Photoinduced carbamoylation of ethereal C-H bonds using pentafluorophenyl isocyanate

Article abstract of DOI:10.1016/j.tetlet.2011.03.128

An intermolecular carbamoylation of ethers has been achieved via photoinduced functionalization of ethereal C-H bonds in the presence of benzophenone at ambient temperature. The carbamoyl group, a one-carbon unit with a high oxidation state, derived from

Full text of DOI:10.1016/j.tetlet.2011.03.128

Tetrahedron Letters 52 (2011) 2885–2888
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photoinduced carbamoylation of ethereal C–H bonds using
pentafluorophenyl isocyanate
⇑
Shin Kamijo, Tamaki Hoshikawa, Masayuki Inoue
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An intermolecular carbamoylation of ethers has been achieved via photoinduced functionalization of
ethereal C–H bonds in the presence of benzophenone at ambient temperature. The carbamoyl group, a
one-carbon unit with a high oxidation state, derived from pentafluorophenyl isocyanate (C6F5NCO) is
chemoselectively introduced at the position geminal to the oxygen functionality in a single step. The
present reaction system effectively activates the tertiary C–H bond at the sterically hindered site of fused
bicyclic systems, and enables introduction of the carbamoyl group, which is then available for further
synthetic elaborations.
Received 4 March 2011
Revised 23 March 2011
Accepted 28 March 2011
Available online 1 April 2011
Keywords:
Photoreaction
Carbamoylation
C–H activation
Isocyanates
Ó 2011 Elsevier Ltd. All rights reserved.
Direct functionalization of C-H bonds of carbon skeletons
greatly simplifies and shortens synthetic routes to structurally
complex organic molecules with multiple functional groups, such
as biologically active natural products and pharmaceuticals.1
Among such C–H functionalizations, direct C–C bond formation of-
fers an extremely efficient way to construct complex carbon frame-
works starting from simple precursors. Intensive investigations
have mainly focused on the development of direct carbon elonga-
tion from the sp2-hybridized C–H bonds of aromatic compounds
utilizing late transition metal catalysts. Despite numerous exam-
ples of such sp2 C–H transformations, direct functionalizations of
sp3-hybridized C–H bonds of saturated carbon skeletons are still
limited due to the lack of general strategies to activate these stable
chemical bonds.2
We recently reported a new strategy for chemo- and stereoselec-
tive sp3 C–H acylation of saturated carbocycles involving the
Norrish–Yang photocyclization of 1,2-diketone 1 and subsequent
ring-opening fragmentation of
a-(hydroxy)cyclobutanone
2
(Scheme 1).3,4 After the two steps, the propyl ketone group in the
starting material 1 is intramolecularly transferred to the vicinal po-
sition of the cyclohexane ring with syn-orientation to the cyano
group in product 3. The key species responsible for the sp3 C–H acti-
vation is the reactive oxygen radical A generated by photo-excita-
tion of the diketone moiety of 1. Importantly, the ethereal C–H
bond adjacent to the oxygen functionality of 1 is chemoselectively
O
H
H
H
O
Pr
Pr
CN
Pr
hν
H2NOH
40%
H
H
O
O
O
O
Pr
OH
70%
H
MeO
H
MeO
H
MeO
O
O
1
2
3
O
hν
H
O
NHC6F5
4
6
8
5
7
9
O
O
Pr
OH
O
OMe
Ph
Ph
OMe
H
H
A
H
MeO
MeO
O
NHC6F5
B
C6F5 N C O
O
O
O
Scheme 1. Chemo- and stereoselective intramolecular acylation of saturated
carbocycles via Norrish–Yang photocyclization and fragmentation (Ref. 3).
NHC6F5
C–H carbamoylation
⇑
Corresponding author. Tel.: +81 3 5841 1354; fax: +81 3 5841 0568.
E-mail address: inoue@mol.f.u-tokyo.ac.jp (M. Inoue).
Scheme 2. Photoinduced intermolecular carbamoylation of ethers.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.128

2886
S. Kamijo et al. / Tetrahedron Letters 52 (2011) 2885–2888
Table 1
activated by radical A in the presence of the corresponding methy-
Investigation of isocyanate reactivitya
lene C–H bonds of the cyclohexane ring to give cyclobutanone 2 via
intermediate carbon biradical B. The highly preferred activation of
the ethereal C–H bonds by the radicals reflects their lower dissoci-
ation energy in comparison to aliphatic C–H bonds.5
Since versatile intermolecular C–H transformations could serve
as a more general methodology for efficient assembly of complex
and functionalized organic molecules, we planned to investigate
an intermolecular version of the above functionalization of sp3
ethereal C–H bonds (Scheme 2).6–8 Here, we report a new method-
ology for chemo- and stereoselective photoinduced intermolecular
C-H carbamoylation of saturated ethers 4, 6 and 8 using benzophe-
none as the oxygen radical generating agent and pentafluorophe-
nyl isocyanate as the carbon radical trapping agent.
The acetonide protected 1,2-diols 4 were designed based on
expectation that the oxygen functionality would secure the
chemoselective hydrogen abstraction and the sterically con-
strained bicyclic system would assist the stereoselective function-
alization.9 At the outset, 5/6-bicyclic ether 4a was treated with
phenyl isocyanate (PhNCO, 8 equiv)8,10 in the presence of benzo-
phenone (1 equiv) under photo-irradiation at ambient temperature
(entry 1 in Table 1). The cis-fused carbamoylated bicycle 5a was
obtained in 16% yield in chemo- and stereoselective fashion. It
was speculated at this stage that the yield of the amide product
Ph2CO (1 equiv), hν
H
H
R–N=C=O (8 equiv)
O
O
O
C6D6 (0.2 M), rt
O
H
H
O
O
NHR
(1 equiv)
4a
5a-h
O
C
Entry
R
t (h)
5
Yield (sm)b (%)
1
2
3
4
5
6
7
8
Ph
16
16
8
9
9
32
16
16
5a
5b
5c
5d
5e
5f
16 (30)
0 (94)
26 (17)
37 (17)
48 (20)
26 (32)
0 (89)
0d
p-(MeO)C6H4
c
p-(CF3)C6H4
3,5-(CF3)2C6H3
C6F5
p-(EtOCO)C6H4
p-(NO2)C6H4
CO2Et
5g
5h
a
Reaction conditions: 4a:isocyanate:Ph2CO (1:8:1), C6D6 (0.2 M), rt, irradiated
for 8–32 h using a Riko 100 W medium-pressure mercury lamp.
b
Isolated yield of 5. Recovery of starting material (sm, 4a) is shown in paren-
theses as calculated yield based on NMR analysis.
c
Up to 1.5 equiv of benzophenone was used.
Mixture of unidentified products.
d
Table 2
Carbamoylation of carbocycles with C6F5NCOa
Entry
Starting material (sm)
t (h)
Product
Yieldb (%)
Product (sm)
48 (20)
Brsm
60
O
O
5e
5e
1
9
O
O
O
O
NHC6F5
4a
O
O
2
3
4
5
8
27
8
34 (16)
55 (16)
34 (12)
45 (13)
40
65
39
52
O
O
NHC6F5
4a’
O
O
O
O
5i
O
NHC6F5
O
4b
O
5j
O
O
O
NHC6F5
4c
O
O
8
5k
O
O
O
NHC6F5
4d
tBu
tBu
4:1
OMe
7a
6
7
24
24
39c (32)
57
39
OMe
O
NHC6F5
6a
tBu
tBu
4:1
OMe
7a
29d (25)
OM
O
NHC6F5
6a’
a
Reaction conditions: 4:C6F5NCO:Ph2CO (1:8:1), C6D6 (0.2 M), rt, irradiated for 8–27 h using a Riko 100 W medium-pressure mercury lamp.
Isolated yield of 5. Recovery of 4 is shown in parentheses as calculated yield based on NMR analysis. Diastereomeric ratio is indicated in the product structure. Brsm,
b
based on recovered starting material.
c
Amide 7b was obtained as an impure form (<5% yield).
Amide 7b0 was isolated in 12% yield.
d

S. Kamijo et al. / Tetrahedron Letters 52 (2011) 2885–2888
2887
would be improved through modification of the isocyanate substi-
tuent (R). Interestingly, p-methoxyphenyl isocyanate completely
suppressed formation of adduct 5b (entry 2), whereas p-(trifluoro-
methyl)phenyl isocyanate increased the yield of adduct 5c and
accelerated the reaction (entry 3).
of the radical species C (Table 1). The introduction of the carbamoyl
group onto both cyclopentane (4b) and cycloheptane rings (4c)
proceeded smoothly to give cis-fused compounds 5i and 5j, respec-
tively (entries 3 and 4). Cyclohexylidene acetal derivative 4d also
underwent the reaction, generating adduct 5k (entry 5).
These results indicate that oxygen-substituted carboradical C
prefers the electrophilic isocyanate presumably due to its nucleo-
philic nature. Thus, isocyanates with various electron deficient
groups were explored (entries 5–8). The employment of 3,5-bis(tri-
fluoromethyl)phenyl isocyanate and pentafluorophenyl isocyanate
(C6F5NCO) further increased the yield of amides 5d and 5e, respec-
tively (entries 4 and 5). On the other hand, the use of aryl isocya-
nates with ester or nitro groups on the aromatic rings and
ethoxycarbonyl isocyanate did not improve the yield of the corre-
sponding amides 5f–h (entries 6–8).11 Among the screened isocy-
anates, C6F5NCO behaved as the most appropriate acceptor for the
radical species C and gave the adduct 5e in the highest yield as
listed in entry 5.12–14 It is important to note that the reaction
stopped at the mono-carbamoylation stage even though an excess
amount of isocyanate was employed and that the present direct
carbamoylation successfully introduced the tetrasubstituted car-
bon at the sterically hindered site of the bicyclic system in a ster-
eoselective manner.
Not only the acetal-protected 1,2-diols 4 but also methyl ether 6
analogs were submitted to the reactions (entries 6 and 7). The pho-
toinduced carbamoylation of both cis- and trans-disubstituted
methoxycyclohexanes 6a and 6a0 afforded a similar inseparable
mixture of diastereomers with b-methoxy 7a as the major isomer
(entries 6 and 7). No apparent reactivity difference between equa-
torial and axial C–H bonds on the cyclohexane ring was observed.
Interestingly, in these cases, a small amount of 7b and 7b0, which
were generated via carbamoylation at the methyl groups of 6a
and 6a0, respectively, was obtained as a minor product. These reg-
ioisomer ratios suggest that the functionalization of the tertiary C–
H bond of 6a is preferential to that of the primary C–H bond under
the present conditions.
tBu
O
O
NHC6F5
7b: cis
7b': trans
To examine substrate generality, various acetal-protected bicy-
cles were subjected to the optimized reaction conditions (Ta-
ble 2).15 Similarly to the cis-fused 1,2-cyclohexanediol derivative
4a, trans-fused analog 4a0 afforded the same 5/6-cis-fused bicyclic
amide 5e as a single product in chemo- and stereoselective fashion
(entry 2). The configurational change of the bicyclic systems that
occurred between 4a0 and 5e strongly supports the intermediacy
Next, simple ethers were utilized as starting materials (Table 3).
The treatment of tetrahydrofuran 8a with C6F6NCO provided the
amide 9a in 68% yield (entry 1). Similarly, the reaction of tetrahy-
dropyran 8b and oxepane 8c proceeded to give the corresponding
amide 9b and 9c, respectively (entries 2 and 3). In the case of
Table 3
Carbamoylation of simple ethers with C6F5NCOa
Entry
Starting material (sm)
t (h)
Product
Yieldb
%
Product (sm)
68 (17)
Brsm
82
O
O
O
O
1
NHC6F5
NHC6F5
26
8a
9a
O
O
2
46
42 (30)
43 (25)
60
57
8b
9b
O
O
O
3
4
NHC6F5
34
10
8c
9c
O
O
O
NHC6F5
42 (10)
47
21
8d
9d
O
O
NHC6F5
19 [1:1]
9d’
O
O
O
NHC6F5
5
34
34 (18)
41
8e
9e
a
Reaction conditions: 8:C6F5NCO:Ph2CO (1:8:1), C6D6 (0.2 M), rt, irradiated for 10–34 h using a Riko 100 W medium-pressure mercury lamp.
Isolated yield of 9. Recovery of 8 is shown in parentheses as calculated yield based on NMR analysis. Brsm, based on recovered starting material.
b

2888
S. Kamijo et al. / Tetrahedron Letters 52 (2011) 2885–2888
M.; Orlinkov, A. V.; Afanas’eva, L. V.; Vitt, S. V.; Petrovskii, P. V. Russ. Chem. Bull.
1998, 47, 918; (d) Kishi, A.; Kato, S.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 1999,
1421; (e) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S.
J. Am. Chem. Soc. 2001, 123, 10935; (f) Uenoyama, Y.; Fukuyama, T.; Morimoto,
K.; Nobuta, O.; Nagai, H.; Ryu, I. Helv. Chim. Acta 2006, 89, 2483; (g) Ryu, I.; Tani,
A.; Fukuyama, T.; Ravelli, D.; Fagnoni, M.; Albini, A. Angew. Chem., Int. Ed. 2011,
50, 1869.
2-methyltetrahydrofuran 8d, the carbamoylation took place at
both ethereal methine and methylene C–H bonds to furnish amides
9d and 9d0 (entry 4). Favorable formation of the tetrasubstituted
9d reflects the superior intrinsic reactivity of the tertiary C–H over
the secondary C–H. Carbamoylation of acyclic ether 8e was less
efficient than that of the cyclic ones, and amide 9e was obtained
in modest yield (entry 5).
In conclusion, we have developed a new method for the direct
carbamoylation of ethers at ambient temperature. The reaction
proceeds through the photoinduced intermolecular functionaliza-
tion of the ethereal C–H bond by the action of benzophenone
and pentafluorophenyl isocyanate. The high chemoselectivity to-
ward the ethereal position and the effective functionalization of
sterically hindered tertiary C–H bonds are particularly noteworthy.
The present transformation should serve as an expedited strategy
for quick access to structurally complex organic molecules since
the carbamoyl group, a one-carbon unit with a high oxidation
state, can act as a handle for further synthetic elaborations.
5. Dissociation energies of CH3CH2OCH2CH3 is 389.1 kJ/mol and that of
CH3CH2CH3 is 410.5 2.9 kJ/mol. See: Molecular Structure and Spectroscopy.
Handbook of Chemistry and Physics; Lide, D. R., Ed.; CRC Press: Boca Raton, FL,
2006; pp 60–61.
6. Examples on photoinduced reaction of acetals, see: (a) Fraser-Reid, B.; Hicks, D.
R.; Walker, D. L.; Iley, D. E.; Yunker, M. B.; Tam, S. Y.-K.; Anderson, R. C.
Tetrahedron Lett. 1975, 16, 297; (b) Mosca, R.; Fagnoni, M.; Mella, M.; Albini, A.
Tetrahedron 2001, 57, 10319; (c) Fernández, M.; Alonso, R. Org. Lett. 2003, 5,
2461; (d) Fagnoni, M.; Dondi, D.; Ravelli, D.; Albini, A. Chem. Rev. 2007, 107,
2725; (e) Hoffmann, N. Chem. Rev. 2008, 108, 1052.
7. Recent reactions involving ethereal C–H activation for formation of C–C bonds,
see: (a) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Org. Chem. 2005, 70, 2342; (b)
Pastine, S. J.; Sames, D. Org, Lett. 2005, 7, 5429; (c) Tu, W.; Liu, L.; Floreancig, P.
E. Angew. Chem., Int. Ed. 2008, 47, 4184; (d) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int.
Ed. 2008, 47, 7497; (e) Shikanai, D.; Murase, H.; Hata, T.; Urabe, H. J. Am. Chem.
Soc. 2009, 131, 3166; (f) Akindele, T.; Yamada, K.; Tomioka, K. Acc. Chem. Res.
2009, 42, 345; (g) Jurberg, I. D.; Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc.
2010, 132, 3543; (h) Mori, K.; Kawasaki, T.; Sueoka, S.; Akiyama, T. Org. Lett.
2010, 12, 1732.
Acknowledgments
8. Photoinduced carbamoylation of sp3 C-H bonds adjacent to nitrogen atom has
been presented, see: Yoshimitsu, T.; Atsumi, C.; Matsuda, K.; Iimori, E.;
Nagaoka, H.; Tanaka, T. Proceedings of the 34th Symposium on Progress in Organic
Reactions and Synthesis, 1O-3, Kyoto, Nov. 4-5, 2008.
This research was financially supported by a Grant-in-Aid for
Young Scientists (S) to MI.
9. (a) Jenkins, I. D. J. Chem. Soc., Chem. Commun. 1994, 1227; (b) Malatesta, V.;
Ingold, K. U. J. Am. Chem. Soc. 1981, 103, 609.
Supplementary data
10. Examples of the reaction between a carbon radical and isocyanate, see: (a)
Minin, P. L.; Walton, J. C. J. Org. Chem. 2003, 68, 2960; (b) Heinrich, M. R.; Pérez-
Martin, I.; Zard, S. Z. Chem. Commun. 2005, 5928; (c) Yoshimitsu, T.; Matsuda,
K.; Nagaoka, H.; Tsukamoto, K.; Tanaka, T. Org. Lett. 2007, 9, 5115.
11. Some of the aryl isocyanates could inhibit the photo-excitation of
benzophenone.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.128.
References and notes
12. Utilization of 4,40-dimethoxybenzophenone instead of benzophenone afforded
only a trace amount of the product 5e (<4%) and a significant amount of the
starting material 4a was recovered (84%).
13. It is worthy to point out that, from the synthetic point of view, the employment
of the ether as a limiting agent is one of the advantages of the present
procedure.
14. The product yield was decreased when the reaction was carried out without
careful removal of oxygen.
15. Procedure for photoinduced carbamoylation of ethereal C–H bonds: To a C6D6
1. (a) Recent reviews on direct C-H transformations, see: Handbook of C-H
Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005; Vols. 1 and 2, (b)
Handbook of Reagents for Organic Synthesis: Reagents for Direct Functionalization
of C-H Bonds; Paquette, L. A., Fuchs, P. L., Eds.; Wiley: Chichester, 2007.
2. Recent reviews on direct C–C bond formation from sp3 C–H bonds, see: (a) Ishii,
Y.; Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001, 343, 393; (b) Fokin, A. A.;
Schreiner, P. R. Adv. Synth. Catal. 2003, 345, 1035; (c) Knorr, R. Chem. Rev. 2004,
104, 3795; (d) Davies, H. M.; Manning, J. R. Nature 2008, 451, 417; (e) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (f) Li,
C.-J. Acc. Chem. Res. 2009, 42, 335; (g) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074.
3. Kamijo, S.; Hoshikawa, T.; Inoue, M. Tetrahedron Lett. 2010, 51, 872.
4. In comparison to sp3 C–H arylation, alkenylation, and alkylation, sp3 C–H
acylation was relatively unexplored. For representative examples, see: (a)
Tabushi, I.; Kojo, S.; Fukunishi, K. J. Org. Chem. 1978, 43, 2370; (b) Fukunishi, K.;
Kohno, A.; Kojo, S. J. Org. Chem. 1988, 53, 4369; (c) Akhrem, I. S.; Churilova, I.
(660
l
L) solution of cis-1,2-cyclohexanediol isopropylidene ketal 4a (20.6 mg,
mol) in 5-mm NMR tube were added benzophenone (24.1 mg,
mol) and pentafluorophenyl isocyanate (140 L, 1.07 mmol) at rt. The
132
132
l
l
a
l
mixture was degassed by freeze-thaw for 3 times. The NMR tube was placed at
5 cm distance from a UV-lamp and irradiated with a Riko 100 W medium-
pressure mercury lamp at rt for 9 h. The reaction was quenched with n-
butylamine (100 lL). Volatile materials were removed by evaporation and the
residue was purified with flash column chromatography (hexane/AcOEt 30:1)
to give N-(perfluorophenyl)amide 5e in 48% yield (23.1 mg).