appropriately deactivated, such as substrates 5–
7.17–19 An impressive example of the steric influence is the
reaction of N-Boc-N-methylbenzylamine (6),17 which is
selectively functionalized at the methyl group over the
electronically activated benzyl group. Dimethoxyethane
(7)18 is preferentially functionalized at the primary C–H
bond because the secondary C–H bond is deactivated by
an electron-withdrawing b-oxygen group. A detailed as-
sessment of the relative rates of reaction of different C–H
bonds with dirhodium complexes confirmed that tertiary
C–H bonds are, in the most part, inaccessible.12,14,20 Very
few examples of selective insertion into tertiary C–H
bonds are known.
Abstract: Rhodium carbenoid induced intermolecular C–H func-
tionalization can occur at either primary, secondary, or tertiary
C–H bonds. This study illustrates the investigation for the optimum
systems for reaction at tertiary C–H bonds
Key words: intermolecular C–H insertion, C–H functionalization,
aryldiazoacetate, dirhodium
The metal-catalyzed selective functionalization of C–H
bonds is an area of intense current interest.1,2 Two distinct
approaches have been developed to achieve such an out-
come. The most widely employed has been the insertion
of a metal complex into a C–H bond, followed by a sub-
sequent transformation to generate synthetically useful
organic products.3–7 An alternative approach has been to
insert a metal carbenoid8–10 or nitrenoid intermediates11
into the C–H bond, leading directly to the functionalized
product (Scheme 1). We have demonstrated that donor/
acceptor-substituted rhodium carbenoid intermediates are
capable of highly regioselective and stereoselective C–H
insertions.10 The insertion occurs in a concerted, nonsyn-
chronous manner, building positive charge at carbon of
the C–H bond.12 Thus, substrates that are capable of stabi-
lizing charge build-up during the insertion are favored in
this chemistry. However, charge stabilization is not the
only factor involved. The generally large nature of the car-
benoid reagent demands that steric considerations play a
role. Hence, sterically crowded sites on the substrate are
effectively protected from C–H functionalization.10
OTBS
TBSO
OAc
1
2
3
N
Boc
N
Si Si
TBDPSO
N
Boc
5
6
4
7
O
O
9
8
a
Figure 1 Examples of selective C–H functionalization (>95:5
regioselectivity) at secondary (1–4), primary (5–7), and tertiary (8
and 9) C–H bonds
LnRh2
EDG
H
C b
EWG
EWG
EDG
EWG
H
EDG
a
c
c
a
c
N2
C
b
δ-
H
C
b
LnRh2
δ+
The two most significant substrates are 2-methylbutane
(8)12 and adamantane (9).12,21 This paper will describe the
expansion of the C–H functionalization to a wider range
of tertiary C–H bonds as part of an extensive ongoing in-
vestigation into the exploration of the scope of C–H func-
tionalization with donor/acceptor carbenoids.
Scheme 1 C–H Functionalization by rhodium carbenoids
In recent years we have demonstrated that highly regiose-
lective C–H insertions can be achieved. In general, sec-
ondary C–H bonds are most favorable because they tend
to display the best balance between steric and electronic
effects. Some illustrative examples of effective substrates
are shown in structures 1–4 (Figure 1).13–16 While many of
these substrates have multiple C–H bonds, selective C–H
functionalization can be efficiently achieved in a highly
Two dirhodium complexes have emerged as the premier
chiral catalysts for this chemistry.22 The most well estab-
lished is Rh2(S-DOSP)423 but in recent years, studies have
indicated that Rh2(S-PTAD)4 has complimentary reactivi-
ty and often displays different product ratios to those of
Rh2(S-DOSP)4 (Figure 2). Consequently, in this study,
both catalysts were evaluated for their effectiveness for
reaction at tertiary C–H bonds.
SYNLETT 2009, No. 1, pp 0151–0154
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x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087388; Art ID: S10408ST
© Georg Thieme Verlag Stuttgart · New York

152
E. Nadeau et al.
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C–H insertion product 20 and the primary C–H insertion
product 21, while the Rh2(S-PTAD)4-catalyzed reaction
gave a 4:1 ratio (Scheme 4). In line with our previous ob-
servations, the highest asymmetric induction in the forma-
tion of 20 (62% ee) was obtained in the reaction with
Rh2(S-DOSP)4.
O
O
Rh
Rh
H
O
Rh
Rh
H
O
O
O
N
N
SO2C6H4(C12H25
)
4
4
Rh2(S-DOSP)4
N2
Rh2(S-PTAD)4
Rh(II)
Ph
CO2Me
CO2Me
16
Figure 2 Chiral dirhodium catalysts
MeO
2,2-DMB
50 °C
MeO
15
Rh(II)
11
The first system examined was isopropylbenzene (10,
Scheme 2). Previously, it has been shown that the aromat-
ic ring in this substrate was reactive towards donor/accep-
tor carbenoids.14 This was indeed the case here, although
both catalysts influenced the overall reaction. In the
Rh2(S-DOSP)4-catalyzed reaction of phenyldiazoacetate
11 with 10, a mixture of the C–H insertion product 12 and
the double cyclopropanation product 13 were formed in
about a 1:2 ratio. The same reaction catalyzed by Rh2(S-
PTAD)4 gave a slightly improved isolated yield of the
C–H insertion product 12, but the byproducts were a mix-
ture of the di- and the monocyclopropanated products, 13
and 14. Neither catalyst generated 12 with much asym-
metric induction (<10% ee). In both cases, no insertion
occurred at the primary C–H positions.
Yield (%)
ee (%)
48
81
48
Rh2(S-DOSP)4
Rh2(S-PTAD)4
11 (–)
N2
Rh(II)
Ph
CO2Me
CO2Me
18
MeO
2,2-DMB
50 °C
MeO
17
11
Yield (%a)
Rh(II)
ee (%)
39
54
20
16
Rh2(S-DOSP)4
Rh2(S-PTAD)4
a Determined from internal 1H NMR standard.
Scheme 3 Reaction of 11 with p-isopropylanisole and p-cyclo-
pentylanisole
Benzene rings can be sterically protected against reactions
of donor/acceptor carbenoids through 1,4-disubstitu-
tion.14,24 Thus, the reactions of p-isopropylanisole (15)
and p-cyclopentylanisole (17) gave reasonable yields of
the tertiary C–H insertion products, 16 and 18, respective-
ly, without evidence of reaction occurring at the aromatic
ring or the primary C–H positions (Scheme 3). In general,
the Rh2(S-PTAD)4-catalyzed reactions gave the highest
yields of product, while the Rh2(S-DOSP)4-catalyzed re-
actions gave the highest enantioselectivity.
CO2Me
11
Rh(II)
+
MeO2C
2,2-DMB
50 °C
19
21
20
ratioa
20/21
Combined
yield (%)
Rh(II)
ee (%) of 20 ee (%) of 21
50
57
65:35
80:20
62
76
Rh2(S-DOSP)4
Rh2(S-PTAD)4
2 (–)
42 (–)
Having discovered systems capable of effective C–H
functionalization at tertiary sites, examination of the reac-
tivity difference between tertiary and primary C–H inser-
tion was undertaken. In this case the choice of catalyst
does have an influence on the product ratios. The Rh2(S-
DOSP)4-catalyzed reaction of phenyldiazoacetate 11 with
p-isopropyltoluene (19) gave a 2:1 mixture of the tertiary
a Determined from analysis of the 1H NMR of the crude reaction mixture.
Scheme 4 Reaction of 11 with isopropyltoluene
Selective C–H insertion at tertiary C–H bonds can also be
achieved with unactivated systems as illustrated in struc-
tures 22 and 24 (Scheme 5). The methylene site adjacent
MeO2C
MeO2C
Ph
N2
Rh(II)
+
Ph
CO2Me
Ph
Ph
CO2Me
2,2-DMB
50 °C
10
MeO2C
11
12
13
14
Yield (%)
12 13 14
Rh(II)
Rh2(S-DOSP)4
Rh2(S-PTAD)4
21 48
0
30 16 20
Scheme 2 Reaction of 11 with isopropylbenzene
Synlett 2009, No. 1, 151–154 © Thieme Stuttgart · New York

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Selective C–H Functionalization
153
to the isopropyl group is sterically inaccessible, while the is relatively low, we have demonstrated a high level of re-
benzoyloxy group behaves as an electron-withdrawing gio- and chemoselectivity upon which to base further in-
group and electronically deactivates the proximal methy- vestigations into the functionalization of tertiary C–H
lene C–H bonds.15 These unactivated systems are not es- bonds.
pecially effective carbenoid traps. Using our standard
conditions (method A), only low yields (<10%) of the ter-
tiary C–H insertion products were observed. Hence, more
forcing conditions were applied. It was observed that un-
der neatlike reaction conditions (method B), with the slow
addition of phenyldiazoacetate (11) solution and concur-
rent removal of solvent, 23 and 25 could be isolated in
41% and 40% yield, respectively, with Rh2(S-DOSP)4 as
catalyst. Even though the isolated yields of tertiary C–H
insertion products 23 and 25 were under 50% with these
two catalysts, there was no significant quantity (<5%) of
other C–H insertion products. Once again, the Rh2(S-
DOSP)4-catalyzed reactions gave the better enantioselec-
tivity.
Method A
An oven-dried 25 mL round-bottomed flask was charged with a so-
lution of substrate (3 mmol, 6 equiv), in anhyd, degassed 2,2-dime-
thylbutane (3 mL, 1 M). Dirhodium catalyst (0.005 mmol, 1 mol%)
was added, and the reaction was brought to reflux under an atmo-
sphere of argon. A solution of methyl phenyldiazoacetate (0.5
mmol, 1 equiv) in anhyd, degassed 2,2-dimethylbutane (6 mL, 0.1
M), was added dropwise over a period of 1 h. Upon completion of
the addition, the reaction was maintained at reflux for 1 h and then
allowed to cool to r.t. The solution was concentrated under reduced
pressure, and the resulting residue was purified by flash chromatog-
raphy.
Methyl 3-(4-Methoxyphenyl)-3-methyl-2-phenylbutanoate (16)
Using Method A: 1H NMR (400 MHz, CDCl3): d = 7.24–7.17 (7 H,
m), 6.79 (2 H, d, J = 9.0 Hz), 3.83 (1 H, s), 3.78 (3 H, s), 3.45 (3 H,
s), 1.47 (3 H, s), 1.30 (3 H, s). 13C NMR (100 MHz, CDCl3): d =
170.7 (C=O), 139.5 (CH), 135.7 (CH), 130.3 (3 × CH), 127.9
(2 × CH), 127.7 (2 × CH), 127.4 (CH), 113.3 (2 × CH), 62.7 (CH),
55.4 (OC), 51.6 (OC), 40.9 (C), 26.7 (CH3), 25.2 (CH3). IR (thin
film): nmax = 2950, 2360, 1734 (C=O), 1610, 1513, 1250 cm–1. MS
(ES): m/z (%) = 299.2 (4) [M + H], 285.1 (28), 150.1 (12), 149.1
(100). HRMS: m/z calcd for C19H23O3 [M + H]: 299.1642; found:
299.1639.
11
O
O
Rh(II)
O
O
70–75 °C
CO2Me
22
23
Rh(II)
Yield (%)
ee (%)
Rh2(S-DOSP)4
Rh2(S-PTAD)4
41
32
30
23
Methyl 3-Methyl-2-phenyl-3-p-tolylbutanoate (20)
O
O
CO2Me
11
Rh(II)
Using method A: 1H NMR (400 MHz, CDCl3): d = 7.25–7.21 (5 H,
m), 7.19 (2 H, d, J = 7.6 Hz), 7.08 (2 H, d, J = 7.6 Hz), 3.89 (1 H,
s), 3.46 (3 H, s), 2.32 (3 H, s), 1.49 (3 H, s), 1.32 (3 H, s). 13C NMR
(150 MHz, CDCl3): d = 172.9 (C=O), 144.2 (C), 135.52 (C), 135.49
(C), 130.1 (CH), 128.5 (CH), 127.6 (CH), 127.1 (CH), 126.3 (CH),
62.3 (CH), 51.3 (OC), 40.9 (C), 26.5 (CH3), 24.8 (CH3), 20.9 (CH3).
IR (thin film): nmax = 3028, 2971, 2950, 1734 (C=O), 1164, 1139,
703 cm–1. ESI-HRMS: m/z calcd for C19H23O2 [M + H]: 283.1698;
found: 283.1693.
O
O
70–75 °C
24
25
Rh(II)
Yield (%)
ee (%)
Rh2(S-DOSP)4
Rh2(S-PTAD)4
40
37
16
3
Scheme 5 Reaction of 11 with unactivated tertiary C–H bonds
Method B
To a 10 mL round-bottomed flask was added the Rh(II) catalyst
(0.005 mmol, 1 mol%) and benzoate 22 (5 mmol, 10 equiv). A
short-path distillation apparatus was attached to the top of the flask.
The mixture was heated to 70–75 °C under argon. Methyl phenyl-
diazoacetate (11, 0.5 mmol) in 10 mL of degassed 2,2-dimethylbu-
tane was added with a syringe pump over 5 h. During the addition,
the solvent was distilled off, and volume of the reaction mixture in
the flask kept constant. After addition, the reaction mixture was
stirred for 15 min, cooled to r.t., and passed through a short silica
gel column, washed with hexanes–Et2O (20:1) to recover the excess
of 22. Then the column was washed with Et2O. Concentration of
ether solution gave the crude product. Further purification with sil-
ica gel flash chromatography eluting with hexanes–Et2O (10:1)
gave the desired product as a clear oil.
While these reactions afford what appear to be modest
yields, these are remarkable transformations considering
the substrates involved. There is a range of potential C–H
bonds for functionalization in these systems, not only pri-
mary and secondary, but also a monosubstituted aromatic
ring. Yet, through judicious choice of the steric and elec-
tronic factors present in the molecule, we can selectively
functionalize the sterically encumbered, electronically
unactivated tertiary C–H position. Similar levels of selec-
tivity were recently reported in iron-catalyzed hydroxyla-
tion of unactivated tertiary C–H bonds.6
In summary, these studies demonstrate that C–H function-
alization at tertiary sites is possible with donor/acceptor
rhodium carbenoids. We have shown that variously sub-
stituted aromatic compounds are suitable substrates, pro-
viding that cyclopropanation can be suppressed through
steric inhibition. Furthermore, unactivated tertiary C–H
bonds can be selectively functionalized ahead of not only
primary and secondary positions, but also, sp2 systems.
While the yields are modest and the asymmetric induction
5-Methoxy-3,3-dimethyl-5-oxo-4-phenylpentyl Benzoate (23)
Using Method B: 1H NMR (500 MHz, CDCl3): d = 8.02 (2 H, dd,
J = 8.0, 1.0 Hz), 7.55 (1 H, t, J = 7.5 Hz), 7.45–7.40 (4 H, m), 7.34–
7.27 (3 H, m), 4.41 (2 H, t, J = 7.5 Hz), 3.64 (3 H, s), 3.58 (1 H, s),
2.00–1.95 (1 H, m), 1.78–1.72 (1 H, m), 1.13 (3 H, s), 1.06 (3 H, s).
13C NMR (75 MHz, CDCl3): d = 173.2 (C), 166.6 (C), 135.3 (C),
132.8 (CH), 130.3 (C), 130.1 (CH), 129.5 (CH), 128.3 (CH), 127.9
(CH), 127.4 (CH), 61.9 (CH2), 60.7 (CH), 51.5 (CH3), 38.1 (CH2),
Synlett 2009, No. 1, 151–154 © Thieme Stuttgart · New York

154
E. Nadeau et al.
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36.3 (C), 24.9 (CH3), 24.7 (CH3). IR (thin film): nmax = 1733, 1719,
1275, 1143, 1113, 711 cm–1. ESI-HRMS: m/z calcd for C21H24O4Na
[M + Na]: 363.1567; found: 363.1568.
(10) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
2861.
(11) Espino, C. G.; Du Bois, J. Modern Rhodium-Catalyzed
Organic Reactions; Wiley: New York, 2005, 379–416.
(12) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem.
Soc. 2000, 122, 3063.
Acknowledgment
(13) Davies, H. M. L.; Ren, P. J. Am. Chem. Soc. 2001, 123,
2070.
(14) Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org.
Chem. 2002, 67, 4165.
(15) Davies, H. M. L.; Beckwith, R. E. J.; Antoulinakis, E. G.;
Jin, Q. J. Org. Chem. 2003, 68, 6126.
Financial support of this work by the National Science Foundation
(CHE-0750273) is gratefully acknowledged. E.N. thanks the Fonds
Québécois de la Recherche sur la Nature et les Technologies
(FQRNT, Québec, Canada) for a postdoctoral research fellowship.
(16) Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper,
D. W. J. Am. Chem. Soc. 2003, 125, 6462.
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(18) Davies, H. M. L.; Yang, J. Adv. Synth. Catal. 2003, 345,
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References and Notes
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