Efficient synthesis of 2,6,9-triazabicyclo[3.3.1]nonanes through amine-mediated formal [4+4] reaction of unsaturated imines

Article abstract of DOI:10.1016/j.tetlet.2012.08.081

Formal [4+4] reaction of the unsaturated benzyl- or allylimines, which is efficiently mediated by primary amine, provides the 2,6,9-triazabicyclo[3.3.1] nonane derivatives. Variously substituted homo- and hetero-coupling products are obtained in good to excellent yields by quite a simple procedure under mild conditions: by mixing the unsaturated aldehydes with the amines at room temperature.

Full text of DOI:10.1016/j.tetlet.2012.08.081

Tetrahedron Letters 53 (2012) 5899–5902
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Tetrahedron Letters
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Efficient synthesis of 2,6,9-triazabicyclo[3.3.1]nonanes through
amine-mediated formal [4+4] reaction of unsaturated imines
a,b,
⇑
a
a
a
a
Katsunori Tanaka
, Eric R. O. Siwu , Shinji Hirosaki , Takayuki Iwata , Risa Matsumoto ,
a
b
a
a,
⇑
Yasutaka Kitagawa , Ambara R. Pradipta , Mitsutaka Okumura , Koichi Fukase
a
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka-shi, Osaka 560-0043, Japan
RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Formal [4+4] reaction of the unsaturated benzyl- or allylimines, which is efficiently mediated by primary
amine, provides the 2,6,9-triazabicyclo[3.3.1]nonane derivatives. Variously substituted homo- and het-
ero-coupling products are obtained in good to excellent yields by quite a simple procedure under mild
conditions: by mixing the unsaturated aldehydes with the amines at room temperature.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 25 June 2012
Revised 11 August 2012
Accepted 22 August 2012
Available online 27 August 2012
Keywords:
Formal [4+4] reaction
2
,6,9-Triazabicyclo[3.3.1]nonane
Benzylamine
Unsaturated imine
Aminoacetal
Unsaturated imines, which are readily obtained by the reaction
of the aldehydes with the amines, are not only the versatile inter-
mediates for the various organic transformations, but also the use-
ful syntons for the material chemistry as well as for the
bioconjugation and/or bioengineering chemistry. The N-alkyl
unsaturated imines have not so far been paid much attention in
comparison with the corresponding imines bearing the electron
withdrawing groups on the nitrogen, presumably due to their exis-
tence as the geometrical isomers, equilibrium with the aldehyde
precursors, and instability during the various synthetic transforma-
tions, that is, hydrolysis, oligomerization, and so on. Nevertheless,
their inherent, but unknown reactivity has a great potentiality to
be explored in pursuit of (1) the new synthetic transformations,
aldehyde 1 with excess amounts of benzylamine (a) (2 equiv) in
chloroform at room temperature for 5 h quantitatively gave a single
1
product associated with a simple H NMR spectrum that indicated
the absence of vinyl protons, a clear departure from the expected
conjugatedbenzylimine(Scheme1). Thenewproductwasunambig-
uously determined to be the symmetrical 2,6,9-triazabicyclo
4
[3.3.1]nonane 1a, based on the mass spectrum, several NMR analy-
ses, and the crystallographic analysis of the product derived from p-
bromobenzylamine (vide infra, Supplementary data). The reaction
1
(in CDCl
3
) was monitored by H NMR, and formation of the benzyli-
mine (Schiff base) was detected as the initial product, which, in the
presence of excess benzylamine, transformed over 5 h to triazabicy-
clononane 1a with two ester groups oriented at the equatorial posi-
tion on chair-like 6-membered rings in 1a. Apparently, formation of
the 8-membered diazacyclooctane through the formal [4+4] reac-
tion of imines and the addition of the extra benzylamine at the amin-
oacetal carbons proceeded (Scheme 1). Although the biological
activity and the other functions of 2,6,9-triazabicyclo[3.3.1]nonanes
(
2) new biosynthetic pathway of the nitrogen-containing natural
products, and (3) efficient covalent bond-forming reaction applica-
ble to bioconjugation chemistry; considering that the unsaturated
aldehydes can smoothly react with the various primary amines in
the biosystems, that is, lysines or ethanolamines, providing the cor-
1
5
responding N-alkyl unsaturated imines in aqueous solutions.
have not throughout been examined. Their structural similarity to
6
During our investigation of the reactivity of the conjugated imi-
sparteine or Troger’s base, 3,7-diazabicyclo[3.3.1]nonanes, pro-
2
2
nes and their application to alkaloid synthesis and/or bioconjuga-
vokes to use these compounds not only for the useful synthetic syn-
thons, but also for the metal chelators and the proton sponges. While
several methods for preparing the 2,6,9-triazabicyclo[3.3.1]nonane
3
tion, we unexpectedly found that the reaction of unsaturated
5
derivatives have been reported, these require harsh reaction condi-
⇑
Corresponding authors. Tel.: +81 48 467 9405; fax: +81 48 467 9379 (K.T.); tel.:
81 6 6850 5388; fax: +81 6 6850 5419 (K.F.).
tions: high temperatures and/or the Lewis acids, and provide the
caged compounds in low yields. In addition, the reaction substrates
are in most cases limited to the conformationally restricted
+
E-mail addresses: kotzenori@riken.jp (K. Tanaka), koichi@chem.sci.osaka-u.ac.jp
(
K. Fukase).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.081

5
900
K. Tanaka et al. / Tetrahedron Letters 53 (2012) 5899–5902
7
2 h, respectively, Entries 2 and 3). Equimolar quantities of alde-
Bn CO Me
N
2
hyde and benzylamine produced only the corresponding imine,
which remained unchanged over 5 days (Entry 4). A minimum of
a 1.5 equiv (excess) amine with respect to aldehyde 1 was neces-
sary to induce the clean formal [4+4] reaction of the pre-formed
imine, hence the triazabicyclo[3.3.1]nonane formation.
The benzylamine was not the only moiety compatible with this
H
O
H
excess BnNH2 (a)
5 h
100%
CHCl , rt, 10 min
3
N
H
1
CO Me
2
MeO C
2
Bn
Bn
CO Me
2
reaction. A variety of electron-donating, p-conjugated, and weakly
N
Bn
N
Bn
electron-withdrawing substituents at the p-position of benzyl
amine were compatible with the reaction: p-methoxy, Boc-pro-
tected p-aminomethyl, p-vinyl, p-phenyl, and p-bromobenzylam-
ines successfully gave the corresponding triazabicyclo [3.3.1]
N
Bn
Bn
MeO C
N
N
N
1a
2
CO2Me
MeO2C
Bn
7
nonanes 1b–1f in quantitative yields (Entries 5–9). A conjugated
Scheme 1. Triazabicyclo[3.3.1]nonane from unsaturated aldehyde and benzyl-
amine through formal [4+4] reaction of unsaturated imines.
imine derived from the allyl amine also participated in the formal
[
4+4] reaction to quantitatively yield 1g (Entry 10). No significant
solvent effects were observed. Chloroform, dichloromethane, tolu-
ene, and DMF, which each dissolved the benzylamines, could be
used. On the other hand, reaction with n-propylamine, propargyl-
amine, or benzylamines with amide and/or sterically hindered sub-
stituents only gave the corresponding imines. No transformations to
the triazabicyclo[3.3.1]nonane derivatives were observed over 24 h
at room temperature (Entries 11–14). Alternatively, the pre-formed
benzylimine was treated with propylamine to produce 1h (in which
2
-aminobenzaldehyde derivatives. On the other hand, the method
entailing unusually simple procedure, namely, by mixing of alde-
hydes with amines at room temperature, is unprecedented. In this
short communication, we report the substituent effects, substrate
scope, and also propose the plausible mechanism of the reaction.
In light of the surprisingly facile formation of triazabicy-
clo[3.3.1]nonane from the simple conjugated N-alkyl imines
through formal [4+4] reaction under such mild conditions, that
is, without heating and/or irradiation with high energy UV light,
the effects of light and/or radical mediators, as well as the sub-
strate scope, were examined (Table 1). The reaction went to com-
pletion within only 5 h on the laboratory bench without blocking
sunlight and/or fluorescent light (Entry 1). The removal of light
and/or addition of 3,5-di-tert-butyl-4-hydroxy toluene (BHT) as a
radical scavenger slowed the rate of reaction (75% and 40% after
the propylamine was incorporated onto the bridgehead position in
8
1
h) in 17% yield (isolated yield by HPLC), accompanied by 1a. This
result demonstrated that the benzyl group on the nitrogen was nec-
essary for the formal [4+4] reaction but not for the bis-acetal linkage
formation of the products.
Substituted triazabicyclo[3.3.1]nonane derivatives were also ob-
tained through the formal [4+4] reaction from the simple a,b-unsat-
urated aldehydes without the conjugated ester function (Scheme 2).
The reaction of acrolein 2 with benzylamine provided 2a in 54%
yield. Similarly, reaction of the a- and b-methyl substituted congen-
ers, methacrolein 3, and crotonaldehyde 4, provided the corre-
Table 1
sponding triazabicyclo[3.3.1]nonanes in modest yields.8 Whereas
Substituent effects of amine on formal [4+4] reaction
3
a was obtained as a 1:1 diastereomeric mixture (mixture of both
R
CO Me
equatorial and both axial methyl configurations on two chair-like
6-membered ring), the corresponding 4a was produced in a stereo-
selective manner (Scheme 2). Hetero-[4+4]coupling using two dif-
ferent imines is also possible; the treatment of the benzylamine
and the pre-formed solution of benzylimines derived from 1 and 4
stereoselectively provided the triazabicyclononane 5 in a 48% yield
2
H
O
N
a
R
N
RNH2
rt, 5 h
1
N
1a-1h
CO2Me
MeO C
R
2
(
stereochemical analysis in the Supplementary data). 8 Unfortu-
nately, the formal [4+4] reaction did not proceed in the presence
of the ,b-disubstituted derivatives or by substitution of the methyl
Entry
1
R
Solvent
Product
Yield (%)
Quant
Bn
Bn
Bn
Bn
CHCl
CHCl
CHCl
CHCl
CHCl
DMF
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
DMF
CHCl
CHCl
3
3
3
3
3
1a
1a
1a
—
1b
1c
1d
1e
1f
1g
—
a
b
c
2
75
40
ND
in 3 or 4 with phenyl groups under the conditions in Scheme 2.
d
c
3
e
f
Although a few examples of the [4+4] dimerization of the unsatu-
4
9
5
6
7
8
9
p-MeO-benzyl
p-BocNHCH -benzyl
p-Vinylbenzyl
p-Ph-benzyl
p-Br-benzyl
Allyl
Propyl
Propargyl
p-PhNHCO-benzyl
1-Phenylethyl
Bn and n-propylg
Quant
Quant
Quant
Quant
Quant
Quant
rated imines has been reported, this is the noteworthy example
2
3
3
3
3
3
3
:toluene (1:1)
Bn R2
N
R2
Bn
10
11
12
13
14
15
f
f
f
f
H
BnNH
R1
H
ND
ND
ND
ND
O
2
H
N
R1
(1.5 eq)
Bn
N
—
—
—
1h
R1
CHCl , rt
5 h
3
R1
R1
N
N
Bn
3
3
R2
R2
h
Bn
R2
17
1
1
1
2
2
: R = H, R = H
2
1
2
a
3: R = Me, R = H
2a: R = H, R = H (54%)
Otherwise noted, 1.5 equiv of amines relative to 1 were reacted on the labo-
ratory bench without blocking sunlight and/or fluorescent light.
2
1 2
4
: R = H, R = Me
3a: R = Me, R = H (51%)
4a: R1 = H, R2 = Me (62%)
b
Performed in the dark.
c
Estimated by 1H NMR. Reaction for 72 h.
BnNH2 (1 eq)
Bn
CO Me
2
d
1
4
Performed in the presence of 0.2 equiv of BHT. Same results were obtained both
CHCl , rt, 10 min
3
N
BnNH2 (0.5 eq)
5 h, 48%
in the dark and without blocking the light.
Bn
N
e
1
equiv of amine was used.
Corresponding imines were obtained.
BnNH2 (1 eq)
f
5
N
g
CHCl , rt, 10 min
1
equiv of benzylamine and then 0.5 equiv of propylamine were applied; R = Bn
on diazacyclooctane nitrogens and R = propyl on bridgehead nitrogen in 1h.
3
Me
Bn
h
Isolated yield by HPLC.
Scheme 2. Synthesis of substituted triazabicyclo[3.3.1]nonanes.

K. Tanaka et al. / Tetrahedron Letters 53 (2012) 5899–5902
5901
of the efficient reaction, producing triazabicyclo[3.3.1]nonanes in
modest to excellent yields under mild conditions and through quite
simple operations.
tion, that is, by the aerobic oxidation of benzyl amine, could poten-
1
2
tially be the photo-induced effectors and/or radical mediators.
The detailed mechanism of the formal [4+4] reaction, the acceler-
ation effects of the amines, and the theoretical treatments of the
1
0
The mechanism of the reaction was suggested by the following
two facts: 1) the unsaturated benzylimine itself did not participate
in the reaction without the extra amine, and 2) the mono-1,4-ad-
ducts of an imino nitrogen to another imine, such as 6 (Scheme 3)
were observed as the intermediates, based on the extensive NMR
analysis of the reaction between the aldehyde 1 and the benzyl-
amine (a) (see time-course NMR data in Supplementary data).
Therefore, the extra amine should mediate the conjugate addition
of an imino nitrogen, namely, by enhancing the nucleophilicity of
the nitrogen atom by forming the transient aminoacetal, as pro-
posed in Scheme 3. Thus, the benzylimine could be transformed to
the mono-1,4-adduct 6 by the help of the excess benzylamine. After
producing the iminium intermediate 7 (path A), it then would par-
ticipate in the second intramolecular 1,4-addition. Bis-acetal forma-
tion of the iminium 8 finally led to the most stable isomer 1a with
two equatorial ester substituents on both 6-membered rings in
1
3
reaction will be reported in due course.
It is rather surprising that the facile preparation of the triazabi-
cyclo[3.3.1]nonane derivatives via formal [4+4] reaction described
here, for example, 1a, has been overlooked until now, but we sus-
pect that the synthesis of imines is usually carried out by treat-
ment of the aldehyde with exact equimolar quantities of the
amine, and this point has not previously been investigated to
greater depth. Even if the reactant ratios were adjusted by chance,
1
as occurred accidentally in our research, the simplified H NMR of
the symmetrical 1a with the marked absence of vinyl protons (see
the NMR spectra in the Supplementary data) might be assumed to
be a polymerized byproduct via D–A, ene-reactions, or some other
mechanism, due to the instability of the alkylamine-derived unsat-
urated imines. Further expansion of the scopes, detailed mechanis-
tic investigation, and application to the natural and the bioactive
compounds are currently in progress.
1
a. Intramolecular aminoacetal formation and the subsequent
eight-membered ring closure in 6 (path B), which after all gives
the same iminium intermediate 8, could be the alternative pathway
to 1a. Compound 1a with the rigid triazabicyclo[3.3.1]nonane skel-
eton, once produced, was thermodynamically so stable that any for-
mation of 1g and/or the amine-scrambled products could not be
observed by the treatment with excess allylamine (3 equiv) under
the reaction conditions in Table 1. Although the proton NMR signals
corresponding to the aminoacetals could not be clearly observed in
the reaction mixture (Supplementary data), the acetal formation
was therefore considered to be the rate-limiting step of whole
Acknowledgments
We thank Dr. Kouzou Matsumoto, Department of Chemistry,
Osaka University, for X-crystallographic analysis of the triazabicy-
clo[3.3.1]nonane derivative. This work was supported in part by
Grants-in-Aid for Scientific Research No. 19681024 and 19651095
from the Japan Society for the Promotion of Science, New Energy
and Industrial Technology Development Organization (NEDO, pro-
ject ID: 07A01014a), and a MEXT Grant-in-Aid Project for Scientific
Research on Innovative Areas, Chemical Biology of Natural Prod-
ucts: Target ID and Regulation of Bioactivity (No. 24102518).
[
4+4] process, and hence the triazabicyclo[3.3.1]nonane formation.
It is a very interesting observation that (1) our [4+4] reaction
smoothly proceeds when utilizing the unsaturated imines which
contain the electron rich benzyl or allyl groups on the nitrogen,
and also (2) the reaction is notably slowed by blocking the room
light (room light contains UV light to some extent) or in the pres-
ence of a radical scavenger. Our trials using the chromatographi-
Supplementary data
Supplementary data (experimental details, characterization and
crystallographic data, and copies of MS and NMR spectra) associ-
ated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.08.081.
1
1
cally purified and/or distilled reagents and solvents,
still
afforded the triazabicyclo[3.3.1]nonane 1a in the similar efficiency
to those observed in Table 1. Nevertheless, molecular oxygen as
well as very small amounts of metals or the other byproducts with
References and notes
the extended
p
-systems being generated in the course of the reac-
1
.
.
(a) Tanaka, K.; Fukase, K.; Katsumura, S. Chem. Rec. 2010, 10, 119–139; (b)
Tanaka, K.; Fukase, K.; Katsumura, S. Synlett 2011, 2115–2139.
2
(a) Tanaka, K.; Katsumura, S. Org. Lett. 2000, 2, 373–375; (b) Tanaka, K.; Mori,
H.; Yamamoto, M.; Katsumura, S. J. Org. Chem. 2001, 66, 3099–3110; (c) Tanaka,
K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124, 9660–9661; (d) Tanaka, K.;
Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906–5925; (e)
Kobayashi, T.; Nakashima, M.; Hakogi, T.; Tanaka, K.; Katsumura, S. Org. Lett.
2006, 8, 3809–3812; (f) Kobayashi, T.; Hasegawa, F.; Tanaka, K.; Katsumura, S.
Org. Lett. 2006, 8, 3813–3816; (g) Sakaguchi, T.; Kobayashi, T.; Hatano, S.;
Tsuchikawa, H.; Fukase, K.; Tanaka, K.; Katsumura, S. Chem. Asian J. 2009, 4,
Nucleophilic activation?
Bn
path A
CO2Me
Bn
CO2Me
Bn
N
BnHN
N
path B
NH2
BnNH2 (a)
1
6
N
Bn
N
MeO2C
MeO C
2
Bn
1573–1577.
path B
3. (a) Tanaka, K.; Masuyama, T.; Hasegawa, K.; Tahara, T.; Mizuma, H.; Wada, Y.;
Watanabe, Y.; Fukase, K. Angew. Chem., Int. Ed. 2008, 47, 102–105; (b) Tanaka,
K.; Fukase, K. Org. Biomol. Chem. 2008, 6, 815–828; (c) Tanaka, K.; Fukase, K.
Mini-Rev. Org. Chem. 2008, 5, 153–162; (d) Tanaka, K.; Minami, K.; Tahara, T.;
Fujii, Y.; Siwu, E. R. O.; Nozaki, S.; Onoe, H.; Yokoi, S.; Koyama, K.; Watanabe, Y.;
Fukase, K. ChemMedChem 2010, 5, 841–845; (e) Tanaka, K.; Minami, K.; Siwu, E.
R. O.; Nozaki, S.; Watanabe, Y.; Fukase, K. J. Carbohydr. Chem. 2010, 29, 118–
path A
Bn
N
CO2Me
Bn
CO2Me
N
7
Bn
Bn
N
Bn
H2N
N
H
N
Bn
MeO2C
132; (f) Tanaka, K.; Siwu, E. R. O.; Minami, K.; Hasegawa, K.; Nozaki, S.;
MeO2C
Bn
Nucleophilic activation?
Kanayama, Y.; Koyama, K.; Chen, C. W.; Paulson, J. C.; Watanabe, Y.; Fukase, K.
Angew. Chem., Int. Ed. 2010, 49, 8195–8200; (g) Tanaka, K.; Kitadani, M.; Fukase,
K. Org. Biomol. Chem. 2011, 9, 5346–5349.
CO2Me
4.
We initially assigned the products as the 1,2-diazetidines and reported in 90th
Annual Meeting of The Chemical Society of Japan, March, 2010, Tokyo, 40th
Congress of heterocyclic Chemistry, Japan, October, 2010, Sendai, International
Chemical Congress of Pacific Basin Societies (PACIFICHEM 2010), December,
2010, Hawaii, and 99th Symposium on Organic Synthesis, Japan, June, 2011,
Tokyo. The structures for these specific compounds should be corrected as
shown in this Communication.
Bn
N
N
1
a
Bn
Bn
Bn
N
N
MeO2C
8
N
H
CO2Me
N
Bn
MeO2C
Most stable structure
Scheme 3. Proposed pathway to triazabicyclo[3.3.1]nonane 1a through amine-
mediated formal [4+4] reaction of benzylimine.
5. (a) Katritzky, A. R.; Baker, V. J.; Ferguson, I. J.; Patel, R. C. J. Chem. Soc. Perkin
Trans. 2 1979, 143–150; (b) Shim, S. C.; Kim, D.-W.; Moon, S.-S.; Chae, Y. B. J.

5
902
K. Tanaka et al. / Tetrahedron Letters 53 (2012) 5899–5902
favorable combination of the reacting imines derived from 1 and 4, that is,
Org. Chem. 1984, 49, 1449–1450; (c) Hagen, H.; Kohler, R. D. Ger. Offen 1985, DE
3
3
340077 A1 19850515.; (d) Hagen, H.; Kohler, R. D. Ger. Offen 1985, DE
412292 A1 19851003.; (e) Molina, P.; Arques, A.; Cartagena, I.; Obon, R.
the reaction between the electron deficient and the rich azadienes.
9. (a) Banwell, M.; Crasto, C. F.; Easton, C. J.; Karoli, T.; March, D. R.; Nairn, M. R.;
O’hanlon, P. J.; Oldham, M. D.; Willis, A. C.; Yue, W. Chem. Commun. 2001,
2210–2211; (b) Noel, R.; Fargeau-Bellassoued, M.-C.; Vanucci-Bacque, C.;
Lhommet, G. Synthesis 2008, 1948–1954.
Tetrahedron Lett. 1991, 32, 2521–2524; (f) Hagen, H.; Dupuis, J.; Roetsch, T. Ger.
Offen 1993, DE 4142173 A1 19930624.; (g) Frank, K. E.; Aube, J. Tetrahedron
Lett. 1998, 39, 7239–7242; (h) Molina, P.; Arques, A.; Tarraga, A.; Obon, M. D. R.
Tetrahedron 1998, 54, 997–1004; (i) Frank, K. E.; Aube, J. J. Org. Chem. 2000, 65,
10. Representative procedure of 2,6,9-triazabicyclo[3.3.1]nonanes: Preparation of 1a.
6
55–666; (j) Paredes, R.; Abonia, R.; Cadavid, J.; Moreno-Fuquen, R.; Jaramillo,
To a solution of fumaraldehydic acid methyl ester (1) (10.0 mg, 87.6
lmol) in
A.; Hormaza, A.; Ramirez, A.; Kennedy, A. Tetrahedron 2002, 58, 55–60; (k)
Leganza, A.; Bezze, C.; Zonta, C.; Fabris, F.; De Lucchi, O.; Linden, A. Eur. J. Org.
Chem. 2006, 2987–2990; (l) Redshaw, C.; Wood, P. T.; Elsegood, M. R. J.
Organometallics 2007, 26, 6501–6504.
Recent representative reviews, see: (a) Margetic, D. In Superbases for Organic
Synthesis: Guanidines, Amidines, Phosphazenes and Related Organocatalysts;
Ishikawa, T., Ed.; John Wiley & Sons Ltd: United Kingdom, 2009. Chapter 2;
chloroform (100 L) was added benzylamine (a) (14.4 L, 131 mol) at room
l
l
l
temperature. After the resulting solution was stirred at room temperature for
5 h, it was directly purified by normal phase HPLC (column: KC-PACK SG-S,
10 Â 250 mm; EtOAc in Hexane (25% over 40 min, 2.0 mL/min); UV detection
6
.
.
.
at 254 nm; retention time:10.0 min); a pale yellow viscous liquid, IR (neat,
À1
cm ) 1733, 1603, 1453, 1356, 1201, 742; 1H NMR (500 MHz, CDCl
3
) d 7.37 (d,
J = 7.2 Hz, 4H), 7.29 (dd, J = 7.5, 7.5 Hz, 4H), 7.22 (dd, J = 7.5, 7.5 Hz, 2H), 7.12
(m, 3H), 7.01 (m, 2H), 4.04 (d, J = 13.0 Hz, 1H), 3.76 (d, J = 13.5 Hz, 2H), 3.75 (d,
J = 13.5 Hz, 2H), 3.72 (d, J = 13.0 Hz, 1H), 3.67 (m, 2H), 3.66 (m, 2H) 3.64 (s, 6H),
2.20–2.14 (m, 2H), 1.87 (ddd, J = 13.5, 5.0, 2.0 Hz, 2H); 13C NMR (125 MHz,
(
b) Michael, J. P. Org. Biomol. Chem. 2005, 22, 603–626.
Reaction of benzylamine with the methyl ketone derivative of 1 only led to
,4-addition to the conjugated ketone moiety under the same conditions
7
8
1
listed in Table 1. An increase in temperature resulted in decomposition of
the products.
Compounds 1h, 2a–4a, and 5 were produced along with imines, aminoacetals,
or polymerized derivatives. They were purified by reverse-phase HPLC
CDCl
3
) d 175.2 (Â2), 138.9 (Â3), 129.1 (Â2), 128.8 (Â4), 128.4 (Â4), 128.2 (Â2),
127.8, 127.0 (Â2), 66.8 (Â2), 55.54 (Â2), 55.48 (Â2), 54.1, 51.3 (Â2), 27.7 (Â2);
+
36 3 4
HRESI-MS m/z calcd for C31H N O (M+H) 514.2700, found 514.2707.
11. Reagents used in this research were purchased from Sigma–Aldrich and/or TCI.
12. Recent examples of photoredox catalysts with visible light, see: (a) Ischay, M.
I.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572–8574; (b) Neumann, M.;
Fuldner, S.; Konig, B.; Zeitler, K. Angew. Chem., Int. Ed. 2011, 50, 951–954.
13. Detailed calculation results including the TS structure, hence the detailed
mechanism will be reported in a full account of this work (in preparation).
(
2
eluents: MeCN and H O) and their structures and yields were determined.
Compounds 1a and 4a could also be produced during the preparation of the
hetero-coupling product 5, but the crude NMR or HPLC with the overlapped
signals failed to detect these compounds. Rather high selectivity of the hetero-
coupling product formation (ꢀ50%) might be due to the electronically