Tetraalkylammonium-templated stereoselective Norrish-Yang cyclization

Article abstract of DOI:10.1021/ol4028732

Tetrabutylammonium salts serve as templates for the Norrish-Yang cyclization of 2-benzyloxy-acylbenzenes to give trans-dihydrobenzofuranols in high stereoselectivities. The dual cation-π interactions between an ammonium with a benzene ring and a carbonyl group play a key role in changing the conformation of the substrate, which was supported by ab initio calculations.

Full text of DOI:10.1021/ol4028732

ORGANIC
LETTERS
2013
Vol. 15, No. 23
5994–5997
Tetraalkylammonium-Templated
Stereoselective NorrishꢀYang
Cyclization
Shinji Yamada,*,† Azusa Iwaoka,† Yuka Fujita,† and Seiji Tsuzuki‡
Department of Chemistry, Ochanomizu University, Bunkyo-ku, Tokyo 112-8610, Japan,
and National Institute of Advanced Industrial Science and Technology (AIST),
Tsukuba, Ibaraki 305-8568, Japan
yamada.shinji@ocha.ac.jp
Received October 5, 2013
ABSTRACT
Tetrabutylammonium salts serve as templates for the NorrishꢀYang cyclization of 2-benzyloxy-acylbenzenes to give trans-dihydrobenzofuranols
in high stereoselectivities. The dual cationꢀπ interactions between an ammonium with a benzene ring and a carbonyl group play a key role in
changing the conformation of the substrate, which was supported by ab initio calculations.
NorrishꢀYang cyclization is an attractive method for
the activation of CꢀH bonds through intramolecular
H-abstraction by an excited carbonyl group,1 providing
various products with a quaternary C-center, and has been
applied to the synthesis of natural products.2 However,
methods for controlling the stereochemistry of the products
remain unexplored due to the difficulty associated with the
conformational control of the excited state as well as the
reactive intermediate except for in solid-state reactions.1b
Recently, template-mediated regio- and stereoselective
photochemical reactions,3 such as [2 þ 2],4 [2 þ 4],5 and
[4 þ 4]6 cycloaddition reactions, and photoelectron trans-
fer reactions7 have extensively been explored, where arti-
ficial templates form complexes with substrates through
H-bonds. Continuing our research on the application
of cationꢀπ interactions8 in synthetic organic photo-
chemistry,9 we focused on the use of ammonium ions as
(5) Wiegand, C.; Herdtweck, E.; Bach, T. Chem. Commun. 2012, 48,
10195–10197.
(6) (a) Kawanami, Y.; Umehara, H.; Mizoguchi, J.-I.; Nishijima, M.;
Fukuhara, G.; Yang, C.; Mori, T.; Inoue, Y. J. Org. Chem. 2013, 78,
3073–3085. (b) Mizoguchi, J.-I.; Kawanami, Y.; Wada, T.; Kodama, K.;
Anzai, K.; Yanagi, T.; Inoue, Y. Org. Lett. 2006, 8, 6051–6054.
† Department of Chemistry, Ochanomizu University.
‡ National Institute of Advanced Industrial Science and Technology.
(1) For reviews, see: (a) Synthetic Organic Photochemistry (Molecular
and Supramolecular Photochemistry), Vol. 12; Griesbeck, A. G., Mattay, J.,
Eds.; Marcel Dekker: New York, 2005; pp 11ꢀ87. (b) Ihmels, H.; Scheffer,
J. R. Tetrahedron 1999, 55, 885–907. (c) Wagner, P. J. Acc. Chem. Res. 1989,
22, 83–91.
€
(7) Bauer, A.; Westkamper, F.; Grimme, S.; Bach, T. Nature 2005,
436, 1139–1140.
(2) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000–1045.
(3) Bassani, D. M. In Supramolecular Photochemistry: controlling
Photochemical Processes; Ramamurthy, V., Inoue, Y., Eds.; Wiley: New
York, 2011; pp 53ꢀ86.
(8) For reviews, see: (a) Dougherty, D. A. Acc. Chem. Res. 2013, 46,
885–893. (b) Mahadevi, A. S.; Sastry, G. N. Chem. Rev. 2013, 113, 2100–
2138. (c) Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303–1324.
(9) For recent examples, see: (a) Yamada, S.; Kusafuka, M.; Sugawara,
M. Tetrahedron Lett. 2013, 54, 3997–4000. (b) Yamada, S.; Kawamura, C.
Org. Lett. 2012, 14, 1572–1575. (c) Yamada, S.; Tokugawa, Y.; Nojiri, Y.;
Takamori, E. Chem. Commun. 2012, 48, 1763–1765.
(4) (a) Coote, S. C.; Bach, T. J. Am. Chem. Soc. 2013, 135, 14948–
€
14951. (b) Muller, C.; Bauer, A.; Maturi, M. M.; Cuquerella, M. C.;
Miranda, M. A.; Bach, T. J. Am. Chem. Soc. 2011, 133, 16689–16697.
r
10.1021/ol4028732
Published on Web 11/13/2013
2013 American Chemical Society

indicating the importance of an ammonium cation as a
template. The use of CF3Ph asa solvent gave 4a exclusively
(entry 17). On the other hand, the addition of Bu4NCl,
Bu4NF, and Bu4NOAc dramatically inverted the stereo-
selectivity to give 3a (entries 18ꢀ20).
Scheme 1. Schematic Representation of NorrishꢀYang
Cyclization through Dual Interactions between an Ammonium
with a Benzene Ring and a Carbonyl Group
Similar results were obtained in the case of 2a. The
NorrishꢀYang cyclization of 2a shows cis-selectivity
(entry 21), whereas irradiation in the presence of Bu4NXs
predominantly afforded the trans-product 5a, with Bu4NF
and Bu4NOAc again being highly effective templates
(entries 22ꢀ25). Decreasing the amount of Bu4NF from
5.0 to 3.0 equiv did not affect the selectivity (entry 26).
However, further decreasing the amount from 3.0 to 0.5
equiv resulted in a reduction in the selectivity (entries 27
and 29). An increase in the concentration from 0.1 to 0.3 M
the cationic template in NorrishꢀYang cyclization reac-
tions, while interactions between an ammonium with a
benzene ring8 and a carbonyl group10,11 have already been
reported. The concept underlying our strategy is outlined
in Scheme 1. The conformation of the substrate can be
controlled by the formation of a complex with tetraalk-
ylammonium. The NorrishꢀYang cyclization of this dual
interaction system would thus produce two stereogenic
centers reflecting the conformation of the complex. Here,
we report tetrabutylammonium halides and acetate can
serve as templates for these reactions.
Table 1. NorrishꢀYang Cyclization of 1a and 2aa
2-Benzyloxyacetophenones (1aꢀ1d) and 2-benzyloxy-
benzophenones (2aꢀ2d) were employed as substrates for
the NorrishꢀYang cyclization reactions. Irradiation of
1a12 in a CH3CN solution (0.1 M) with a 450 W high-
pressure mercury lamp gave cis-dihydrobenzofuranol (4a)
as a major product with a trans/cis ratio of 17:83, as shown
in Table 1 (entry 1), which is in line with that previously
reported.12 A variety of cationic organic compounds, such
as pyridinium, imidazolium, and ammonium salts, were
employed to survey their ability to act as a template for this
reaction, as these cationic compounds have been known to
interact with an aromatic ring.5 The stereochemistry of the
products was determined through a comparison of the 1H
NMR spectral data with those previously reported.12b
Among these templates, Bu4NF was the most effective
to give trans-dihydrobenzofuranol as a major product
(entries 2ꢀ11). It should be noted that the selectivity was
significantly decreased in the presence of 10% water (entry
12). The highest selectivity was obtained when Bu4NOAc
was used as a template (entry 13). Interestingly, the con-
versions were significantly increased by the addition of
Bu4NX, suggesting that these templates enhance the reac-
tion rate by changing the conformation of the substrate. In
contrast, Bu4NBF4 and Bu4NPF6 had little influence on
the selectivity (entries 14 and 15). The effect of the anions
on the selectivity was in the order AcOꢀ g Fꢀ > Clꢀ >
Brꢀ . PF6ꢀ, BF4ꢀ, which is almost in agreement with the
order of the coordinating property, suggesting the impor-
tance of the H-bond with the reaction intermediate.
In addition, CsF did not affect the selectivity (entry 16),
time conv
entry compd
template
equiv (h)
(%)b trans:cisb
1
la
la
la
la
la
la
la
la
la
la
la
la
la
la
la
la
la
la
la
la
2a
2a
2a
2a
2a
2a
2a
2a
2a
ꢀ
0
10
10
5
35
17:83
44:56
71:29
42:58
18:82
62:38
65:35
68:32
66:34
74:26
84:16
48:52g,h
91:9
2
C5H5NMeBr
[emim][Cl]c
[emim-OH][Cl]d
[bmim][Cl]e
Et4NBr
Pr4NBr
Bu4NBr
Oct4NBr
Bu4NCl
Bu4NFf
Bu4NFf
Bu4NOAc
Bu4NBF4
Bu4NPF6
CsF
2.5
5
9
3
53
4
5
5
18
5
5
5
24
6
5
5
41
7
5
5
10
8
5
5
39
9
5
5
21
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
5
10
10
10
10
10
10
10
6
100
96
5
5
86
5
100
87
5
27:73
18:82
21:79
0:100i
91:9i
5
100
72
5
ꢀ
0
17
Bu4NCl
Bu4NFf
Bu4NOAc
ꢀ
5
10
10
10
5
100
93
5
93:7i
5
100
100
100
99
88:12i
39:61
62:38
72:28
85:15
85:15
85:15
78:22
84:16j
63:37
0
Bu4NBr
Bu4NCl
Bu4NFf
Bu4NOAc
Bu4NFf
Bu4NFf
Bu4NFf
Bu4NFf
5
3
5
5
5
3
100
79
5
3
3
3
100
100
80
1
3
1
3
0.5
3
100
(10) Thomas, C.; Milet, A.; Peruch, F.; Bibal, B. Polym. Chem. 2013,
4, 3491–3498.
(11) The interaction between a carbonyl group and a pyridinium ring
has been reported; see: Yamada, S.; Misono, T.; Tsuzuki, S. J. Am.
Chem. Soc. 2004, 126, 9862–9872.
(12) (a) Wagner, P. J.; Meador, M. A.; Park, B.-S. J. Am. Chem. Soc.
1990, 112, 5199–5211. (b) Horaguchi, T.; Tsukada, C.; Hasegawa, E.;
Shimizu, T.; Suzuki, T.; Tanemura, K. J. Heterocyclic Chem. 1991, 28,
1261–1272.
a 0.1 M CH3CN solution was used unless otherwise noted. b Deter-
mined by 1H NMR spectra. c [emim][Cl]:1-ethyl-3-methylimizazolium
chloride. d [emimꢀOH][Cl]:1-hydroxyethyl-3-methylimizazolium chloride.
e [bmim][Cl]:1-butyl-3-methylimidazolium chloride. f Trihydrate was used.
g A 9:1 mixture of CH3CN and H2O was used as a solvent. h Dihydroiso-
benzofuranols were also obtained in a 31% yield as byproducts (see,
ref 12b). i CF3Ph was used as a solvent. j A 0.3 M solution was used.
Org. Lett., Vol. 15, No. 23, 2013
5995

increased the selectivity, despite the use of 1 equiv of TBAF
(entry 28). These results show the importance of the
association between the substrate and the template, con-
firming the role of the ammonium salt as a template.
In order to clarify the contribution of the cationꢀπ
interaction to these reactions, the effect of the substituent
R2 on the aromatic ring on stereoselectivity was examined
(Table 2). Irradiation of 1bꢀ1d in CH3CN gave cis-dihy-
drobenzofuranols 4bꢀ4d as major products, respectively
(entries 1, 3, and 5). On the other hand, in the presence of
Bu4NF, photolysis of 1b and 1c,13 both having electron
donating groups, produced trans-dihydrobenzofuranols
3b and 3c, respectively, in high selectivities (entries 2 and
4). Irradiation of 1d, having a trifluoromethyl group,
afforded 3d in lower selectivity (entry 6). Similar results
were also obtained for 2bꢀ2d (entries 7ꢀ12). These results
confirmed that the substituent on the benzyl aromatic ring
affects the stereoselectivity. The selectivities increased in
the order OMe > CH3 > H > CF3,14 strongly suggesting
the contribution of the cationꢀπ interaction between the
ammonium and the benzyl moieties.
absence of Bu4NF, were obtained to clarify the existence
of the interaction (see Supporting Information (SI)).
To elucidate the role of the ammonium ion in the control
of stereoselectivity, the conformational changes produced
by the addition of Bu4Nþ were investigated by ab initio
calculations using the Gaussian 09 program.15 Details
of the computational methods are given in the SI. Six
stable conformers of 1a were obtained by geometry opti-
mizations. Figure 1a shows a conformer capable of in-
tramolecular H-abstraction due to having a much shorter
˚
O
HꢀCHPh distance (2.32 A), although the energy
3 3 3
is 2.03 kcal/mol higher than that of the lowest energy
conformer at the MP2/6-311G** level. The geometry opti-
mization for the complexes formed between 1a and Bu4Nþ
gave seven stable geometries. Among the seven orienta-
tions, three have a structure in which two interactions exist
between an ammonium with a benzene ring and a carbonyl
group. These comprise 96% of the population in all of the
orientations. Figure 1b shows the most stable orientation
of the complex with a CdO HꢀCHPh distance of
3 3 3
˚
2.934 A, which would permit H-abstraction by a carbonyl
group. The H-atom of the R-methylene moiety is close to the
˚
centroid of the benzene ring (3.357 A).
A comparison of the conformation of 1a and the or-
ientation of the complex shown in Figure 1 revealed
significant differences in the geometries of 1a. While the
two benzene rings of the conformer in 1a are in a syn
orientation, those of the complex are in an anti orientation,
showing the remarkable effect of the ammonium on con-
formational change. Although the distances between the
N-atom of the ammonium and the aromatic ring and the
carbonyl group are greater than those for the sum of van
der Waals radii of the corresponding atoms,16 the cationic
charge of the N-atom is distributed to the C-atoms next to
the N-atom,8a which is suggested by calculations17 and the
X-ray structure of a complex of an ammonium with an
enolate.18
Table 2. NorrishꢀYang Cyclization of 1bꢀ1d and 2bꢀ2d
time
(h)
conv
(%)
3:4 or
entry
substrate
template
5:6a
1
1b
1b
1c
lc
ꢀ
24
24
24
24
24
24
3
35
84
70
99
33
6
20:80
93:7
2
Bu4NF
ꢀ
3
11:89
94:6
4
Bu4NF
ꢀ
5
1d
1d
2b
2b
2c
2c
2d
2d
23:77
59:41
37:63
88:12
42:58
88:12
45:55
72:28
6
Bu4NF
ꢀ
7
100
99
100
57
100
92
8
Bu4NF
ꢀ
3
9
3
10
11
12
Bu4NF
ꢀ
3
3
Bu4NF
3
a Determined by 1H NMR spectra.
Studies on the dependence of the H and 13C NMR
chemicalshiftsonthe concentration of Bu4NFrevealedthe
existence of an interaction between the ammonium and the
carbonyl group. The Δδ values, which represent the differ-
ences between the chemical shifts in the presence and
1
Figure 1. (a) A conformer of 1a capable of H-abstraction and (b)
the most stable orientation for a complex of 1a with Bu4Nþ.
(15) Frisch, M. J. et al. Gaussian 09, revision C.01; Gaussian, Inc.:
Wallingford, CT, 2009.
(16) Bondi, A. J. Phys. Chem. 1964, 68, 441–451.
(17) Tsuzuki, S.; Tokuda, H.; Hayamizu, K.; Watanabe, M. J. Phys.
Chem. B 2005, 109, 16474–16481.
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C.-M. Org. Lett. 2003, 5, 2535–2538. (b) Hodgetts, K. J.; Maragkou,
K. I.; Wallace, T. W.; Wootton, R. C. R. Tetrahedron 2001, 57, 6793–
6804.
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(18) Reetz, M. T.; Hutte, S.; Goddard, R.; Robyr, C. Chem.;Eur. J.
1996, 2, 382–384.
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2007, 129, 12100–12101.
5996
Org. Lett., Vol. 15, No. 23, 2013

selectivity (Table 1, entry 12). These results strongly sug-
gest the importance of the H-bond in the intermediate B. It
has been reported that the H-bonded conformation of
a biradical is the key to stereoselectivity in the Norrish-
Type II reaction of β-methoxy ketones.19 Moreover, as the
combination of an ion pair and a H-bond has been
postulated in the several catalytic reactions using ionic
liquids20 and in the ammonium betaine catalysis in
Mannich reactions,21 the ion pair of the ammonium cation
and the anion may contribute to the stabilization of the
intermediate B.
Although there have been several examples of the use of
organic cations as a template for organic synthesis, such as
formation of hosts,22 catenane syntheses,23 and macrocyc-
lic RCM reactions,24 to the best of our knowledge, there
has been little work on their application to stereoselective
reactions.
In summary, we have reported that TBAXs serve as
templates for diastereoselective NorrishꢀYang cycliza-
tions. The dual interactions between an ammonium with
a benzene ring and a carbonyl group significantly changed
the conformation of the substrate. The counteranions also
have a significant effect on the stereoselectivity. The
weakly basic anions are speculated to stabilize the inter-
mediary biradical by forming a H-bond with the hydroxy
group of the intermediate, the cyclization of which leads to
trans-dihydrobenzofuranols in high stereoselectivities. As
TBAXs are common reagents, they would be useful for
various template-controlled organic syntheses.
Scheme 2. Postulated Reaction Mechanism for
TBAX-Templated NorrishꢀYang Cyclization
The stabilization energy of the complex shown in
Figure 1b was calculated for that orientation to be ꢀ15.3
kcal/mol. The electrostatic (ꢀ10.6 kcal/mol) and induction
(ꢀ4.3 kcal/mol) components are mainly responsible for
the strong attraction. The significant contribution of the
electrostatic and induction components toward the stabi-
lization energy suggests that these interactions can be
categorized as cationꢀπ interactions.17
Taken together, the above results led us to conclude that
the mechanism for the stereoselective NorrishꢀYang cy-
clization of 2-benzyloxyacylbenzenes is as shown in
Scheme 2. As predicted by the calculations, the substrate
forms a complex A with Bu4Nþ through dual interac-
tions at the aromatic ring and the carbonyl group.
The abstraction of the benzyl hydrogen by an excited
carbonyl group produces a biradical and a hydroxy group
as shown in B. Ring closure of the biradical would thus
produce trans-dihydrobenzofuranol 3 or 5. Although the
role of the counteranions toward the stereoselectivity still
remains unclear, the H-bond acceptor ability seems to be
animportant factor. Thehalideandacetate ionscan forma
H-bond with the hydroxy group of the intermediate B,
which would contribute to the stabilization of the con-
formation of B. The order of the basicity of the anions are
AcOꢀ > Fꢀ > Clꢀ > Brꢀ, whichcorrespondsclosely with
the order of their stereoselectivities (Table 1, entries 7, 10,
11, and 13, and entries 22ꢀ2ꢀ5). On the other hand, the
noncoordinating anions, PF6 and BF4ꢀ, are much less
effective (Table 1, entries 14 and 15). The observation that
a solvent containing 10% water significantly decreased the
selectivity supports the contribution of the H-bond to the
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research on Innovative Areas
‘Advanced Molecular Transformations by Organocata-
lysts’ from MEXT (24105508).
Supporting Information Available. Experimental and
computational details, characterization data, and 1H and
13C NMR spectra of new compounds. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(22) (a) Li, J.; Nowak, P.; Otto, S. J. Am. Chem. Soc. 2013, 135, 9222–
9239. (b) Otto, S. Acc. Chem. Res. 2012, 45, 2200–2210.
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Stoddart, J. F. Chem. Soc. Rev. 2009, 38, 1802–1820.
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(19) Moorthy, J. N.; Samanta, S.; Koner, A. L.; Saha, S.; Nau, W. M.
J. Am. Chem. Soc. 2008, 130, 13608–13617.
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The authors declare no competing financial interest.
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