Stereoselective intra- and intermolecular [2+2] photocycloaddition reactions of 4-(2′-aminoethyl)quinolones

Article abstract of DOI:10.1055/s-2004-834817

The 4-(2′-aminoethyl)quinolones 6, 8 and 9 were prepared starting from 4-(2′-bromoethyl)quinolone (4) in two steps and overall yields of 56-93%. They underwent inter- and intramolecular [2+2] photocycloaddition reactions with an alkene to provide the cycl

Full text of DOI:10.1055/s-2004-834817

2588
LETTER
Stereoselective Intra- and Intermolecular [2+2] Photocycloaddition Reactions
of 4-(2¢-Aminoethyl)quinolones
Q
uinolone Pho
e
tocycloadd
b
ition astian Brandes, Philipp Selig, Thorsten Bach*
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 20 July 2004
The [2+2] photocycloaddition of the parent 2-quinolone
Abstract: The 4-(2¢-aminoethyl)quinolones 6, 8 and 9 were pre-
pared starting from 4-(2¢-bromoethyl)quinolone (4) in two steps and
overall yields of 56–93%. They underwent inter- and intramolecular
[2+2] photocycloaddition reactions with an alkene to provide the
(carbostyril) has been intensively studied.4 Due to the
high intersystem crossing rate a triplet pathway is fol-
lowed which involves 1,4-biradical intermediates.4f Sim-
cyclobutanes 1–3 in racemic form (61–89% yield). The photochem- ple 4-alkyl-2-quinolones have also been used in
intermolecular photocycloaddition reactions.4c,d,5 More
ical reaction proceeded with very good chemo-, regio- and stereo-
selectivity. It was in one case (8b → 2b) also performed
complex 4-alkyl-2-quinolones, however, have not yet
been employed nor have, to the best of our knowledge, in-
tramolecular [2+2] photocycloaddition reactions of 4-
enantioselectively (93% ee).
Key words: asymmetric synthesis, cycloadditions, cyclobutanes,
alkyl-2-quinolones been studied.6 Our own work com-
diastereoselectivity, photochemistry, quinolones
menced with the synthesis of potential precursors for the
photocycloaddition. The starting material 4 was prepared
One of the hallmarks of organic photochemistry is the
ease with which strained cyclobutanes can be prepared by
[2+2] photocycloaddition reactions.1 Consecutive trans-
formations allow for the conversion of the cyclobutane
ring into acyclic carbon substituents by ring-opening, or
into other rings by rearrangement reactions.2 In the course
of a study directed towards the rearrangement of 3-azabi-
cyclo[4.2.0]octanes into 2-azabicyclo[3.3.0]octanes, we
required stereoselective access to compounds 1–3
(Figure 1). An apparent synthetic pathway involves the
intra- or intermolecular [2+2] photocycloaddition reac-
tions of 4-(2¢-aminoethyl)quinolones which in turn ap-
peared to be accessible from 4-(2¢-bromoethyl)quinolone
(4).3 In this communication we report on our preliminary
results in this field. We could show that the desired reac-
tion was feasible with excellent chemo-, regio- and stereo-
selectivity. An enantioselective protocol was employed to
provide cyclobutane 2b in high enantiomeric excess (93%
ee).
from commercially available 4-methyl-2-quinolone by a
sequence of carboxylation,3a,b esterification,3c reduction,3c
and Appel bromination (60% overall). In order to get our
hands at least on one of the three compounds 1–3 all
possible routes were pursued in a parallel direction
(Scheme 1). The parent N-benzyl(Bn)-N-tert-butyloxy-
carbonyl(Boc)-4-(2¢-aminoethyl)quinolone (6), which is
the precursor for an intermolecular [2+2] photocycloaddi-
tion, was obtained by treatment of bromide 4 with neat N-
benzylamine and by subsequent acylation of amine 5 with
Boc2O. In an analogous fashion the N-allyl derivatives 8
were synthesized via the secondary N-allylamines 7. The
acrylamides 9 were obtained from amine 5 by acylation
with acryloyl chloride and methacryloyl chloride, respec-
tively.
Irradiation experiments were conducted in toluene solu-
tion at room temperature using a conventional merry-
go-round apparatus (Duran filter).7 Based on previous
work4–6 the successful intramolecular [2+2] photocy-
cloadditon of substrates 8 was least surprising (Table 1,
entries 3, 4). The most remarkable aspect concerns the
ease with which the two quaternary stereogenic centers
are formed in cyclobutane rac-2b. The regioselectivity is
determined by the preferred formation of six-membered
rings and the stereochemistry is a result of a preferred an-
nulation to the cyclobutane in a cis-fashion. Cycloaddi-
tions of acrylates are less common than reactions of
electron-rich alkenes with photoexcited a,b-unsaturated
carbonyl compounds.1 In this respect, the smooth photo-
cycloaddition of methyl acrylate (entry 1) and even more
importantly of methyl methacrylate (entry 2) to quinolone
6 came as a pleasant surprise. Attempted reactions at 300
nm (Rayonet RPR-3000 Å lamps) were sluggish but the
reactions proceeded smoothly at 350 nm (RPR-3500 Å).
Yields increased at higher concentration (30 mM vs. 5
mM) without any detectable quinolone dimerization. In a
Boc
N
PG
Br
X
N
COOMe
R
Bn
R
H
O
H
O
N
N
N
H
O
H
H
X = H2, PG = Boc
X = O, PG = Bn
rac-2
rac-3
rac-1 a R = H
b R = Me
4
Figure 1 Structures of the cyclobutane targets 1–3 and of the
readily available starting material 4
SYNLETT 2004, No. 14, pp 2588–2590
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834817; Art ID: G27604ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Quinolone Photocycloaddition
2589
R
ration of products rac-1a and rac-1b was unambiguously
proven by H NMR NOESY experiments. Moreover,
R
HN
BocN
1
Boc2O, Et3N
(CH2Cl2)
compounds rac-1a and rac-1b could be readily converted
into the tetracyclic products rac-3a and rac-3b upon N-
Boc deprotection (Scheme 2, TFA = trifluoracetic acid).
This transformation is only possible if the methoxycarbo-
nyl group in cyclobutanes rac-1a and rac-1b is located cis
to the corresponding N-protected 2-aminoethyl substitu-
ent. The transformation rac-1a → rac-3a proceeded sim-
ply after deprotection by heating the crude N-benzylamine
in toluene for 1 hour under reflux (90% yield).
N
O
N
H
O
H
7a 67%
7b 80%
8a 84%
8b 73%
R
H2N
NHBn
NBnBoc
Boc2O, Et3N
BnNH2
(CH2Cl2)
4
Boc
N
Bn
N
99%
94%
O
N
O
N
H
O
COOMe
1. TFA (CH2Cl2)
2. NaH (THF)
H
Bn
H
H
H
H
5
6
O
R
H
61%
O
H
Et3N
(CH2Cl2)
N
O
R
BnN
N
O
Cl
H
H
rac-1b
rac-3b
Scheme 2 Strong 1H NOESY contacts recorded for compound rac-
1b and for compound rac-3b, which could be obtained by intramole-
cular lactam formation from rac-1b
a
b
R = H
R = Me
9a 74%
9b 75%
N
H
O
9
Scheme 1 Preparation of various 4-(2¢-aminoethyl)quinolones 6, 8,
and 9 from 4-(2¢-bromoethyl)quinolone (4)
The presence of a lactam moiety in 2-quinolones allowed
for the [2+2] photocycloaddition to be conducted in an
enantioselective fashion (Scheme 3).8 Employing the
chiral complexing reagent 109 (2.3 equiv), the reaction of
8b → 2b proceeded with excellent enantiomeric excess
(93% ee). Toluene was used as the solvent at low temper-
ature to facilitate association of the quinolone to lactam 10
by hydrogen bonds.10 The photocycloaddition was
performed using a high pressure mercury lamp (TQ 150,
Duran filter).11
similar fashion the acrylamides 9 gave cyclobutanes rac-
3 in an intramolecular reaction (entries 5, 6). Quinolone
9a was not soluble in toluene and the reaction was there-
fore conducted in a suspension.
If a triplet pathway is assumed for the [2+2] photo-
cycloaddition,1 the regioselectivity of the intermolecular
reactions (entries 1, 2) can be accounted for by the forma-
tion of the most stable 1,4-biradical. The relative configu-
Boc
BocN
N
Table 1 Inter- (Entries 1, 2) and Intramolecular (Entries 3–6) Pho-
tocycloaddition of the Quinolones 6, 8 and 9 in Toluene as the Solvent
(Duran Filter)7
hν, −60 °C (PhCH3)
HN
H
O
O
N
N
O
Entry
Substrate l (nm)
Product Yield (%)a drb
N
O
H
H
10
1
2
3
4
5
6
6c
350
350
300
300
350
350
rac-1a
rac-1b
rac-2a
rac-2b
rac-3a
rac-3b
80
89
85
84
65
61
>95:5
75:25
>95:5
>95:5
>95:5
>95:5
8b
78%
2b (93% ee)
6d
Scheme 3 Enantioselective intramolecular [2+2] photocycloadditi-
on of substrate 8b in the presence of the chiral complexing agent 10
8a
8b
9ae
9b
In summary, the intra- and intermolecular [2+2] photocy-
cloaddition of the title compounds gave access to the tri-
or tetracyclic products 1–3 in good to excellent chemical
yields. The reaction proceeded with high regioselectivity
and in all but one case with excellent simple diastereose-
lectivity. Three stereogenic centers were formed in one
step, the absolute configuration of which can be con-
trolled in an enantioselective variant of the reaction. The
potential of complexing reagent 10 to achieve an efficient
face differentation was shown for one example (8b →
2b).
a Yield of isolated product.
b The diastereomeric ratio (dr) was determined by integration of
appropriate 1H NMR signals from the crude product.
c The reaction was conducted in the presence of an excess (20 equiv)
of methyl acrylate.
d The reaction was conducted in the presence of an excess (20 equiv)
of methyl methacrylate.
e A suspension of compound 9a was irradiated in toluene.
Synlett 2004, No. 14, 2588–2590 © Thieme Stuttgart · New York

2590
S. Brandes et al.
LETTER
M) in toluene (70 mL) was irradiated at 350 nm (RPR-3500
Å) in a merry-go-round apparatus at r.t. for 4 h. After
removal of the solvent in vacuo, the crude product was
purified by flash chromatography (silica 60: 5 × 20 cm,
pentane–EtOAc = 50:50) to give 750 mg (80%) rac-1a as a
white foam. 1H NMR (360 MHz, DMSO-d6, 80 °C):
d = 9.91 (s, 1 H, NH), 7.30–7.20 (m, 3 H, Har), 7.15–7.05 (m,
4 H, Har), 6.99 (virt. t, 3J = 7.5 Hz, 1 H, Har), 6.89 (d, 3J = 7.9
Hz, 1 H, Har), 4.27 (s, 2 H, CH2Ph), 3.65 (s, 3 H, COOCH3),
3.18 (virt. t., 3J = 10.0 Hz, 1 H, CHCOOMe), 3.01–2.90 (m,
2 H, CHHN, COCH), 2.72–2.58 (m, 2 H, CHCHH, CHHN),
2.38–2.19 (m, 1 H, CHCHH), 2.06–1.93 (m, 1 H, CCHH),
1.86–1.73 (m, 1 H, CCHH), 1.40 [s, 9 H, C(CH3)3].
13C NMR (90.6 MHz, DMSO-d6, 80 °C): d = 171.4
(COOMe), 168.8 (CONH), 154.3 (COOtBu), 138.1 (s, Car),
137.0 (s, Car), 127.9 (d, CarH), 127.6 (d, CarH), 127.0 (d,
CarH), 126.6 (d, CarH), 125.7 (d, CarH), 124.5 (s, Car), 122.5
(d, CarH), 115.3 (d, CarH), 78.7 [C(CH3)3], 50.9 (COOCH3),
49.7 (CH2Ph), 48.8 (CHCOOMe), 44.8 (CCH2), 41.7
(CH2N), 39.2 (CHCH2), 33.9 (CCH2), 27.7 [C(CH3)3], 24.4
(CCH2). Anal. calcd for C27H32N2O5 (464.55): C, 69.81; H,
6.94; N, 6.03. Found: C, 69.54; H, 6.79; N, 5.87.
Further work directed towards an enantioselective ap-
proach to compounds 1–3 continues, as does research di-
rected towards possible rearrangement and ring-opening
reactions of these compounds.
Acknowledgment
This work was supported by the 2001 AstraZeneca research award
to T. B. and by an AstraZeneca research assistantship to S. B. We
are grateful to Dr. Kevin Foote (AstraZeneca, Alderley Park, UK)
for many fruitful discussions and for his help throughout the course
of this project.
References
(1) Reviews: (a) Fleming, S. A.; Bradford, C. L.; Gao, J. J. In
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Photochemistry, Vol. 1; Ramamurthy, V.; Schanze, K. S.,
Eds.; Dekker: New York, 1997, 187. (b) Bach, T. Synthesis
1998, 683. (c) Pete, J.-P. Adv. Photochem. 1996, 21, 135.
(d) Mattay, J.; Conrads, R.; Hoffmann, R. In Methoden der
Organischen Chemie (Houben-Weyl), 4th ed., Vol. E 21c;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995, 3085. (e) Crimmins, M. T.;
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(8) Review: Grosch, B.; Bach, T. In CRC Handbook of
Photochemistry and Photobiology, 2nd ed.; Horspool, W.
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E. Synthesis 2001, 1395.
(10) For investigations on the binding of lactams to complexing
agent 10, see: (a) Bach, T.; Bergmann, H.; Grosch, B.;
Harms, K. J. Am. Chem. Soc. 2002, 124, 7982. (b)Bach,T.;
Grosch, B.; Strassner, T.; Herdtweck, E. J. Org. Chem. 2003,
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Pharm. Bull. 1985, 33, 3775.
(11) Enantioselective Intramolecular [2+2] Photocyclo-
addition of Compound 8b:
A solution of 8b (20.0 mg, 5.84·10–2 mmol) and 10 (47.6 mg,
1.35·10–1 mmol) in toluene (8 mL) was degassed with argon.
After cooling to –60 °C the solution was irradiated with a
mercury high pressure arc (Original Hanau TQ 150) using a
Duran filter in a merry-go-round apparatus at –60 °C for 8 h.
After removal of the solvent in vacuo, the crude product was
purified by flash chromatography (silica 60: 2 × 30 cm,
CH2Cl2–MeOH = 98:2) to give 15.6 mg (78%) 2b as a white
solid (93% ee); 41.3 mg of the chiral complexing agent 10
were recovered. 1H NMR (360 MHz, CDCl3): d = 9.73 (s, 1
H, NH), 7.16 (dd, 3J = 6.6 Hz, 3J = 7.7 Hz, 1 H, Har), 7.08–
6.95 (m, 2 H, Har), 6.86 (d, 3J = 7.7 Hz, 1 H, Har), 3.72–3.63
(m, 2 H, NCH2CH2), 3.72–3.63 and 3.45 (d, 2J = 14.0 Hz, 1
H, NCHH), 3.30 (dd, 3J = 6.9 Hz, 3J = 10.9 Hz, 1 H, CH),
3.22 and 3.08 (d, 2J = 14.0 Hz, 1 H, NCHH), 2.62 and 2.54
(virt. t, 3J = 12.0 and 11.7 Hz, 1 H, CHCHH), 2.44–2.24 (m,
1 H, NCH2CHH), 2.05 (dd, 3J = 6.9 Hz, 3J = 12.5 Hz, 1 H,
CHCHH), 1.90–1.77 (m, 1 H, NCH2CHH), 1.50 and 1.49 [s,
9 H, C(CH3)3], 0.79 and 0.76 (s, 3 H, CH3). 13C NMR (90.6
MHz, CDCl3): d = 172.6 and 172.4 (CONH), 155.9 and
155.3 (COOtBu), 136.6 (s, Car), 128.0 (d, CarH), 127.4 and
126.9 (d, CarH), 124.4 and 124.2 (s, Car), 123.3 (d, CarH),
116.1 (d, CarH), 79.7 [C(CH3)3], 50.5 and 48.6 (NCH2), 43.5
and 43.0 (s, Cal), 42.0 (s, Cal), 39.8 and 39.4 (NCH2CH2),
36.1 and 35.5 (CH), 35.2 (CHCH2), 32.4 and 31.9
(4) The formation of photodimer was also observed. The simple
diastereoselectivity in the [2+2] photocycloaddition of
monosubstituted alkenes was low: (a) Evanega, G. R.;
Fabiny, D. L. J. Org. Chem. 1970, 35, 1757. (b) Cantrell, T.
S. J. Org. Chem. 1974, 39, 3063. (c) Buchardt, O.;
Christensen, J. J.; Harrit, N. Acta Chem. Scand. B 1976, 30,
189. (d) Chiba, T.; Kato, T.; Yoshida, A.; Moroi, R.;
Shimomura, N.; Momose, Y.; Naito, T.; Kaneko, C. Chem.
Pharm. Bull. 1984, 32, 4707. (e) Nonoyama, S.; Yonezawa,
N.; Saigo, K.; Hasegawa, M.; Hirano, T. Bull. Chem. Soc.
Jpn. 1988, 61, 2387. (f) Lewis, F. R.; Reddy, G. D.; Elbert,
J. E.; Tillberg, B. E.; Meltzer, J. A.; Kojima, M. J. Org.
Chem. 1991, 56, 5311.
(5) (a) Chiba, T.; Okada, M.; Kato, T. J. Heterocycl. Chem.
1982, 19, 1521. (b) Naito, T.; Momose, Y.; Kaneko, C.
Chem. Pharm. Bull. 1982, 30, 1531. (c) Sato, M.;
Kawakami, K.; Kaneko, C. Chem. Pharm. Bull. 1987, 35,
1319.
(6) Intramolecular [2+2] photocycloaddition reactions of 4-
alkenyloxy-2-quinolones are known: (a) Kaneko, C.; Naito,
T.; Somei, M. J. Chem. Soc., Chem. Commun. 1979, 804.
(b) Kaneko, C.; Suzuki, T.; Sato, M.; Naito, T. Chem.
Pharm. Bull. 1987, 35, 112.
(7) Representative Procedure for the Intermolecular [2+2]
Photocycloaddition:
(NCH2CH2), 28.5 [C(CH3)3], 23.5 (CH3). [a]D20 –31.7 (c 0.4,
CHCl3). HRMS (EI): m/z calcd for C20H26N2O3: 342.1943.
Found: 342.1935.
A solution of quinolone 6 (767 mg, 2.03 mmol, 30.0 mM)
and methacrylate (3.67 mL, 3.49 g, 40.5 mmol, 20 equiv, 0.6
Synlett 2004, No. 14, 2588–2590 © Thieme Stuttgart · New York