Lossen-type rearrangement products in the reaction of N-(phthalimidoyloxy)-3-phenylpropionate and -tosylate with benzyl alcohol

Article abstract of DOI:10.3987/COM-09-11643

This paper reports the reaction of N-(phthalimidoyloxy)-3-phenylpropionate (2a) and -tosylate (6) with benzyl alcohol as a nucleophile to afford the products via Lossen-type rearrangement. To study the scope of this reaction mechanism, we also studied the

Full text of DOI:10.3987/COM-09-11643

HETEROCYCLES, Vol. 78, No. 6, 2009
1433
HETEROCYCLES, Vol. 78, No. 6, 2009, pp. 1433 – 1438. © The Japan Institute of Heterocyclic Chemistry
Received, 8th Jaunuary, 2009, Accepted, 24th February, 2009, Published online, 25th February, 2009
DOI: 10.3987/COM-09-11643
LOSSEN-TYPE REARRANGEMENT PRODUCTS IN THE REACTION
OF
N-(PHTHALIMIDOYLOXY)-3-PHENYLPROPIONATE
AND
– TOSYLATE WITH BENZYL ALCOHOL
Shunsuke Takagi,† Md. Chanmiya Sheikh,† Asako Ogasawara,† Masayuki
Ohira,† Hitoshi Abe,‡ and Hiroyuki Morita†*
Department of Material System s Engine ering and Life Scie nce, Faculty of
Engineering, University of Toya ma, 3190 Gofuku, Toya ma 930-8555, Japan
e-mail: morita@eng.u-toyama.ac.jp
Abstract – This paper reports the reaction of
N-(phthalimidoyloxy)-3-phenylpropionate ( 2a) and -tosylate ( 6) with benzyl
alcohol as a nucleophile to afford the pr oducts via Lossen-type rearrangement. To
study the scope of this reaction mechanism, we also studied the reaction of several
N-sulfonyloxyimide derivatives with benz yl alcohol under sim ilar conditions and
found that the same types of products were obtained in high yields.
In the field of the conj ugation chem istry, hetero-func tional bi-den tate cross-linking reagents, such as
MBS ( m-Maleimidobenzoyl-N-hydroxysuccinimide ester) and relate d m odified linke rs, are widely
used.1-2 However, the lim itation of MBS is that the m aleimidoyl group is only useful funda mentally for
the Michael addition of SH group, which is som etimes hard or laborious to in troduce into the target
molecule. Non-symme trical bi-denta te cross-linking reagents beari ng two different reactive groups
towards nucleophiles (Figure 1) are apparently considered to be very useful fo r modification of organic
compounds even biological com pounds, but, their devel opments have been left unexplored. W hen these
kinds of non-symm etrical bi-func tional cross-linking reagents are newly developed, the chem
ical
modification toward proteins (antigens formation) will become quite easy by almost one-pot procedure.
Recently, we succeeded in synthesizing several examples (1a: L1 = OPhth, L2 = OBtz; 1b: L1 = OPhth, L2
= Bt; 1c: L1 = OPhth, L 2 = Cl) and dem onstrated their usefulness for preparation of pre-antigen.3 In the
course of these syntheses, we ne ed to determ ine the com bination of the leaving groups and hence, to
estimate th e reactivity difference a mong these "active ester" an
d other leaving grou
ps, i.e.,
phthalimidoyloxy, benzotriazolyloxy, benzothiazolyloxy, and benzotriazolyl groups.

1434
HETEROCYCLES, Vol. 78, No. 6, 2009
O
O
L1
L2
L1, L2 = -OPhth (phthalimidoyloxy), -OBtz (benzothiazolyloxy),
-OBt (benzotriazolyloxy), -Bt (benzotriazolyl), -Cl, etc.
Figure 1. Examples of the non-symmetrical bi-dentate cross-linking reagents (1a-1c)
Therefore, we prepared the m odel com pounds, ie., N-(phthalimidoyloxy)-3-phenylpropionate ( 2a),
N-(3-phenylpropionyloxy)benzotriazole ( 2b), and 3-phenylpropi onyloxybenzothiazole ( 2c), and their
reactivities towards several nucleophiles were studied.3-5 In the reaction of 2b or 2c with benzyl alcohol,
benzyl 3-phenylpropionate (3) was obtained as a sole product. However, in the reaction of 2a with benzyl
alcohol in the presence of 4-di methylaminopyridine (4-DMAP) for 24 h, we found unexpectedly the
formation of 2-benzyloxycarbonyl 1-[ N-(benzyloxycarbonyl)]aniline ( 4)6 in very low yields (5% as
shown in entry 1 in Table 1), besides the desired normal product 3 as shown in Scheme 1.
O
O
O
O
BnOH, DMAP
CH2Cl2, rt
OBn
NH2
L
OBn
OBn
+
+
OBn
N C
2a-c (1 equiv.)
H
4
O
L= OPhth (2a), Bt (2b), OBtz (2c)
3
5
Scheme 1. Reaction of 2 with benzyl alcohol in the presence of base
We presumed that the reaction proceeded via Lossen-type rearrangement7-17 as shown in Scheme 2.
O
-OX
OX
R
N
O
O
base
nitrene mechanism
OX
R N C=O
isocyanate
R
N
H
R
N
O
-OX
OX
-OX = leaving group
R
N
concerted mechanism
Scheme 2. Mechanism of Lossen rearrangement
In order to obtain furth er clue, we exam ined the reaction of 2a (1.0 equiv.) with benzyl alcohol (2.0-3.0
equiv.) in the presence of 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) as a stronge r base (2.0 equiv.) in
CH2Cl2 changing the reaction tim e (12-24 h), and furthe r, the reaction of the corresponding tosyl ester 6

HETEROCYCLES, Vol. 78, No. 6, 2009
1435
having a better leaving group than 2a was also carried out under sim ilar conditions. The results were
summarized in Table 1.
Table 1. Reaction of 2a or 6 with benzyl alcohol in the presence of base
O
BnOH
N OR
3
4
+
5
+
base
O
R = -CO(CH2)2Ph(2a), -Ts(6)
Product (% yield)*
Entry
Time (h)
Compounds Equiv.(BnOH)
Base
3
4
5
1
2
2a
2a
24
12
82
62
5
21
0
9
2.0
2.0
4-DMAP
DBU
3
4
5
2a
6
6
3.0
2.0
2.0
24
0.5
24
48
0
0
24
91
93
20
trace
trace
DBU
DBU
DBU
*: yields were not optimized
The yield of the rearranged product, i.e., 4 was greatly increased to 21% ( 12 h; entry 2) and 24% (24 h;
entry 3), and in addition, the product 2-aminobenzoic acid benzyl ester ( 5) was also increased to 20%
from 9%. The probable m echanism for the form ation of 4 will be depicted as shown in Schem e 3.
However, the mechanism for the fo rmation of 5 was unclear yet. Furtherm ore, as seen in entry 4 and 5,
the reaction of 6 revealed to afford the product 4 in excellent yield. The results clearly indicate that in the
cases of the stronger base and better leaving group the Lo ssen-type rearrangement product 4 is favored
and increased.
O
BnO
O
O
OBn
BnOH, DBU
O
2a
N O
Ph
N
O
Ph
O
O
O
nitrene mechanism
or
OBn
BnOH
5
4
concerted mechanism
N
C
O
-Lossen rearrangement-
Scheme 3. Probable mechanism for the formation of 4

1436
HETEROCYCLES, Vol. 78, No. 6, 2009
Next, we prepared 1,8-naphthalim idoyloxy tosylate ( 7) by the reaction of N-hydroxy-1,8-naphthalimide
with tosyl chloride, and exam ined the reaction with benzyl alcohol ( 2.1 equiv.) in th e presence of DBU
(2.1 equiv.). In this case, th e product 1-(benzyloxycarbonyl)benzo[ c,d]indol-2-one (8)18 was obtained in
60% yield after 2 h reaction tog
ether with benzo[ c,d]indol-2-one ( 9) in 15% yield, probably via
isocyanate 10 as shown in Scheme 4.
O
O
O
O
O
BnOH
DBU
OTs
OBn
N
N
OBn
NH
CH2Cl2
N C O
O
OBn
8 (60%)
9 (15%)
7
10
Scheme 4. Reaction of 7 with benzyl alcohol in the presence of DBU
It is interesting to apply in the reaction of the aliphatic dicarboxylic acid imide derivatives. Therefore, we
prepared N-succinimidoyloxy tosylate ( 11) an d N-glutalimidoyloxy tosylate ( 12), and exam ined thei r
reaction with benzyl alcohol under sim
ilar co nditions. The resu lts are summ arized in Sch eme 5.
Expectedly, the corresponding ω-amino acid derivatives, 3-benz yloxycarbonylaminopropionic acid
benzyl ester ( 13)19 and 3-benzyloxycarbonylam inobutinic acid benzyl ester ( 14)20 were obtained in
moderate to high yields 75% and 100% respectively.
O
O
O
O
BnOH, DBU
O
N
O
n
n
N O S
H
CH2Cl2, rt, 2 h
O
O
11 (n=1)
12 (n=2)
13 n = 1 (75%)
14 n = 2 (100%)
Sheme 5. Reaction of aliphatic dicarboxylic acid imide derivatives with benzyl alcohol
In summary, we have exam ined the reaction of 2a and 6 with benzyl alcohol in the presence of DBU
under several conditions, and m ade clear that the product
4 and 5 is for med via the Lossen-type
rearrangement. In order to obtain in additional exam ples, we prepared 1,8-naphthlene derivatives 7 and
aliphatic dicarboxylic acide derivatives 11 and 12, and exam ined their reacti ons with benzyl alcohols
under the similar conditions, resulted in the form ation of the Lossen-type rearrangement products 8 (+9)
and 13 and 14 in m oderate to h igh yields, respe ctively. These finding will p rovide the utiliza tion in the
new synthetic application of a mino acid derivatives, which are usually ha rd to prepare, starting from less

HETEROCYCLES, Vol. 78, No. 6, 2009
1437
expensive dicarboxylic acid derivatives. W e are now undergoing to make clear the scope and lim itations
of the reactions using various nucleophiles.
REFERENCES AND NOTES
1. For reviews and recent exam ples, see: (a) G. M. Dubowchick and M. A. Walker, Pharmacol. Ther.,
1999, 83, 67; (b) V. K. Rusiecki and S. A. W arne, Bioorg. Med. Chem. Lett., 1993, 3, 707; (c) K. D.
Janda, J. A. Ashley, T. M. Jones, D. A. McLeod, D. M. Schloeder and M. I. W einhouse, J. Am.
Chem. Soc., 1990, 112, 8886; (d) G. A. Pietersz, Bioconjugate Chem., 1990, 1, 89.
2. K. H. Dalton, G. M. Dubowchik, and A. W. Michael, Tetrahedron Lett., 2002, 43, 1987.
3. M. C. Sheikh, S. Takagi, M. Sakai, A. H. Abe, and H. Morita, J. Org. Biomol. Chem., 2008, 6, 4505.
4. H. Morita,* M. C. Sheikh, S. Takagi, M. Ohira, M. Sakai, A. Narita, A. Ogasawara, T. Mori, and H.
Abe. Syntheses and R eactivities o f Non-Symm etrical "A ctive Es ter" Bi-dentate Cross-Link ing
Reagents having a Phthalim idoyl and Acid Chlo ride, 2-Benzothiazole, or 1-Benzotriazol Group," J.
Org. Biomol. Chem.,” submitted as a full paper.
5. A. R. Katrizky, X. Lan, J. Z. Yang, and O.V. Denisko, Chem. Rev., 1998, 98, 409.
6. 2-Benzyloxycarbonyl-1-[N-(benzyloxycarbonyl)]aniline (4). Typical procedure: A solution of DBU
(76.3 μL, 0.51 mmol) was added to a stirred solution of 2a (50.0 mg, 0.17 mmol) and benzyl alcohol
(52.8 μL, 0.51 mm ol) in CH Cl2 (2 m L) at rt under N 2 and stirred for 24 h. Then, the reaction
2
mixture was neutralized by dil. AcOH and extracted with C H2Cl2. The organic layer was separated,
successively washed with water and brine, and dried over anhydrous MgSO4. Removal of solvent in
vacuum ga ve a colorless oil crude product,
which was purified by preparative TLC (3:1
CH2Cl2/hexane) to give
4 (15.2 m g, 24%) as a colorless solid. Mp 74.0-74.5 °C (
from
1
CH2Cl2/hexane); H NMR (CDCl , 400 MHz) δ 5.21 (s, 2H), 5.33 (s, 2H), 6.98-7.02 (m
, 1H),
3
7.29-7.43 (m, 10H), 7.49-7.54 (m , 1H), 8.04 (dd, J = 2.0, 1.6 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H),
10.57 (s, 1H); 13C NMR (CDCl 3, 100 MHz) δ 66.9, 66.9, 114.5, 118.8, 121.6, 128.2, 128.2, 128.2,
128.4, 128.5, 128.6, 130.9, 134.7, 135.4, 136.1, 141.8, 153.4, 167.7; IR (KBr) 1738, 1685 cm-1. Anal.
Calcd for C22H19NO4: C, 73.12; H, 5.30; N, 3.88. Found: C, 73.37; H, 5.30; N, 3.97.
7. W. Lossen, Liebigs Ann. Chem., 1872, 175, 271.
8. (a) H. Ulric h, B. Tucer, and R. Ric hter, J. Org. Chem., 1978, 43, 1544. (b) T. L. Maillard, M.
Benohoud, P. Durand, and B. Badet, J. Org. Chem., 2005, 70, 6303.
9. (a) M. A. Stolberg, R. C . Tweit, G. M. Steinberg, and T. Wagner-Jauregg, J. Am. Chem. Soc., 1955,
77, 765; (b) C. D. Hurd and L. Bauer, J. Am. Chem. Soc., 1954, 76, 2791.
10. E. A. Castro, P. Pavez, and J. G. Santos, J. Org. Chem., 2002, 67, 4494.
11. P. Tundo and M. Selve, Acc. Chem. Res., 2002, 35, 706.

1438
HETEROCYCLES, Vol. 78, No. 6, 2009
12. E. A. Castro, Chem. Rev., 1999, 99, 3505.
13. D. G. Hoare, A. Olson, and D. E. Koshland, J. Am. Chem. Soc. 1968, 90, 1638.
14. S. Linke, G.T. Tisue, and W. J. Lwowski, J. Am. Chem. Soc., 1967, 89, 6308.
15. N. A. Joensson and P. Moses, Acta Chem. Scand., 1974, 28, 441.
16. W. C. Groutas, M. A. Stanga, and M. J. Brubaker, J. Am. Chem. Soc., 1989, 111, 1931.
17. G. W. Adams, J. H. Bowie, and R. N. Hayes, J. Chem. Soc., Perkin Trans. 2, 1991, 689.
18. Analytical data for 8: Colorless solid. Mp 120-121 °C (from CH2Cl2-hexane); 1H NMR (CDCl3, 400
MHz) δ 5.49 (s, 2H), 7.33-7.43 (m , 3H), 7.50-7.57 (m, 3H), 7.66 (d, J = 8.8 Hz, 1H), 7.71-7.75 (m,
2H), 7.80 (d, J = 7.6 Hz, 1H), 8.10 (t, J = 7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 68.4, 112.4,
122.1, 124.5, 124.9, 126.1, 128.1, 128.5, 128.6, 128.7, 128.9, 129.3, 132.0, 135.1, 151.2, 165.0; IR
(KBr) 1761, 1733 cm-1. HRMS (EI) m/z calcd for C19H13NO3: 303.0895. Found 303.0897.
19. Analytical data for 13: Colorless liquid; 1H NMR (CDCl3, 400 MHz) δ 2.58 (t, J = 4.0 Hz, 2H), 3.47
(q, J = 4.0 Hz, 2H), 5.08 (s, 2H), 5.11 (s, 2H), 7.24-7.34 (m, 10H).
13C NMR (CDCl 3, 100 MHz)
δ 34.4, 36.5, 66.4, 66.6, 128.0, 128.0, 128.1, 12 8.3, 128.4, 128.5, 135.5, 136.4, 156.2, 172.1. IR
(KBr) 1728, 1719 cm-1. HRMS (EI) calcd for (M+) 313.1314, found 313.1311.
1
20. Analytical data for 14: Colorless liquid; H NMR (CDCl3, 400 MHz) δ 1.81-1.88 (m, 2H), 2.40 (t, J
= 7.2 Hz, 2H), 3.20-3.25 (q, J = 6.4 Hz, 2H), 4.92 (s, 1H), 5.08 (s, 1H), 5.08 (s, 2H), 5.10 (s, 2H),
7.24-7.38 (m, 10H); 13C NMR (CDCl3, 100 MHz) δ 25.1, 31.4, 40.3, 66.3, 66.6, 128.1, 128.2, 128.2,
128.5, 135.8, 136.5, 156.4, 172.9; IR (KBr) 1730, 1706 c m-1. HRMS (EI) calcd for (M +) 327.1471,
found 327.1452.