Efficient and mild microwave-assisted stepwise functionalization of naphthalenediimide with α-amino acids

Article abstract of DOI:10.1021/jo061195h

Microwave dielectric heating proved to be an efficient method for the one-pot and stepwise syntheses of sym-metrical and unsymmetrical naphthalenediimide derivatives of a-amino acids. Acid-labile side chain protecting groups are stable under the reaction

Full text of DOI:10.1021/jo061195h

Efficient and Mild Microwave-Assisted Stepwise
Functionalization of Naphthalenediimide with
r-Amino Acids
and porphyrins. In recent years, some derivatives of naphtha-
lenediimide have enjoyed a new role as building blocks in the
synthesis of hetero-oligomers that have the capability to fold,
4
in aqueous solution, into well-defined super-structures. Water-
soluble naphthalenediimide derivatives also strongly interact
Paolo Pengo, G. Dan Panto s¸ , Sijbren Otto,* and
5
with DNA in a threading mode, and this feature has been
Jeremy K. M. Sanders*
6
exploited for the design of molecular probes. As a part of our
ongoing projects, we needed an easy entry to structurally
sophisticated naphthalenediimides having additional functional
groups for postsynthetic modification. The functionalization of
naphthalene tetracarboxylic dianhydride 1 with R-amino acids
was an attractive route because of the large diversity of
functional groups that could be thus introduced. Despite the
UniVersity Chemical Laboratory, UniVersity of Cambridge,
Lensfield Road, Cambridge CB2 1EW, United Kingdom
so230@cam.ac.uk; jkms@cam.ac.uk
ReceiVed June 9, 2006
7
well-documented preparation of phthalimido amino acids, the
simplest derivatives of R-amino acids featuring an aromatic
imide, the literature concerning the structurally related naph-
thalene and pyromellitic diimides is scant. This is due to the
harsh conditions used in the condensation of primary amines
with naphthalene- and pyromellitic tetracarboxylic dianhydrides.
8
The published reaction conditions consist of refluxing the two
components for prolonged periods of time in high boiling
solvents such as DMF, 2-propanol, or pyridine. Although these
8
,9
conditions may be used with free amino acids, they may not
be compatible with sensitive amines or with protected R-amino
acids. We decided to use microwave-induced dielectric heating
to reduce the reaction times and to broaden as much as possible
the span of the reaction conditions.
Microwave dielectric heating proved to be an efficient
method for the one-pot and stepwise syntheses of sym-
metrical and unsymmetrical naphthalenediimide derivatives
of R-amino acids. Acid-labile side chain protecting groups
are stable under the reaction conditions; protection of the
R-carboxylic group is not required. The stepwise condensa-
tion of different amino acids resulted in high yields of
unsymmetrical naphthalenediimides. The reaction proceeds
without racemization and is essentially quantitative.
(3) For selected examples, see (a) Kaiser, G.; Jarrosson, T.; Otto, S.;
Ng, Y.-F.; Bond, A. D.; Sanders, J. K. M. Angew. Chem. 2004, 43, 1959-
1
962. (b) Hamilton, D. G.; Davies, J. E.; Prodi, L.; Sanders, J. K. M.
Chem.-Eur. J. 1998, 4, 608-620. (c) Try, A. C.; Harding, M. M.; Hamilton,
D. G.; Sanders, J. K. M. Chem. Commun. 1998, 723-724. (d) Hamilton,
D. G.; Sanders, J. K. M.; Davies, J. E.; Clegg, W.; Teat, S. J. Chem.
Commun. 1997, 897-898. (e) Vignon, S. A.; Jarrosson, T.; Lijima, T.;
Tseng, H.-R.; Sanders, J. K. M.; Stoddart, J. F. J. Am. Chem. Soc. 2004,
126, 9884-9885. (f) Hansen, J. G.; Feeder, N.; Hamilton, D. G.; Gunter,
M. J.; Becher, J.; Sanders, J. K. M. Org. Lett. 2000, 2, 449-452. (g) Kieran,
A. L.; Pascu, S. I.; Jarrosson, T.; Gunter, M. J.; Sanders, J. K. M. Chem.
Commun. 2005, 1842-1844. (h) Hamilton, D. G.; Feeder, N.; Teat, S. J.;
Sanders, J. K. M. New. J. Chem. 1998, 1019-1021. (i) Hamilton, D. G.;
Prodi, L.; Feeder, N.; Sanders, J. K. M. J. Chem. Soc., Perkin Trans. 1
Electron-deficient and electron-rich subunits are common
structural motifs in the design of supramolecular architectures
including topologically interlocked molecules, molecular de-
1
999, 1057-1065
4) (a) Cubberley, M. S.; Iverson, B. L. J. Am. Chem. Soc. 2001, 123,
560-7563. (b) Gabriel, G. J.; Sorey, S.; Iverson, B. L. J. Am. Chem. Soc.
(
1
vices, and machines. The electron donor-acceptor interaction
7
that arises has been exploited to direct the syntheses of these
supramolecules under either thermodynamic or kinetic control.
In this respect, the electron-deficient naphthalenediimides and
2005, 127, 2637-2640.
(5) (a) Lee, J.; Guelev, V.; Sorey, S.; Hoffman, D. W.; Iverson, B. L. J.
Am. Chem. Soc. 2004, 126, 14036-14042. (b) Guelev, V.; Sorey, S.;
Hoffman, D. W.; Iverson, B. L. J. Am. Chem. Soc. 2002, 124, 2864-2865.
(c) Gianolio, D. A.; Segismundo, J. M.; McLaughlin, L. W. Nucleic Acids
Res. 2000, 28, 2128-2134. (e) Rogers, J. E.; Weiss, S. J.; Kelly, L. A. J.
Am. Chem. Soc. 2000, 122, 427-436. (f) Gianolio, D. A.; McLaughlin, L.
W. Bioorg. Med. Chem. 2001, 9, 2329-2334.
2
pyromelliticdiimides have been extensively employed by others
3
and us for the preparation of catenanes, rotaxanes and pseudo-
rotaxanes in conjunction with electron-rich dialkoxynaphthalenes
(6) (a) Takagi, M. Pure Appl. Chem. 2001, 73, 1573-1577. (b) Mokhir,
(1) For general discussions and examples, see (a) Amabilino, D. B.;
A. A.; Kraemer, R. Bioconj. Chem. 2003, 14, 877-883. (c) Mokhir, A.;
Kr a¨ mer, R.; Wolf, H. J. Am. Chem. Soc. 2004, 126, 6208-6209. (d) Sato,
S.; Kondo, H.; Nojima, T.; Takenada, S. Nucleic Acids Symp. Ser. 2005,
49, 237-238.
Stoddart, J. F. Chem. ReV. 1995, 95, 2725-2828. (b) Raymo, F. M.;
Stoddart, J. F. Chem. ReV. 1999, 97, 11643-1664. (c) Pease, A. R.; Jeppesen,
J. O.; Stoddart, J. F.; Luo, Y.; Collier, C. P.; Heath, J. R. Acc. Chem. Res.
2
001, 34, 433-444. (d) Balzani, V.; G o´ mez-L o´ pez, M.; Stoddart, J. F. Acc.
(7) For conventional methods in the synthesis of phthalimido amino acids,
see (a) Bose, A. K.; Greer, F.; Price, C. C. J. Org. Chem. 1958, 23, 1335-
1338. (b) Hoffmann, E.; Schiff-Shenhav, H. J. Org. Chem. 1962, 27, 4686-
4688. (c) Billman, J. H.; Harting, W. F. J. Am. Chem. Soc. 1948, 70, 1473-
1474. For microwave assisted methods, see (d) Shendage, D. M.; Fr o¨ hlich,
R.; Haufe, G. Org. Lett. 2004, 6, 3675-3678. (e) Hajipour, A. R.;
Mallakpour, S.; Imanzadeh, G. Ind. J. Chem., Sect. B 2001, 40, 250-251.
(8) For some examples, see refs 2b-f, 3b, 5c, 5e-f. See also Jursic, B.
S.; Patel, P. K. Carbohydr. Res. 2005, 340, 1413-1418.
Chem. Res. 1998, 31, 405-414 (e) Talukdar, P.; Bollot, G.; Mareda, J.;
Sakai, N.; Matile, S. J. Am. Chem. Soc. 2005, 127, 6528-6529.
(2) For selected examples, see (a) Fallon, G. D.; Lee, M. A.-P.; Langford,
S. J.; Nichols, P. J. Org. Lett. 2004, 6, 655-658. (b) Wang, X.-Z.; Li,
X.-Q.; Shao, X.-B.; Zhao, X.; Deng, P.; Jiang, X.-K.; Li, Z.-T.; Chen, Y.-
Q. Chem.-Eur. J. 2003, 9, 2904-2913. (c) Li, X.-Q.; Feng, D.-J.; Jiang,
X.-K.; Li, Z.-T. Tetrahedron 2004, 60, 8275-8284. (d) Gunter, M. J.;
Farquhar, S. M. Org. Biomol. Chem. 2003, 1, 3450-3457. (e) Johnstone,
K. D.; Yamaguchi, K.; Gunter, M. J. Org. Biomol. Chem. 2005, 3, 3008-
(9) Abraham, B.; McMasters, S.; Mullan, M. A.; Kelly, L. A. J. Am.
Chem. Soc. 2004, 126, 4293-4300.
3
017. (f) Gunter, M. J. Eur. J. Org. Chem. 2004, 8, 1655-1673.
1
0.1021/jo061195h CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/26/2006
J. Org. Chem. 2006, 71, 7063-7066
7063

SCHEME 1. General Synthetic Method for the
Symmetrical Naphthalinediimine Derivatives 2a-p
1
FIGURE 1. (a) Sections of the H NMR spectrum of compound (R,R)-
1
TABLE 1. Condensations of Naphthalene Tetracarboxylic
Dianhydride (1) with Protected and Unprotected r-Amino Acids
and r-Amino Acid Esters
2b. (b) Sections of the H NMR spectrum of the naphthalene diimide
derivative obtained using H-(D,L)-Cys(Trt)-OH. The spectra were
recorded at 400 MHz in CDCl at 298 K. A Lorentzian/Gaussian
3
window function with LB ) -0.3 Hz and GB ) 1 was used for
entry
amino acid
time [min:sec]
yield (%)
resolution enhancement.
a
1
2
3
4
5
6
7
8
9
2a
H-Gly-OH
1:00
94
95
86
a
b
(R,R)-2b
(S,S)-2b
(R,R)-2c
(S,S)-2d
(S,S)-2e
(S,S)-2f
(S,S)-2g
(S,S)-2h
(S,S)-2i
(S,S)-2j
(S,S)-2k
(S,S)-2l
(S,S)-2m
(S,S)-2n
(S,S)-2o
2p
H-L-Cys(Trt)-OH
H-D-Cys(Trt)-OH
H-L-Cys(Trt)-OMe
H-L-Ser(Bzl)-OH
H-L-Leu-OMe
H-L-Phe-OMe
H-L-Tyr-OH
H-L-His(Trt)-OMe
H-L-His(Trt)-OH
H-L-Trp-OH
2:20 /5:00
To explore the scope of the reaction, both unprotected and
protected amino acids were used. We mainly focused on acid-
labile protecting groups because of their well-established use
for the protection of amino acids in solid-phase synthesis. All
the protecting groups tested, trityl (Table 1, entries 2-4, 9, 10),
benzyl (5), tert-butyl (13), Boc (14), and Pmc (16), were stable
under the reaction conditions. No side reactions related to the
loss of a protecting group were observed. Remarkably, both
free amino acids and amino acid esters could be used without
significant differences in the efficiency of the reaction (Table
b
5:00
5:00
2:20
1:30
1:50
3:30
2:20
5:00
b
c,d
70
a
86
95
74
a
d
a
d
a
91
73
a
d
b
10
11
12
13
14
15
16
17
75
89
82
88
92
84
98
40
a
a
a
a
b
b
3:10
3:00
2:40
2:40
5:00
5:00
H-L-Trp-OMe
H-L-Glu(OtBu)-OH
H-L-Lys(Boc)-OH
H-L-Ala-OH
H-L-Arg(Pmc)-OH
H-Ac6c-OH
1
, entries 9,10 and 11,12, respectively). This is somewhat
surprising because, in these conditions, one may expect self-
condensation of amino acid esters to give dipeptides or
diketopiperazines and higher oligomers, but such side reactions
were never observed. Finally, in the case of unprotected tyrosine,
entry 8, the reaction was completely selective for the formation
of the symmetrical imide, no formation of esters being detected
b
20:00
a
Reaction performed at atmospheric pressure with a domestic microwave
appliance (800 W) at full power (see Experimental Section, Method A).
Reaction performed with a dedicated microwave reactor in pressure tight
reaction vessels (see Experimental Section, Method B). Over two steps,
starting from H-L-Cys-OMe‚HCl. After column chromatography.
b
c
d
1
by H NMR and reverse phase HPLC. The synthesis of
compound 2p, where 1-aminocyclohexanecarboxylic acid was
The synthesis of the symmetrical naphthalenediimides 2a-p
is outlined in Scheme 1. The derivatives reported in Table 1
were obtained in a pure state after simple workup, and only in
a few cases was a purification step necessary. Preliminary
experiments were run with a domestic microwave appliance,
in an open container and at atmospheric pressure, preventing
solvent (DMF) reflux.10
used, constitutes a special case in this study as we wanted to
test our synthetic protocols on sterically demanding C -
R
tetrasubstituted amino acids. The synthesis required longer
reaction times due to a combination of the poor solubility of
the starting material (H-Ac6c-OH) and steric hindrance imposed
by the cyclohexane ring. Compound 2p was isolated in 40%
yield, the lowest observed in this study, along with trace amounts
(
2%) of the corresponding imide-anhydride derivative, 3 (vide-
Other preparations were run in a dedicated microwave reactor
in pressure-resistant, tightly closed reaction vessels. The reac-
tions were carried out at 140 °C for a period of five minutes.
In these conditions, the power required to warm the reaction
mixture was between 330 and 390 W and the heating process
took between 25 and 30 s, followed by pulses of 30-50 W to
maintain the reaction mixture at 140 ( 5 °C. To test the viability
of this temperature-controlled method with respect to both
reaction temperature and reagent concentration, the synthesis
of (R,R)-2b was studied at 100 and 140 °C and on 0.2 and 1 g
of 1,4,5,8-naphthalenetetracarboxylic dianhydride. All the prepa-
rations gave similar results, with (R,R)-2b being obtained in
over 90% yields.
infra).
We also briefly explored synthetic protocols compatible with
ꢀ
the base-labile Fmoc group installed at the N nitrogen of
lysine. Regrettably, under the standard reaction conditions,
complex mixtures were obtained, likely as the result of some
Fmoc cleavage. Complex mixtures were obtained as well when
arginine methylester and unprotected arginine were reacted using
the standard conditions.
11
(11) In an attempt to solve this problem, the reaction was conducted in
the presence of a stoichiometric and substoichiometric amounts of triethy-
lamine, or using the more hindered base, diisopropylethylamine (Hunig’s
base). Unfortunately, in all the cases, complex mixtures were obtained with
no sign of product formation. When no base was added, the reaction was
not complete, even after irradiation for 30 min at 140 °C, using the dedicated
microwave reactor.
(
10) A 800 W domestic microwave oven (home appliance); in these
conditions and irradiating at full power, the solvent refluxes in about 20 s.
7
064 J. Org. Chem., Vol. 71, No. 18, 2006

SCHEME 2. General Synthetic Method for the Unsymmetrical Naphthalinediimine Derivatives 4a-d
TABLE 2. Stepwise Syntheses of Unsymmetrical L-r-Amino Acid
to the unreacted naphthalene dianhydride 1. In contrast, the
a
Functionalized Naphthalenediimides
standard methods for the synthesis of unsymmetrical naphtha-
lenediimides usually result in almost statistical mixtures. A
reasonable explanation for this difference is that in our condi-
tions, the reaction proceeds under kinetic control as a conse-
quence of the dramatic increase of the reaction rate, few minutes
against several hours for the reported procedures.
entry
amino acid 1
amino acid 2
yield (%)b
85c
1
2
3
4
(R,S)-4a H-L-Cys(Trt)-OH H-L-His(Trt)-OH
(S,S)-4b
(S,S)-4c
(S,S)-4d
H-L-Phe-OMe
H-L-Asp-OMe
H-L-Ile-OMe
H-L-Gln-OH
H-L-Tyr-OH
H-L-Trp-OMe
77
90
c
d
65
a
Reaction performed with a dedicated microwave reactor in pressure
Structural proof for compound 2f came from single-crystal
X-ray diffraction analyses of crystals grown by slow evaporation
of an acetone solution and a dichloromethane/acetonitrile
mixture. Figure 2 shows the single molecule and packing views
of 2f obtained from acetone. This compound adopts a C222(1)
space group, where the unit cell contains molecules arranged
in parallel fashion, as depicted in Figure 2 (bottom left) when
crystallized from acetone, and a P1 space group when crystal-
lized from dichloromethane/acetonitrile mixtures (see Supporting
Information). Regardless of the solvent used to obtain the single
crystals of 2f, there are two electron donor-acceptor (phenyl-
naphthalenediimide core) interactions per molecule, each with
a different partner. The two aromatic systems are almost parallel,
such that the smallest distance between them is 3.32 Å, with
the biggest distance being 3.53 Å.
b
c
1
tight reaction vessels. From dianhydride 1. Determined by H NMR on
the crude mixture. After column chromatography.
d
1
The H NMR spectra of compounds 2b-p display a sharp
singlet that broadens at higher concentration12 for the naphtha-
lenediimide moiety and a single set of signals for the amino
acid part. All the materials were also found to be homogeneous
by reverse phase HPLC analysis. This indicates that the reaction
proceeds without racemization at the R-center.
However, because the two amino acid fragments are quite
1
far apart, one may argue that H NMR may not be a reliable
method to distinguish between the diastereoisomers of the
naphthalenediimide formed upon racemization of the R-centers.
To specifically address this point, we used H-(D,L)-Cys(Trt)-
OH as the amino acid component in the condensation with
anhydride 1. In this case, three compounds are expected: the
symmetrical (S,S)-2b and (R,R)-2b and the unsymmetrical (S,R)-
In conclusion, microwave dielectric heating proved to be an
efficient and high-yielding method for the syntheses of sym-
metrical and unsymmetrical amino acid derivatives of naph-
thalenediimide. The reaction proceeds without racemization at
the R-center, and the synthetic conditions are compatible with
acid-labile protecting groups. The application of these amino
2
2
b in a 1:1:2 ratio. Because the enantiomeric (S,S)-2b and (R,R)-
b cannot be distinguished by NMR, they give a single set of
signals that is in a 1:1 ratio with the set for the (S,R)
1
diastereoisomer. The H NMR spectrum in Figure 1 (trace b)
clearly illustrates this situation; this is particularly evident when
the aromatic protons of the naphthalenediimide are concerned.
1
Trace a shows the H NMR spectrum of (R,R)-2b obtained using
H-L-Cys(Trt)-OH; its comparison with trace b clearly indicates
the absence of any diastereomeric species within the NMR
detection limit.
The one-pot procedure for the synthesis of symmetric amino
acids derivatives of naphthlenediimides proved to be reliable
and efficient, but we were interested in an equally easy route
to desymmetrize the dianhydride 1, obtaining unsymmetrical
amino acid functionalized diimides. We thus explored the
stepwise method outlined in Scheme 2. To our delight, we found
that it is possible to obtain a fairly high yield of unsymmetrical
naphthalene diimides with very little contamination by the
corresponding symmetrical species. The results of these findings
are summarized in Table 2. We speculate that this selectivity is
due to the decreased reactivity of intermediate 3 with respect
FIGURE 2. Side and crystal packing ORTEP-POVray rendered views
of 2f. The thermal ellipsoids are scaled at 50% probability level. All
hydrogen atoms and a disordered solvent molecule (acetone) have been
removed for clarity.
(12) Some concentration-dependent changes in chemical shift were also
observed.
J. Org. Chem, Vol. 71, No. 18, 2006 7065

acid functionalized diimides is under investigation and will be
reported in due course.
4
mL and added dropwise to 200 mL of 2.5% aqueous KHSO kept
under vigorous stirring. The resulting suspension was allowed to
coagulate overnight, and the precipitate was collected using a
B u¨ chner funnel, washed with water, and dried under vacuum. The
product was obtained as a brown-grey powder in 94% yield. mp >
Experimental Section
300 °C (Lit:13 > 390 °C); 1H NMR (400 MHz, DMSO-d
)
Synthesis of Symmetrical Naphthalenediimide Derivatives of
R-Amino Acids (2a-p): (A) General Procedure. 1,4,5,8-Naph-
thalenetetracarboxylic dianhydride (200 mg, 0.746 mmol) and the
corresponding R-amino acid derivative (1.491 mmol) were sus-
pended in 20 mL of DMF in a 150-mL Erlenmeyer flask. To this
6
13
1
δ(ppm): 13.19 (bs, 2H), 8.73 (s, 4H), 4.77 (s, 4H); C NMR { H}
(100.62 MHz, DMSO-d ) δ(ppm): 169.1, 162.3, 131.1, 126.4,
6
+
126.1, 41.6; HRMS (ESI+) calcd for C18
(m/z): 405.0335, found: 405.0329.
10 2 8
H N NaO [M + Na]
suspension was added 0.2 mL of dry Et
3
N. The suspension was
(S)-4-Carbamoyl-2-[7-((S)-1-methoxycarbonyl-2-phenyl-eth-
yl)-1,3,6,8-tetraoxo-3,6,7,8-tetrahydro-1H-benzo[lmn][3,8]-
phenanthrolin-2-yl]-butyric Acid, (S,S)-4b. The dark brown oil
sonicated until the mixture became homogeneous. The reaction
mixture was heated under microwave irradiation at full power
according to the times specified in Table 1, in 4 × 5 s intervals
followed by 10 s intervals. During this stage, the reaction mixture
was prevented from refluxing (reaction temperature 120-140 °C).
The solvent was removed under reduced pressure, and each reaction
mixture was worked-up using a suitable method.
3
was taken up into CH CN (15 mL). This solution was added under
stirring to 75 mL of 1 N HCl. The resulting suspension was allowed
to coagulate overnight and was then filtered using a B u¨ chner funnel.
The solid was then washed with 100 mL deionized water and dried
in vacuo. The product was obtained in the form of a light-brown
1
(B) General Procedure. 1,4,5,8-Naphthalenetetracarboxylic di-
solid in 77% yield. mp 164-166 °C (dec); H NMR (400 MHz,
anhydride (200 mg, 0.746 mmol) and the corresponding R-amino
acid derivative (1.491 mmol) were suspended in 10 mL of DMF
in a pressure-tight 20-mL microwave vial. To this suspension was
6
DMSO-d ) δ(ppm): 12.87 (bs, 2H), 8.68-8.67 (d, J ) 2.0, 4H),
7.17-7.02 (m, 6H), 6.58 (bs, 1H), 6.03-5.99 (dd, J
5.5, 1H), 5.55-5.52 (dd, J ) 14.5, J ) 4.5, 1H), 3.67 (s, 3H),
3.63-3.58 (dd, J ) 19.5, J ) 5.5, 1H), 3.36-3.29 (dd, J
25.0, J ) 10.0, 1H), 2.45-2.38 (m, 1H), 2.33-2.24 (m, 1H), 2.19-
2.07 (m, 2H); C NMR { H} (100.62 MHz, DMSO-d
1
) 15.0, J
2
)
1
2
added 0.2 mL of dry Et
3
N. The suspension was sonicated until the
1
2
1
)
mixture became homogeneous. The reaction mixture was heated
for 5 min at 140 ( 5 °C (direct flask temperature measurement)
under microwave irradiation using a dedicated microwave system.
The solvent was removed under reduced pressure, and each reaction
mixture was worked-up using a suitable method.
Synthesis of Unsymmetrical Naphthalenediimide Derivatives
of R-Amino Acids (4a-d). 1,4,5,8-Naphthalenetetracarboxylic
dianhydride (200 mg, 0.746 mmol) and the first R-amino acid
derivative, amino acid 1 according to Table 2, (0.746 mmol) were
suspended in 10 mL of DMF in a pressure-tight 20-mL microwave
2
13
1
6
) δ(ppm):
173.4, 170.5, 169.3, 162.3, 162.0, 137.1, 131.4, 131.0, 129.0, 128.2,
126.5, 126.3, 126.0, 125.1, 54.2, 53.2, 52.4, 34.0, 31.6, 23.9; HRMS
+
(ESI+) calcd for: C29
558.1531.
H
24
N O
3 9
[M + H] (m/z): 558.1513, found:
Acknowledgment. The access to the dedicated microwave
reactor is courtesy of the Innovative Technology Centre at the
University Chemical Laboratory, for which we thank Professor
Steven V. Ley. We acknowledge Dr. Ian Baxendale and Mr.
Lukas Kreis for their assistance with the use of this equipment.
We thank Dr. J. E. Davis for determining the crystal structures.
Financial support from EPSRC and the Royal Society is
gratefully acknowledged.
3
vial. To this suspension was added 0.1 mL of dry Et N. The
suspension was sonicated until the mixture became homogeneous.
The reaction mixture was heated for 5 min at 140 ( 5 °C (direct
flask temperature measurement) under microwave irradiation, using
a dedicated microwave system. At this stage, the second R-amino
acid derivative (amino acid 2, in Table 2) was added in one portion.
Supporting Information Available: Detailed experimental
3
An additional 0.1 mL of dry Et N was added, and the mixture was
1
procedures and characterization data for all new compounds, H
sonicated for 30 min. The reaction mixture was heated for an
additional 5 min at 140 ( 5 °C (direct flask temperature measure-
ment) under microwave irradiation, using a dedicated microwave
system. The solvent was removed under reduced pressure, and each
reaction mixture was worked-up using a suitable method.
NMR and 13C NMR spectra for compounds 2a-p and 4a-d, X-ray
crystallographic data for compound 2f. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO061195H
(
7-Carboxymethyl-1,3,6,8-tetraoxo-3,6,7,8-tetrahydro-1H-
benzo[lmn][3,8]phenanthrolin-2-yl)-acetic Acid, 2a. The reaction
(13) Tomasulo, M.; Naistat, D. M.; White, A. J. P.; Williams, D. J.;
mixture was concentrated under reduced pressure to a volume of 3
Raymo, F. M. Tetrahedron Lett. 2005, 46, 5695-5698
7
066 J. Org. Chem., Vol. 71, No. 18, 2006