Regio- and stereoselective acylation of saturated carbocycles via Norrish-Yang photocyclization

Article abstract of DOI:10.1016/j.tetlet.2009.12.027

A regio- and stereoselective acylation of saturated carbocycles has been achieved through two-step reactions involving the Norrish-Yang photocyclization of 1,2-diketones and subsequent ring opening of the α-hydroxy-cyclobutanones. The C-H activation of the carbocycle proceeds regioselectively at vicinal to the diketone moiety resulting in stereoselective formation of cis-fused bicycles. The following C-C cleavage affords vicinally cis-acylated carbocycles. Predictability, generality, and practicality of the present strategy have been demonstrated using variously modified saturated carbocycles.

Full text of DOI:10.1016/j.tetlet.2009.12.027

Tetrahedron Letters 51 (2010) 872–874
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regio- and stereoselective acylation of saturated carbocycles via Norrish–Yang
photocyclization
*
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:
A regio- and stereoselective acylation of saturated carbocycles has been achieved through two-step reac-
tions involving the Norrish–Yang photocyclization of 1,2-diketones and subsequent ring opening of the
Received 13 November 2009
Revised 4 December 2009
Accepted 8 December 2009
Available online 11 December 2009
a
-hydroxy-cyclobutanones. The C–H activation of the carbocycle proceeds regioselectively at vicinal to
the diketone moiety resulting in stereoselective formation of cis-fused bicycles. The following C–C cleav-
age affords vicinally cis-acylated carbocycles. Predictability, generality, and practicality of the present
strategy have been demonstrated using variously modified saturated carbocycles.
Ó 2009 Elsevier Ltd. All rights reserved.
The demand for more efficient ways to construct complex
chemical structures from simple precursors continues unabated.
A very attractive way to meet this demand would be through selec-
tive C–C bond formation from sp3-hybridized carbon–hydrogen
bonds of saturated carbocycles.1,2 The successful development of
such C–H functionalizations would greatly simplify the strategies
available for the synthesis of natural products and pharmaceuti-
cals, because they enable C–C bond formations at any desired posi-
tion starting from inert but readily available carbon frameworks.
However, the ubiquitousness of sp3 C–H bonds in organic mole-
cules and the highly reactive agents necessary for cleavage of
strong C–H bonds make selective and controllable reactions very
challenging. Herein we report a general strategy for regio- and
stereoselective C–H functionalization of saturated carbocycles by
applying photocyclization and subsequent ring-cleavage reaction.
We planned to employ an intramolecular C–H activation of car-
bocycles, since spatial proximity between the reactive moiety and
the sp3 C–H bond might accelerate the desired transformation at a
specific position in a predictable manner. In this context, Norrish–
eral transformations, for example, sp3-sp or sp2-sp fragment cou-
pling at either bond a or bond b in 1 followed by one-step RuO2-
catalyzed oxidation.7 The cyclized 3 would be then transformed
into acylated carbocycles (4 and 5) by inducing C–C bond rupture
of the cyclobutanone structure. Overall, these mild two-step reac-
tions would enable unique acylation of carbocycles, which is other-
wise a difficult task. To test the scope and limitations of the
methodology, we systematically investigated the structural ele-
ments influencing the regio- and stereoselectivity of the Norrish–
Yang reaction using variously modified carbocycles.
At the outset, we designed and synthesized 1,2-diketone 2a,8
which possesses the saturated carbocycle and the carbon chain
(Scheme 2). Excitation of diketone 2a would generate a biradical,
represented as two resonance structures 6a and 7a, each of which
could abstract hydrogens from proximal sites, potentially leading
to numerous products. Despite this situation, the irradiation of
2a in benzene using a medium-pressure mercury lamp in the pres-
ence of benzophenone at room temperature9 resulted in selective
activation of the carbocycle over the carbon chain, leading to cis-
fused bicyclo[4.2.0]octanone 3a as the sole isomer. This remark-
able regio- and stereoselectivity was further confirmed by running
the reaction using acetoxy-diketone 2b under the same conditions
(2b?3b). Since only the radical abstraction of the methylene C–H
bond vicinal to the 1,2-diketone group (colored in circle) (7?8)
Yang photocyclization3,4 of 1,2-diketone
2
was selected
(Scheme 1).5 Photoactivation would convert the C–H bond of car-
bocycle 2 into the C–C bond of 3 with simultaneous formation of
the four-membered ring. The 1,2-diketone of 2 has advantageous
features for controlling both reaction pathways and functional
group selectivity:6 (1) 1,2-diketones generally prefer Norrish–Yang
cyclization over competing unproductive Norrish type-II fragmen-
tation; (2) the long excitation wavelength of the 1,2-diketone
(kmax = approximately 450 nm) allows its selective activation over
other photochemically excitable groups. Moreover, for application
to the assembly of complex molecules, it would seem expedient
that 1,2-diketone 2 can be readily prepared from fragments in sev-
a
R1
O
H
b
R2
R3
R2
R3
R2
R3
R2
R3
R4
O
O
R1
hν
R1
O
R1
OH
H
1
2
3
4: R4 = CO2Me
coupling
a
b
or )
(
4
5
: R = CN
* 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 1. Plan for acylation of carbocycles.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.027

S. Kamijo et al. / Tetrahedron Letters 51 (2010) 872–874
873
Table 1
R2
O
hν, Ph2CO (0.1 equiv)
O
O
R2
Cyclization of vicinally substituted carbocycles
benzene, rt, 40-120 min
O
hν, Ph2CO (0.1 equiv)
H
2a: R2 = OTBS
2b: R2 = OAc
3a (59%)
3b (70%)
H
O
O
O
H
O
HO
R1
benzene, rt, 30-80 min
H
O
O
R1
OH
n
H
R3
n
R3
2
3
R1
O
8e,f,i,j
n
O
H
R2
H
R2
R2
H
MeO
H
OH
O
Substrate
n
R1
R3
Yield
6a,b
7a,b
8a,b
2e
2f
2g
2h
2i
1
1
1
1
0
2
Me
OMe
74% (3e)
70% (3f)
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
OMe
OTBS
OAc
OMe
OMe
Scheme 2. Cyclization of geminally substituted carbocycles.
71%a,b (3g + 3g0)
c
—
51% (3i)
74% (3j)
goes through the unstrained bicyclo[4.4.0]decane-like transition
state without the large conformational reorganization, the regiose-
lectivity would be explained by the preorganized nature of the ab-
stracted C–H bond in comparison with the C–H bonds of the other
sites. On the other hand, the exclusive stereoselectivity (8?3)
should originate from the lower strain energy of the 6/4-cis-fused
system compared to that of the highly strained trans-fused
counterpart.
We next examined the reactions of the cis-decalin skeleton at-
tached to the 1,2-diketone structure (Scheme 3). Irradiation of
methyl diketone 2c activated both the methylene and methine
C–H bonds of the decalin at room temperature giving rise to tricy-
clic compounds 3c and 3c0.10 Under the same reaction conditions,
n-propyl diketone 2d was similarly transformed into 3d and 3d0,
again showing that the C–H functionalization reaction preferred
the carbocycle over the carbon chain. Formation of the three con-
secutive tetra-substituted carbons of 3c0 and 3d0 demonstrated
the power of the Norrish–Yang reaction for building sterically con-
gested ring systems. Furthermore, the generation of the two ring
isomers suggested that the regioselectivity between the methylene
and methine C–H bonds came from a balance between the intrinsic
reactivity toward abstraction (R3CH > R2CH2) and steric congestion
(R3CH > R2CH2).
To further clarify the controlling factors of the regioselectivity
of the C–H bonds, we utilized mono-carbocycles 2e–j that possess
the 1,2-diketone and the oxygen functionality in a vicinal relation-
ship (Table 1). Intriguingly, the photocyclization of methoxy dike-
tones 2e (R1 = Me) and 2f (R1 = n-Pr) proceeded at the more
hindered methine C–H bond to afford cyclobutanones 3e and 3f,
respectively, in a regio- and stereoselective manner. Even the ste-
rically bulky siloxy group of 2g promoted the cyclization at the
methine site providing 3g along with its alcohol epimer 3g0. These
results indicated that the electron-rich ether functionalities acted
as the effective directing groups of the photocyclization by increas-
ing the reactivity of the C–H bonds. This consideration was corrob-
orated by the lack of selective cyclization from 2h, which had the
electron-withdrawing acetoxy functionality. The generality of the
ether-directed photocyclization was further demonstrated using
five-membered 2i and seven-membered 2j, which gave rise to
5,4- (3i) and 7,4-fused bicyclic systems (3j), respectively. It is note-
2j
a
Calculated yield.
b
3g and its epimer 3g0 at the hydroxylated carbon center were formed
(3g:3g0 = 3.7:1).
c
Diketone 2h was consumed within 60 min to give complex mixture.
worthy that all the newly formed hydroxy groups of 3e,f,i,j are
positioned syn to the methyl ethers suggesting that hydrogen
bonding fixed the transition state 8e,f,i,j during cyclization.
Having established the regio- and stereoselective C-H function-
alization of the carbocycles through Norrish–Yang reaction, the
next step was the ring-opening reaction of the a-hydroxy-cyclobu-
tanone structures to build the various acylated carbocycles
(Scheme 4). These reactions were realized by either direct oxida-
tive cleavage or hydroxylamine-promoted 1,3-elimination. Oxida-
tion of 3a with periodic acid in aqueous methanol furnished 1,2-
cis-substituted ketoester 4a.6i Alternatively, treatment of 3c, 3c0,
and 3f with hydroxylamine hydrochloride led to the corresponding
b-hydroxy-oximes, which underwent in situ 1,3-elimination
through expulsion of water to afford 1,2-cis-substituted cyanoke-
tones 5c, 5c0, and 5f, respectively.11 No epimerizations were ob-
served for the obtained acyl and cyano cyclohexanes under these
conditions, thus the stereochemistries of the cyclobutanones were
successfully retained.
In conclusion, we have developed an operationally simple and
structurally predictable protocol for the regio- and stereoselective
acylation of saturated carbocycles using the Norrish–Yang photo-
cyclization of 1,2-diketones in combination with ring-opening
reactions. The factors affecting the cyclization selectivity have been
examined. Since the generated acyl and carbomethoxy/nitrile
groups would function as useful handles for further synthetic
transformations, the present acylation of sp3 C–H bonds should
serve as a unique strategy for the construction of structurally com-
plex organic molecules. Further studies along this line are under-
way in our laboratory.
3a
3c
3c'
3f
H2NOH·HCl
EtOH
0 °C to rt, 4 h
H2NOH·HCl
EtOH
rt to 65 °C, 1 d
H2NOH·HCl
EtOH
rt to 65 °C, 1 d
H5IO6, MeOH
0 °C to rt, 2 h
R1
R1
OH
H
O
O
O
hν, Ph2CO (0.1 equiv)
benzene, rt, 100 min
N
O
O
O
H
N
TBSO
H
N
+
OMe
R1
OH
H
H
MeO
O
2c: R1 = Me
3c (43%)
3d
3c' (27%)
3d'
(28%)
O
H
O
5c'
1
2d
: R = Pr
(31%)
n-
5c
5f
4a (55%)
(70%)
(66%)
(40%)
Scheme 3. Cyclization of cis-decalin derivatives.
Scheme 4. Ring-opening reactions of a-hydroxy-cyclobutanones.

874
S. Kamijo et al. / Tetrahedron Letters 51 (2010) 872–874
S.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 1999, 1421; (c) Akhrem, I. S.;
Acknowledgments
Churilova, I. M.; Orlinkov, A. V.; Afanas’eva, L. V.; Vitt, S. V.; Petrovskii, P. V.
Russ. Chem. Bull. 1998, 47, 918; (d) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda,
T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935; (e) Uenoyama, Y.;
Fukuyama, T.; Morimoto, K.; Nobuta, O.; Nagai, H.; Ryu, I. Helv. Chim. Acta 2006,
89, 2483.
This research was financially supported by Grant-in-Aids for
Young Scientists (S), the Uehara Memorial Foundation and TORAY
Science Foundation to M.I., and Grant-in-Aids for Young Scientists
(B) to S.K.
3. Yang, N. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, 2913.
4. For reviews on the Norrish–Yang reaction, see: (a) Wagner, P. J. In Synthetic
Organic Photochemistry; Griesbeck, A. G., Mattay, J., Eds.; Marcel Dekker: New
York, 2005; pp 11–39. Chapter 2; (b) Wessig, P.; Mühling, O. In Synthetic
Organic Photochemistry; Griesbeck, A. G., Mattay, J., Eds.; Marcel Dekker: New
York, 2005; pp 41–87. Chapter 3.
Supplementary data
5. For a recent review on applications of photochemistry in organic synthesis, see:
Hoffmann, N. Chem. Rev. 2008, 108, 1052.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.027.
6. For representative examples of the Norrish–Yang photocyclization of 1,2-
diketones, see: (a) Urry, W. H.; Trecker, D. J. J. Am. Chem. Soc. 1962, 84, 118; (b)
Turro, N. J.; Lee, T.-J. J. Am. Chem. Soc. 1969, 91, 5651; (c) Hirao, K.; Unno, S.;
Miura, H.; Yonemitsu, O. Chem. Pharm. Bull. 1977, 25, 3354; (d) Obayashi, M.;
Mizuta, E.; Noguchi, S. Chem. Pharm. Bull. 1979, 27, 1679; (e) Hamer, N. K.
Tetrahedron Lett. 1982, 23, 473; (f) Sarphatie, L. A.; Verheijdt, P. L.; Cerfontain,
H. J. R. Neth. Chem. Soc. 1983, 102, 9; (g) Hamer, N. K. Tetrahedron Lett. 1986, 27,
2167; (h) Herrera, A. J.; Rondón, M.; Suárez, E. Synlett 2007, 1851; (i) Herrera, A.
J.; Rondón, M.; Suárez, E. J. Org. Chem. 2008, 73, 3384.
7. (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981,
46, 3936; (b) Zibuck, R.; Seebach, D. Helv. Chim. Acta 1988, 71, 237.
8. See Supplementary data for preparation of the 1,2-diketones.
9. The yield was lower without using benzophenone as the sensitizer. The
reaction was slower when irradiated with sunlight.
References and notes
1. For recent reviews on direct C–C bond formation from sp3 C–H bonds, see: (a)
Handbook of C–H Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005;
vols. 1-2, (b) Ishii, Y.; Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001, 343,
393; (c) Knorr, R. Chem. Rev. 2004, 104, 3795; (d) Dick, A. R.; Sanford, M. S.
Tetrahedron 2006, 62, 2439; (e) Davies, H. M.; Manning, J. R. Nature 2008, 451,
417; (f) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 5094; (g) Li, C.-J. Acc. Chem. Res. 2009, 42, 335; (h) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
2. In comparison to sp3 C–H arylation, alkenylation, and alkylation, sp3 C–H
acylation was relatively unexplored. For representative examples, see: (a)
Fukunishi, K.; Kohno, A.; Kojo, S. J. Org. Chem. 1988, 53, 4369; (b) Kishi, A.; Kato,
10. See Supplementary data for the detailed structure assignments.
11. Zhang, X.; Li, W. Z. Synth. Commun. 2006, 36, 249.