Novel borane reduction of ether-protected aromatic lactams

Article abstract of DOI:10.1021/jo040103q

Borane reduction of ether-protected aromatic lactams produces 1-alkyl-1,2,3,4-tetrahydroquinolines (5 and 6) in excellent yields. This reaction provides a novel onepot tandem process for reduction of amide group and N-protected groups. Experimental results demonstrate that the reaction proceeds through two consecutive elimination and reductions via two C-O bond cleavages to form the foresaid products.

Full text of DOI:10.1021/jo040103q

Novel Bor a n e Red u ction of
SCHEME 1. Hyd r id e Red u ction of
N-Meth oxym eth ylp yr r olo[2,1-c][1,4]ben zod ia zeoin e-
Eth er -P r otected Ar om a tic La cta m s†
5
-11-d ion es (1)
‡
§
§
Wan-Ping Hu, Pei-Ching Tsai, Ming-Kuan Hsu, and
J eh-J eng Wang*,
‡,§
Faculty of Biotechnology and Faculty of Medicinal and
Applied Chemistry, Kaohsiung Medical University,
Kaohsiung City 807, Taiwan
Received J anuary 6, 2004
jjwang@kmu.edu.tw
Abstr a ct: Borane reduction of ether-protected aromatic
lactams produces 1-alkyl-1,2,3,4-tetrahydroquinolines (5 and
6
) in excellent yields. This reaction provides a novel one-
pot tandem process for reduction of amide group and
N-protected groups. Experimental results demonstrate that
the reaction proceeds through two consecutive elimination
and reductions via two C-O bond cleavages to form the
foresaid products.
SCHEME 2. 3-Aza -Gr ob F r a gm en ta tion
TABLE 1. P r od u cts of Bor a n es Red u ction of
Eth er -P r otected Ar om a tic La cta m s
The reduction of tertiary lactams to their respective
amines has been approached with various hydrides such
as lithium aluminum hydride, sodium borohydride, and
lithium borohydride.1 In a previous article, we described
an unusual amide bond cleavage of N-methoxymethyl-
pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones (1) by com-
plex hydride reduction. Rather than simple deoxygenation
products (2), ring-opening secondary amines (3) were
entry substrate reaction conditionsa
product
yield (%)
,2
1
2
3
4
5
6
7
8
9
0
1
12
13
4
5
6
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
4f
a
b
a
b
a
b
a
b
a
b
a
b
a
b
a
b
5
5
5
5
5
5
5
5
5
5
5
5
6a
6a
6b
6b
92
85
85
90
94
81
91
89
94
79
70
78
95
98
89
75
3
formed, as detailed in Scheme 1. On the basis of the pro-
ducts obtained, we proposed that this reaction proceeds
via 3-aza-Grob fragmentation, as shown in Scheme 2.3
We subsequently extended our studies to a variety of
ether-protected aromatic lactams. The results showed
that hydride reduction of MOM-, MEM-, SEM-, and
BOM-protected oxindole analogues afforded ring-opening
products via the same path as seven-membered ring
1
1
4f
4g
4g
4h
4h
1
1
1
4
lactams (1) in excellent yields. More recently, we dem-
a
a: 15 equiv of BH3-THF; b: 15 equiv of BH3-S(CH3)2.
onstrated the first example to directly support 3-aza-Grob
fragmentation with evidence that the nucleofuges stay
with the parent molecules after fragmentation. Further
examination by stable isotope studies corroborates our
original observations.5
Boranes have been used as reducing agents for ap-
plication in organic synthesis for six decades. Their
reactions on reduction of functionalities, such as alkenes,
done is selectively reduced to methyl 1-benzyl-3-pyro-
lidinecarboxylate in moderate yield by borane. We
decided to explore whether ether-protected aromatic
lactams would be deoxygenated to the corresponding
amines by borane. The present note documents the
results of our studies.
8
aldehydes, ketones, amides, and lactams etc., have been
A variety of ether-protecting groups such as EOM
extensively studied.1
,2,6
For instance, ꢀ-carprolactam is
(ethoxymethyl) (a , Figure 1), MOM (methoxymethyl) (b),
rapidly and quantitatively reduced to the corresponding
MEM (2-methoxyethoxymethyl) (c), MTM (thiomethoxym-
ethyl) (d), SEM (2-(trimethylsilyl)ethoxymethyl) (e), BOM
7
amine by borane-dimethyl sulfide complex. In the class
of tertiary lactams, 1-benzyl-3-methoxycarbonyl-5-pyroli-
(benzyloxymethyl) (f), THF (tetrahydrofuranyl) (g), and
THT (tetrahydrothienyl) (h ) were introduced to 3,4-
dihydro-2(1H)-quinolinones (4) as previously reported.
The results of borane reduction of ether-protected 3,4-
dihydro-2(1H)-quinolinones are shown in Table 1. In the
examples of protecting groups possessing open chain
systems such as the EOM analogues (a -f), the reductive
*
To whom correspondence should be addressed. Tel. (886) 7-312-
2
-4
1
101, ext. 2275. Fax (886) 7-312-5339. Email: jjwang@kmu.edu.tw.
†
Dedicated to Professor Heinz G. Floss on the occasion of his 70th
birthday.
‡
Faculty of Biotechnology.
Faculty of Medicinal and Applied Chemistry.
§
(1) Hudlicky, M. Reductions in Organic Chemistry, 2nd ed.; Ameri-
can Chemical Society: Washington, DC, 1998.
2) Abmed-agid, A. F. Reductions in Organic Synthesis, American
Chemical Society: Washington, DC, 1996.
3) Wang, J . J .; Hu, W. P.; Chung, H. W.; Wang, L. F.; Hsu, M. H.
(
(6) Lane, C. F. Chem. Rev. 1976, 76, 773.
(7) Brown, H. C., Choi; Y. M.; Narasimhan, S. J . Org. Chem. 1982,
47, 3153.
(8) (a) Kornet, J .; Thio, P. N.; Tan, S. I. J . Org. Chem. 1968, 33,
3637. (b) Brown, H. C.; Heim, P. J . Org. Chem. 1973, 38, 912.
(
Tetrahedron 1998, 54, 13149-13154.
(
(
4) Wang, J . J .; Hu, W. P. J . Org. Chem. 1999, 64, 5725.
5) Hu, W. P.; Wang, J . J .; Tsai, P. C. J . Org. Chem. 2000, 65, 4208.
1
0.1021/jo040103q CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/24/2004
J . Org. Chem. 2004, 69, 3983-3985
3983

F IGURE 1. Structures of 3,4-dihydro-2(1H)-quinolinone (4) and other protective groups: EOM, MOM, MEM, MTM, SEM, BOM,
THF, THT.
SCHEME 3. P la u sible Rea ction P a th w a y for th e Con ver sion of EOM-P r otected 4 in to 5
SCHEME 4. P la u sible Rea ction P a th w a y for th e Con ver sion of THF -P r otected 4g in to 6a
reactions were completed with addition of 15 equiv of
borane-tetrahydrofuran or borane-dimethyl sulfide at
room temperature for 24 h to form 1-methyl-1,2,3,4-
tetrahydroquinoline (5) in excellent yields (Table 1,
entries 1-12). Similar results were observed for ring-
bearing protecting groups, producing 4-(3,4-dihydro-2H-
quinolin-l-yl)-butan-1-ol (6a ) (Table 1, entries 13-14) and
electron-deficient agents they behave as Lewis acids.
Reduction proceeds with an electrophilic attack on the
center of highest electron density, the carbonyl oxygen,
to form complex 7. After a hydride transfer, a six-
membered ring of dioxyborane complex 8 is generated,
followed by consecutive elimination (9), reduction (10),
elimination (11), and another reduction to give 1-methyl-
1,2,3,4-tetrahydroquinoline (5). The aforementioned re-
duction process involves two C-O bond cleavages. We
propose that THF- and THT-protecting groups undergo
a similar reaction as shown in Scheme 4. The ring
4
1
-(3,4-dihydro-2H-quinolin-l-yl)-butane-1-thiol (6b) (Table
, entries 15-16).
A plausible mechanistic interpretation of this intrigu-
ing reaction is shown in Scheme 3. Since boranes are
3
984 J . Org. Chem., Vol. 69, No. 11, 2004

systems of tetrahydrofuranyl and tetrahydrothienyl moi-
eties are reductively cleaved to amino alcohol (6a and
ported. This reaction provides a novel one-pot tandem
process for reduction of amide and N-protected groups.
The results are consistent with a reaction that proceeds
through two consecutive eliminations and reductions via
two C-O bond cleavages with excellent product yields.
6
b) in excellent yields under mild conditions.
To examine the proposed mechanism, the key inter-
mediate 1-(ethoxymethyl)-1,2,3,4-tetrahydroquinoline (10)
was synthesized by reaction of 1,2,3,4-tetrahydroquino-
line with ethoxymethyl chloride in 63% yield. The reduc-
tion of compound 10 using 1 equiv of borane-tetrahy-
drofuran proceeded at room temperature for 2 h to form
Ack n ow led gm en t. We would like to thank the
National Science Council of the Republic of China for
financial support. We also thank Dr. Henry Huang for
valuable discussions.
1
-methyl-1,2,3,4-tetrahydroquinoline (5) in excellent yields
(
98%). A similar result was observed with borane-
dimethyl sulfide. This evidence suggests that the schemes
proposed here offer practical routes leading to tertiary
amine and amino alcohols in aromatic series.
In conclusion, we have examined borane reduction of
ether-protected aromatic lactams. The mechanism is
distinct from that of complex hydrides previously re-
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for borane reduction of ether-protected aromatic
lactams and spectra data for compounds 5, 6a , 6b, and 10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O040103Q
J . Org. Chem, Vol. 69, No. 11, 2004 3985