Rh-catalyzed intramolecular debenzylative cyclization of amines. Butyrolactams from benzylamines having a chloroacetylene moiety

Article abstract of DOI:10.1016/j.tetlet.2011.02.104

When benzylamines having a chloroacetylene moiety were heated in wet toluene with a catalytic amount of rhodium trifluoroacetate dimer, intramolecular debenzylative cyclization took place to give butyrolactams. This method is a new entry to selective debenzylation of amines.

Full text of DOI:10.1016/j.tetlet.2011.02.104

Tetrahedron Letters 52 (2011) 2458–2461
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Rh-catalyzed intramolecular debenzylative cyclization of amines.
Butyrolactams from benzylamines having a chloroacetylene moiety
⇑
Yun Taek Oh, Kousuke Senda, Takeshi Hata, Hirokazu Urabe
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-59, Nagatsuta-cho,
Midori-ku, Yokohama, Kanagawa 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
When benzylamines having a chloroacetylene moiety were heated in wet toluene with a catalytic
amount of rhodium trifluoroacetate dimer, intramolecular debenzylative cyclization took place to give
butyrolactams. This method is a new entry to selective debenzylation of amines.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 21 December 2010
Revised 18 February 2011
Accepted 25 February 2011
Available online 2 March 2011
Keywords:
Rhodium catalyst
Chloroacetylene
Benzylamine
Butyrolactam
Debenzylation process
Benzylamines are widely distributed in natural products1 and
are useful building blocks2 as well as a versatile form of protected
amines.3 When one considers to use these benzylamines for fur-
ther synthetic modification, one should require a debenzylation
process to give back to the parent amines or, more preferably, di-
rectly to other requisite amino derivatives. Although there are
many standard protocols for the removal of benzyl group(s) on
amino group,3,4 which include hydrogenation,4a dissolving-metal
reduction,4b oxidation,4c or dealkylation via quaternarization,4d
new methods are still called for, as these may contribute to the
development of selective and mild transformations that are hith-
erto unexpected. While the former three methods afford the parent
amines, the last one is characteristic of the formation of amides. If
this amide formation can be carried out in an intramolecular man-
ner, this will become a unique debenzylative cyclization, directly
forming lactams as shown in Eq. 1.
port herein that a chloroacetylene moiety is a convenient surrogate
of acid chloride in Eq. 1 so that an alternative debenzylative lacta-
mization is viable under Rh catalysis as shown in Eq. 2.
ð2Þ
During our study on a new Rh-catalyzed cyclization between
sulfonylacetylene and benzyl ether,5 we happened to examine
the same reaction between haloacetylene6 and benzylamine, that
is, 1 as shown in Eq. 3. While this reaction did not afford a desired
product 3, a new product, butyrolactam 2, was detected albeit in a
low yield.
ð1Þ
ð3Þ
However, such applications have not been documented due
perhaps to the incompatibility of labile acid chloride with other
functional groups and/or their harsh reaction conditions. We re-
As this reaction provides a new debenzylative cyclization just as
formulated in Eq. 2, we started optimization of its reaction condi-
tions that are summarized in Table 1. The overall outcome of Eq. 3
suggested the necessity of water for this transformation, because
the amide oxygen in 2, in any event, must come from hydrolysis
⇑
Corresponding author. Tel./fax: +81 45 924 5849.
E-mail address: hurabe@bio.titech.ac.jp (H. Urabe).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.104

Y. T. Oh et al. / Tetrahedron Letters 52 (2011) 2458–2461
2459
Table 1
Optimization of Rh-catalyzed intramolecular debenzylative cyclization
Entry
Rh cat. or Lewis acid cat.
X
Solvent
Isolated yielda (%)
1
2
3
4
5
6
7
Rh2(tfa)4
Rh2(tfa)4
Rh2(OAc)4
Rh2(tfa)4
Rh2(tfa)4
BF3ꢁOEt2
BF3ꢁOEt2
CI
CI
CI
Br
I
(1)
(1)
(1)
—
—
(1)
(1)
100:1-toluene/H2O
100:10-toluene/H2O
100:10-toluene/H2O
100:1-toluene/H2O
100:1-toluene/H2O
Toluene
95
58
37
(13)
(28)
(0)
CI
CI
100:1-toluene/H2O
(0)
a
Yields determined by 1H NMR are in parentheses.
Table 2
Debenzylative cyclization of benzylamines
Entry
Substrate
Rh2(tfa)4 (mol %)
Product
Isolated yield (%)
1
2
3
4
Ar = Ph
(1)
(4)
(5)
(6)
10
20
20
10
(2)
(7)
(8)
(9)
95
81
p-MeC6H4ꢀ
p-CIC6H4ꢀ
p-MeOC6H4ꢀ
82
57a
5
6
7
8
R = CH3(CH2)8ꢀ
Ph(CH2)3ꢀ
(10)
(11)
(12)
(13)
10
15
20
20
(15)
(16)
(17)
(18)
59
65
58
68
BnO(CH2)6ꢀ
C6H11ꢀ
9
10
56
a
As a by-product, N,2-bis[(4-methoxyphenyl)methyl]butyrolactam was obtained in 9% yield.

2460
Y. T. Oh et al. / Tetrahedron Letters 52 (2011) 2458–2461
of a certain intermediate with water. This expectation was soon
found true, as the product yield increased to 95% when the reaction
was performed in the presence of a small amount of water (entry
1). Increase in the amount of water (entry 2) or the use of rhodium
acetate (Rh2(OAc)4) instead of Rh2(tfa)4 (entry 3) decreased the
yield of 2. Variation of the halogen on haloacetylenes was also
examined (entries 1, 4, and 5). Of the three halides examined,
chloro-derivative 1 afforded the best result. Probably, the other
haloacetylenes are rather fragile under these reaction conditions.
It should be also noted that the use of a Lewis acid, such as
BF3ꢁOEt2, did not promote the cyclization at all (entries 6 and 7),
showing the indispensable role of the Rh salt.
Other products prepared from various dibenzylamines or ben-
zylamines are summarized in Table 2.7 Dibenzylamines 1, 4, and
5 having an electron-rich or -deficient aromatic ring gave the de-
sired products in almost similar yields (entries 1–3). However, in
the case of bis[(4-methoxyphenyl)methyl]amine 6 (entry 4), the
product yield decreased owing in part to the formation of a by-
product, N,2-bis[(4-methoxyphenyl)methyl]butyrolactam, which
will be discussed later. In all cases of dibenzylamines, only one
benzyl group was cleanly dealkylated to give desired butyrolac-
tams. This is in stark contrast to other debenzylation methods,
where exhaustive debenzylation often occurs. Mono-benzyl deriv-
atives 10–14 (entries 5–9) also underwent debenzylative cycliza-
tion to give alkyl-substituted butyrolactams 15–18 in good
yields. A benzyloxy group in the side chain of 12 survived the reac-
tion conditions to give desired compound 17 retaining this group
(entry 7), which is again an advantageous feature of this method
over other debenzylation methods. Even sterically hindered ben-
zylamine 13 having a cyclohexyl group smoothly reacted to afford
N-cyclohexylbutyrolactam (18) (entry 8). When mono[(p-
methoxyphenyl)methyl]amine 14 was submitted to this cycliza-
tion, the benzyl-migrated product such as that in entry 4 was not
detected (entry 9).
At first glance, this reaction appears to involve hydrolysis of the
chloroacetylene moiety under Rh catalysis to give acid chloride,
which then effected the debenzylative cyclization as mentioned
in Eq. 1. However, the treatment of 19 with the Rh catalyst under
the same reaction conditions as shown in Table 2 yielded neither
the corresponding acid chloride 20 nor carboxylic acid 21 in a
detectable amount (Eq. 4). Thus, this experiment negotiates the
above possibility that the chloroacetylene works solely as a precur-
sor of acid chloride.
Scheme 1. Proposed mechanism.
b from the common intermediate 23, involving 1,3-benzyl migra-
tion (?28) and the hydrolysis as above via 29, afforded the by-
product 30. While this type of 1,3-benzyl migration has been doc-
umented in the relevant transition metal-catalyzed isomerization
of acetylenic ethers and sulfides,8a–d it is retarded in the present
reaction, as evidenced by the fact that product 30 was not usually
isolated (except for entry 4 of Table 2) even in dry toluene (Eq. 3).
Thus, the chloroacetylene serves for controlling the reaction to pro-
ceed exclusively along the path a.
As both introduction of an alkynyl group to amines and chlori-
nation of terminal acetylenes can be carried out by various stan-
dard methods, the above reaction provides a useful tool for the
debenzylative cyclization, directly giving butyrolactams as formu-
lated in Eq. 5. Further application of this method to more complex
substrates or naturally occurring products is in progress in our
laboratory.
ð4Þ
ð5Þ
An alternative and more likely mechanism of this reaction is
proposed in Scheme 1. The Rh catalyst first activates the acetylenic
bond of 22 like a Lewis acid to promote quaternarization of the
amino group (to 23).8 The resulting benzylammonium salt 23 is
attacked by water or chloride anion (via 24), which cleaves the
benzyl-nitrogen bond (path a) to give transient 25.9 This scission
of the carbon–nitrogen bond appears important to bring the first
equilibrium to an irreversible process. Subsequent hydrolysis of
Acknowledgment
This work was supported in part by the Mitsubishi Chemical
Corporation Fund (to T.H.).
References and notes
a
-chloroenamine 25 and the carbon–Rh bond in 26 affords the
observed butyrolactam 27.10 This mechanism is consistent with
the formation of the by-product, N,2-bis[(4-methoxyphenyl)-
methyl]butyrolactam, in entry 4 of Table 2, because the side path
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Cordell, G. A., Ed.; Chapman and Hall: London, 1989.

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2461
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An authentic sample of this compound was prepared by the alkylation of
butyrolactam with [(4-chlorophenyl)methyl] bromide and NaH in DMF. The
two samples prepared by the rhodium-catalyzed reaction and the alkylation
were identical in all respects.
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6. Forsome transitionmetal-catalyzedcyclizations of haloacetylenes, see: (a) Allen,
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1981–1984;Forpreparationof haloacetylenes, see:(f)Harrison, I. T.; Harrison, S.;
Hegedus, L. S.; Wade, L. G., Jr.; Smith, M. B. Compendium of Organic Synthetic
Methods; Wiley: New York, 1974–1992. Vols. 2–7.
7. Typical procedure for chlorination of terminal acetylene. Bis[(4-
chlorophenyl)methyl](4-chloro-3-butynyl)amine (5): To a solution of bis[(4-
chlorophenyl)methyl](3-butynyl)amine (115 mg, 0.362 mmol) in THF (4 mL)
was added BuLi (1.57 M in hexane, 0.370 mL, 0.580 mmol) at ꢀ78 °C under
argon. After stirring at –78 °C for 1 h, N-chlorosuccinimide (87.1 mg,
0.652 mmol) in THF (6 mL) was introduced to the mixture at –78 °C and the
solution was stirred at room temperature for 7 h. The reaction was terminated
by the addition of aqueous saturated NH4Cl solution. The organic products
were extracted with ethyl acetate. The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated in vacuo to give a crude oil,
which was chromatographed on silica gel (hexane) to afford the title
compound (110 mg, 86%) as an oil. The yield has not been optimized. 1H
NMR d 2.31 (t, J = 7.1 Hz, 2H), 2.62 (t, J = 7.1 Hz, 2H), 3.55 (s, 4H), 7.23–7.35 (m,
9. In
a typical case, the formation of benzyl alcohol and the corresponding
chloride (ca. 1:1 ratio, from 24) was detected in a comparable yield to that of
27.
10. An alternative mechanism, consisting of demetallation of the rhodium moiety
followed by the hydrolysis of the resultant chloroenamine as shown below, is
also likely, but we could not isolate the intermediate chloroenamine 31 or 32
for now.
8H). 13C NMR
d 17.59, 51.82, 57.50 (2 carbons), 58.21, 68.01, 128.48 (4
carbons), 129.26 (4 carbons), 132.83 (2 carbons), 137.72 (2 carbons). IR (neat)
3060, 3030, 2243, 1489, 1090, 1014, 838, 808 cmꢀ1. Anal. Calcd for C18H16Cl3N:
C, 61.30; H, 4.57. Found: C, 61.54; H, 4.84.
Typical procedure for debenzylative cyclization. N-[(4-Chlorophenyl)methyl]-
butyrolactam (8):
A mixture of bis[(4-chlorophenyl)methyl](4-chloro-3-
butynyl)amine (5) (31.8 mg, 0.090 mmol) and rhodium trifluoroacetate dimer
(Rh2(tfa)4, 11.8 mg, 0.018 mmol) in toluene (1.0 mL) and water (0.01 mL) was
heated at reflux for 10 h under argon. After being cooled to room temperature,
the mixture was filtered through a short pad of Celite with the aid of ethyl
acetate. The combined filtrates were concentrated to give a crude oil, which
was chromatographed on silica gel (hexane–ethyl acetate) to afford the title
compound (15.5 mg, 82%) as an oil. 1H NMR d 2.01 (quintet, J = 7.7 Hz, 2H), 2.45
(t, J = 7.7 Hz, 2H), 3.26 (t, J = 7.7 Hz, 2H), 4.42 (s, 2H), 7.18 (d, J = 8.4 Hz, 2H),
7.30 (d, J = 8.4 Hz, 2H). 13C NMR d 17.78, 30.81, 46.02, 46.60, 128.87 (2 carbons),
129.51 (2 carbons), 133.51, 135.22, 174.97. IR (neat) 3060, 3049, 2926, 1682
(C@O), 1493, 1093, 1016, 802 cmꢀ1
.