Highly regioselective Diels-Alder reactions of 9-substituted anthracenes and 2-acetamidoacrylate: Synthesis of conformationally constrained α-amino acids

Article abstract of DOI:10.1016/j.tetlet.2005.02.131

The highly regioselective Diels-Alder reactions of 9-substituted anthracenes and 2-acetamidoacrylate afford a series of novel and conformationally constrained bicyclic bisaryl α-amino acids.

Full text of DOI:10.1016/j.tetlet.2005.02.131

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2857–2860
Highly regioselective Diels–Alder reactions of 9-substituted
anthracenes and 2-acetamidoacrylate: synthesis of
conformationally constrained a-amino acids
*
Bingwei V. Yang and Lidia M. Doweyko
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Chemistry, PO Box 4000, Princeton, NJ 08543, USA
Received 3 February 2005; accepted 21 February 2005
Abstract—The highly regioselective Diels–Alder reactions of 9-substituted anthracenes and 2-acetamidoacrylate afford a series of
novel and conformationally constrained bicyclic bisaryl a-amino acids.
Ó 2005 Elsevier Ltd. All rights reserved.
5
a
Conformationally constrained a-amino acids are valu-
able in biochemistry as modified peptides, enzyme inhibi-
tors, and ligands for probing receptor recognition.
Consequently considerable efforts have been devoted
to the de novo design of novel structures and methods
for their synthesis. A recent approach employed Diels–
Alder reactions of dehydroalanine derivatives to form
anthracene. However, this procedure using unsubsti-
tuted anthracene limited the adduct diversity in that it
might not be widely applicable for substituted anthrac-
enes. In particular, regioselectivity of the cycloadducts
from Diels–Alder reaction of 9-substituted anthracenes
and 2-acetamidoacrylate has not been investigated pre-
1
6
viously. In this communication, we wish to report our
studies on Diels–Alder reactions of 9-substituted
the constrained bicyclic aliphatic a-amino acids 1 (Fig.
2
7
1
analogs of phenylalanine, were prepared from the cor-
). The bicyclic monoaryl a-amino acids (e.g., 2), rigid
anthracenes with 2-acetamidoacrylate whereby a range
of bicyclic bisaryl a-amino acids 4 are readily obtained
with high regioselectivity.
3
responding ketone via Bucherer–Bergs reaction, a non
4
Diels–Alder route. On the other hand, the highly con-
strained bicyclic bisaryl a-amino acids have received lit-
tle attention. Only one approach has been reported for
entry to the bicyclic bisaryl a-amino acid skeleton.
Kotha et al. described the synthesis of 3 from the
Diels–Alder reaction of 2-acetamidoacrylate and
Our first investigation into the Diels–Alder reaction of
2-acetamidoacrylate with 9-methylanthracene or 9-chlo-
roanthracene in toluene employed the literature proce-
dure, that is, heating reaction in a sealed tube at
135 °C for 3 days (Scheme 1). However, these reactions
5
H3N
n
AcHN
3
H N
COO
H3N
COOCH3
COO
COO
m
R
4
1
2
3
Figure 1.
Keywords: Regioselective; Diels–Alder reaction; 9-Substituted anthracenes; Conformationally constrained a-amino acids.
*
Corresponding author. Tel.: +1 609 252 3436; fax: +1 609 252 6804; e-mail: bingwei.yang@bms.com
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.131

2858
B. V. Yang, L. M. Doweyko / Tetrahedron Letters 46 (2005) 2857–2860
AcHN
COOCH3
AcHN
COOCH3
R
solvent
R
o
1
35 -165 C
8 - 72 hr
NHAc
4
+
+
COOCH3
R
meta
6a-h
ortho
7a-h
5a-h
Scheme 1.
a,b
Table 1. Diels–Alder reactions of 9-substituted anthracenes and 2-acetamidoacrylate
c
d
Entry
5
R
Solvent
Toluene
T (°C)
Time (h)
6/7 m/o-Ratio
%meta Yield
e
44
1
2
3
4
5
6
7
8
9
5a
5a
5a
5b
5b
5b
5c
5d
5e
5f
CH
CH
CH
Cl
3
3
3
135
165
165
135
165
165
165
165
165
165
165
165
72
72
72
72
48
72
48
72
72
72
72
72
7/1
20/1
>99/1
—
PhNO
DMF
2
47
(31)
0
Toluene
Toluene
e
19
Cl
Cl
4/1
PhNO
PhNO
PhNO
PhNO
PhNO
PhNO
PhNO
2
2
2
2
2
2
2
49/1
>99/1
27/1
>99/1
>99/1
14/1
—
42
60
25
39
39
NO
Br
2
CH
CH
2
OAc
10
11
12
OCH
2 3
f
5g
5h
COOCH
CN
3
(25)
0
a
General procedure: Anthracene (1 equiv), 2-acetamidoacrylate (2 equiv) and hydroquinone (0.1 equiv) in the specified solvent were placed in a
sealed tube and were heated at the designated (oil bath) temperature and for the times indicated in the table.
All isolated products are fully characterized by NMR, MS, and HPLC.
b
c
The ratio of meta and ortho isomers 6/7 was determined by HPLC analysis of the crude reaction mixture. When there is no ÔdetectableÕ ortho isomer,
the minimum meta/ortho ratio is at least >99/1 within the lowest limits of detection in HPLC.
d
Isolated yield of meta isomer after flash chromatography, with no optimization. %Conversion of 9-substituted anthracenes, determined by HPLC
analysis of the reaction mixtures, are in parentheses.
Combined yield of a mixture of meta and ortho isomers after flash chromatography.
e
f
The product characterized by HPLC and LCMS was identical to the authentic sample obtained from a microwave assisted reaction (vide infra).
were either not sufficiently regioselective or low yielding
Table 1, entries 1 and 4).
tography in moderate to good yields. The structural
assignment of the regioisomers was determined by H
1
(
NMR analysis of the bridgehead protons. The bridge-
head proton in the meta isomer is a singlet, whereas in
the ortho isomer itis a rt iple t.
We next turned our attention to the reaction medium
and temperature. When the oil bath temperature was
raised to 165 °C, reaction with 9-chloroanthracene in
toluene for 48 h generated adducts in 19% yield as a
1
0
The bulky bromoanthracene 5d was found to produce a
meta/ortho mixture of 27/1 in only 25% yield under the
same conditions (entry 8). The methyl anthracene-9-car-
boxylate 5g proceeded in about25% conversion by
HPLC (entry 11). Attempts to apply the above proce-
dures to anthracene-9-carbonitrile 5h resulted in no cyc-
loadduct, presumably due to the effects of the strong
electron-withdrawing cyano group (entry 12). It is worth
mentioning that in DMF, reaction of 5a generated the
meta isomer 6a with meta/ortho ratio >99/1 (entry 3), a
substantial increase over that using nitrobenzene
(meta/ortho 20/1, entry 2). However, the reaction yield
was low (31% conversion).
4
solvents have been shown to increase the reaction rate
:1 mixture of meta and ortho isomers (entry 5). Polar
8
for certain Diels–Alder reactions. Nitrobenzene, an
aprotic polar solvent, was selected because its high boil-
ing point and low reactivity would allow reactions to be
carried out under elevated temperatures for extended
times. Additionally, the solubility of anthracenes in
nitrobenzene was an added advantage. The results are
summarized in Table 1.
To our delight, we found that using nitrobenzene, cyclo-
addition of 9-methylanthracene 5a or 9-chloroanthra-
cene 5b (165 °C, 72 h) afforded the corresponding meta
isomers 6a or 6b as the predominant products with
meta/ortho ratios of 20/1 and 49/1, respectively (entries
Microwave assisted Diels–Alder reactions are gaining
1
1
increased importance. As an extension of the thermal
reaction of 2-acetamidoacrylate and 9-substituted
anthracenes, we decided to use microwave irradiation
to determine the effects on the yield and regioselectivity
of the Diels–Alder reaction. The results are summarized
in Table 2.
2
and 6). More encouraging, 9-nitroanthracene 5c, 9-
acetoxymethylene 5e and 9-methoxymethylene 5f in nitro-
benzene produced the meta adducts with no detectable
9
ortho isomers (entries 7, 9, and 10). All meta isomers
were readily obtained in pure form using flash chroma-

B. V. Yang, L. M. Doweyko / Tetrahedron Letters 46 (2005) 2857–2860
2859
a
b
Table 2. Microwave assisted Diels–Alder reactions of 9-substituted anthracenes and 2-acetamidoacrylate (200 °C, 1 h)
c
c
d
Entry
5
R
Solvent eA (c er qy ul ai tv )
6/7 m/o-Ratio
%Conversion of 5
%meta Yield
1
2
3
4
5
6
7
8
9
5a
5a
5b
5c
5d
5d
5e
5f
CH
CH
Cl
3
PhNO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
2
2
2
2
2
2
5
5
5
5
5
19/1
20/1
35
42
33
19
20
43
48
50
25
3
30/1
NO
Br
2
50/1
>99/1
>99/1
>99/1
>99/1
35/1
Br
40
45
48
19
CH
CH
2
OAc
OCH
2
3
5g
5h
COOCH
CN
3
e
10
nd
<1
nd: notde te rmined.
a
TM
TM
Reactions were run in the Emry process vials under microwave irradiation using the Smith Synthesizer from Personal Chemistry.
Reactions run at the scale of 100 mg of 9-substituted anthracene with a molar ratio of 1:2:0.1 or 1:5:0.1 for anthracene/2-acetamidoacrylate/
hydroquinone at200 °C for 1 h.
b
c
d
e
The reaction mixtures were directly assayed by HPLC for the ratio of meta and ortho isomers 6/7 and %conversion of the 9-substitued anthracenes.
Isolated yields of meta isomer after flash chromatography, with no optimization.
Product was characterized by HPLC and LCMS without isolation.
The bestresul st were achieved in DMF, a polar and
1
bility of a retro Diels–Alder reaction mechanism, we
investigated the reaction of ortho isomer 7a with 5 equiv
of 2-acetamidoacrylate in the presence of a catalytic
amountof hydroquinone ( Scheme 2). When exposed
to microwave irradiation in DMF at 200 °C for
60 min, the reaction produced a product mixture con-
taining 10% of the meta isomer 6a and 89.2% 9-methyl-
anthracene 5a with 0.8% of the ortho isomer 7a (HPLC
analysis). Evidently, the ortho isomer 7a undergoes a
retro Diels–Alder reaction that generates the 9-methyl-
anthracene eventually leading to the formation of the
thermodynamically more stable meta isomer 6a.
1d,e
high-absorbing (microwave energy) solvent.
Reac-
tion of 5a at200 °C for 1 h resulted in 42% conversion
with a good meta regioselectivity (meta/ortho 20/1, entry
2
) similar to the results using conventional heating in
nitrobenzene (Table 1, entry 2). In this case, nitrobenz-
ene was not the optimal solvent under the microwave
irradiation (entry 1). 9-Bromoanthracene 5d in DMF
afforded the meta isomer 6d exclusively (entry 5). When
5
equiv of 2-acetamidoacrylate were employed, reactions
of 5d,e, and 5f in DMF attained meta isomers 6d,e, and 6f
in 40%, 45%, and 48% yields, respectively (entries 6–8).
Under the same conditions, reaction of methyl anthra-
cene-9-carboxylate 5g gave the meta isomer 6g in 19%
yield with a meta/ortho ratio of 35/1 (entry 9).
Finally, hydrolysis of the Diels–Alder adduct esters 6a–d
and 3 in HCl–dioxane furnished the corresponding bicy-
clic bisaryl a-amino acids 4a–d and 8 uneventfully
(Table 3).
As demonstrated by the results in Table 2, compared to
thermal conditions, microwave irradiation offers the
advantage of significant increases in reaction rate. In
addition, employment of an excess of the dienophiles
accompanied by a decrease of side reactions under
microwave heating and the facile purification of the
reaction mixture in DMF resulted in increased reaction
yields in mostcases.
In summary, we have developed a facile preparation of a
series of novel and conformationally constrained bicy-
clic bisaryl a-amino acids with high regioselectivity via
Diels–Alder reactions of 9-substituted anthracenes and
2-acetamidoacrylate. Suppression of ortho isomerÕs for-
mation via retro Diels–Alder reaction followed by
regeneration of the meta isomer resulted in the high
meta regioselectivity. Use of nitrobenzene in a thermal
Diels–Alder reaction or DMF under microwave irradi-
ation at elevated temperatures was shown to enhance the
meta regioselectivity and improve reaction yields. Fur-
ther studies on the scope and regioselectivity of the
Diels–Alder reactions of substituted anthracenes with
We observed that under both conventional heating and
microwave irradiation conditions, the formation of the
ortho isomer was suppressed at elevated temperatures.
This is probably due to retro Diels–Alder reaction of
the initially formed ortho isomer which is thermodynam-
ically less stable than the meta isomer. To test the possi-
AcHN
AcHN
COOCH3
COOCH3
NHAc
hydroquinone(cat.)
o
DMF, 200 C,
+
+
+ 7a
60 min. µw
COOCH3
ortho
meta
6a
7a
5a
Scheme 2.

2860
B. V. Yang, L. M. Doweyko / Tetrahedron Letters 46 (2005) 2857–2860
Table 3. Hydrolysis of Diels–Alder reaction adduct 6
AcHN
COOCH3
H N
3
COO
Conc.HCl / dioxane 1:1
o
1
00 C, 12-40 h
R
R
6
3
a-d
R = H
4a-d
8 R = H
a
Entry
Ester
R
Time (h)
Acid
% Yield
1
2
3
4
5
6a
6b
6c
6d
CH
Cl
3
18
16
40
12
12
4a
4b
4c
4d
8
89
99
91
89
90
NO
Br
H
2
b
3
a
Yields of isolated products with no optimization.
Compound 3 was prepared from the Diels–Alder reaction of 2-acetamidoacrylate and anthracene in 60% yield employing the procedure described in
Table 1 entry 2.
b
a variety of dienophiles under microwave irradiation are
in progress.
5. (a) Kotha, S.; Ghosh, A. K.; Behera, M. Indian J. Chem.
002, 41B, 2330; (b) The reaction yield based on the
2
starting material anthracene that employed in the Diels–
Alder reaction is calculated as 42% using the reported data
in this paper.
Acknowledgement
6
. (a) The regioselectivity for Diels–Alder reactions of some
9
-substituted anthracenes with acrylic acid, acrylonitrile,
The authors thank Drs. Murali Dhar, John Dodd, and
Joel Barrish for their helpful comments and proof-read-
ing this manuscript.
and allyl alcohol have been studied. These reactions were
reported to give predominately the ortho regioisomers in
all but two cases tested (acrylic acid with 9-nitro- and
9-carboxyanthracene) ; (b) Alston, P. V.; Ottenbrite, R.
M.; Newby, J. J. Org. Chem. 1979, 44, 4939.
6
b
References and notes
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1
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(
8. Cativiela, C.; Garcia, J. I.; Mayoral, J. A.; Salvatella, L.
Chem. Soc. Rev. 1996, 209, and references cited therein.
9. At the lowest limits of detection in HPLC the minimum
meta/ortho ratio is at least >99 to 1 (absence of the ortho
3
2
1
isomer confirmed by H NMR as well).
10. Analytical data for representative compounds, meta iso-
1
mer 6a and ortho isomer 7a (Table 1, entry 1): 6a H NMR
4
(500 MHz, MeOH-d ) d 7.34 (t, J = 8 Hz, 2H), 7.25 (m,
1
2789; (g) Shuman, R. T.; Rothenberger, R. B.; Campbell,
3H), 7.17 (m, 2H), 7.09 (td, J = 8, 1.3 Hz, 1H), 5.64 (br s,
1H), 4.44 (s, 1H), 3.48 (s, 3H), 2.89 (d, J = 13.6 Hz, 1H),
C. S.; Smith, G. F.; Gifford-Moore, D. S.; Paschal, J. W.;
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Mendel, D.; Ellman, J.; Schultz, P. G. J. Am. Chem. Soc.
1
3
1.93 (s, 3H), 1.78 (s, 3H), 1.53 (d, J = 13.6 Hz, 1H);
C
NMR (100 MHz, CDCl ) d 172.2, 169.5, 146.3, 145.2,
3
1
993, 115, 4359.
138.8, 138.4, 127.2, 126.8, 125.9, 125.7, 124.9, 124.7, 121.4,
120.9, 63.8, 52.5, 52.2, 47.4, 42.6, 22.8, 17.1; MS (ESI): m/z
336.29 [M+H] . 7a H NMR (400 MHz, MeOH-d ) d 7.50
4
2
. (a) Abellan, T.; Mancheno, B.; Najera, C.; Sansano, J. M.
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+
1
(dd, J = 8, 1.6 Hz, 1H), 7.32 (td, J = 8, 1.6 Hz, 2H), 7.21
(m, 3H), 7.15 (m, 2H), 4.34 (t, J = 2.6 Hz, 1H), 3.38 (s,
3H), 3.06 (dd, J = 13.3, 2.6 Hz, 1H), 2.02 (s, 3H), 1.85 (dd,
J = 13.3, 2.6 Hz, 1H), 1.84 (s, 3H); MS (ESI): m/z 336.29
2
000, 65, 3034; (d) Chinchilla, R.; Falvello, L. R.;
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+
1
[M+H] .
Tetrahedron: Asymmetry 1990, 1, 379; (f) Cativiela Carlos,
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6
1.
. Gibson, S. E.; Guillo, N.; Yozer, M. J. Tetrahedron 1999,
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3
4
5
. (a) Grunewald, G. L.; Kuttab, S. H.; Pleiss, M. A.;
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