One-step coupling of tris(hydroxymethyl)aminomethane to aliphatic and aromatic carboxylic acids

Article abstract of DOI:10.1055/s-2000-7105

A convenient and general method was established to append tri-, hexa-, and nonadentate ligands about an aromatic or aliphatic core. This approach allows a variety of commercially available carboxylic acids to be transformed to their N-tris(hydroxymethyl)m

Full text of DOI:10.1055/s-2000-7105

PAPER
1435
One-Step Coupling of Tris(hydroxymethyl)aminomethane to Aliphatic and
Aromatic Carboxylic Acids
Ignacio Villanueva, Bernadette Hernandez, Virginia Chang, Michael D. Heagy*
Department of Chemistry, New Mexico Institute of Mining & Technology, Socorro, New Mexico 87801, USA
Fax +1(505)8355364; E-mail: mheagy@nmt.edu
Received 9 December 1999; revised 19 April 2000
Entry 5) and aromatic dicarboxylic acids (Table 2, Entries
Abstract: A convenient and general method was established to ap-
pend tri-, hexa-, and nonadentate ligands about an aromatic or ali-
phatic core. This approach allows a variety of commercially
3
, 4). Finally, two nonadentate ligands were produced
from cis-1,3,5-cyclohexanetricarboxylic acid (Table 1,
available carboxylic acids to be transformed to their N-tris(hy- Entry 6) and 1,3,5-benzenetricarboxylic acid (Table 2,
droxymethyl)methylcarboxamides in one step. The selective activa- Entry 5) with this peptide-coupling agent.
tion of the acid functionality to form the polyhydroxylated dendritic
cores has been achieved using the acyl transfer agent N-ethoxycar-
bonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).
Key words: carboxylic acids, dendrimers, coupling, amides,
Table 1 Polydentate Aliphatic Cores Obtained by EEDQ-activated
ligands
Coupling between TRIS and Carboxylic Acids
a
Entry
Substrate
Product
Yield (%)
Numerous methods exist to form carboxamides from car-
1
boxylic acids and simple primary amines. Fewer reac-
tions are known which can make this conversion in a
single step. Generally, reactions of this type have been ex-
plored in the context of peptide synthesis through the use
of such amino acid coupling reagents as, ethoxyacety-
2
a
2b,c
2d
2e
lene, DCC, ketenimes, ynamines, and copper com-
2
f
plexes. However, many of these methods give less than
satisfactory results when the primary amine in question
involves a sterically crowded, polyhydroxylated amine
such as tris(hydroxymethyl)aminomethane, (TRIS). The
importance of the TRIS group to dendrimer synthesis lies
in its use as a 1 → 3 branching component in the
poly(amido alcohols) class of arborol dendrimers.3 Cur-
rent methods towards appending TRIS to dendritic cores
in a single step are limited as TRIS has slight solubility in
polar aprotic solvents and forms adventitious mixtures of
carboxylic esters when the carboxyl component is strong-
ly activated as either the acyl halide or symmetrical anhy-
,4
5
dride.
Since this amine is of current interest for TRIS connectiv-
ity in the generation of dendritic cores, as well as our
project that utilizes the TRIS moiety for the production of
6
polydentate ligands , we wish to report a convenient route
towards the synthesis of such N-tris(hydroxymethyl)me-
7
thylcarboxamides. The selective conversion of either ali-
phatic or aromatic carboxylic acids to their corresponding
TRIS carboxamides has been achieved in one step using
the acyl-transfer reagent N-ethoxycarbonyl-2-ethoxy-1,2-
8
dihydroquinoline, (EEDQ) (Scheme).
Using this method tridentate ligands have been produced
directly from linear and cyclic aliphatic monocarboxylic
acids (Table 1, Entries 1−4) and aromatic monocarboxylic
acids (Table 2, Entries 1, 2). Hexadentate ligands were
synthesized from cyclohexane dicarboxylic acid (Table 1,
a
Isolated yield of analytically pure product.
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436
I. Villanueva et al.
PAPER
Table 2 Polydentate Aromatic Cores Obtained by EEDQ-activated
Coupling between TRIS and Carboxylic Acids
Single crystals of N-tris(hydroxymethyl)methyl-4-tert-
butylbenzenecarboxamide (Table 2, Entry 3) were ob-
tained and found to be suitable for X-ray structure analy-
sis (Figure). As this compound was prepared for the
eventual application in ceramic thin-film materials, the
solid-state motif is of particular interest. Since aromatic
compounds have a higher C:H ratio than aliphatic com-
pounds, aromatics have a propensity to maximize van der
Waals C,C interactions in the crystal lattice via close-
a
Entry
Substrate
Product
Yield (%)
9
packing of phenyl groups. Due to the steric congestion
introduced by the bulky tert-butyl groups as well as mul-
tiple hydrogen-bonding groups of the TRIS-triol, we were
curious as to how this compound is arranged in the unit
cell. The tridendate ligand shows an offset stacking ar-
rangement of the tert-butylbenzene rings where the aro-
matic contact distance along the z-axis between phenyl
rings was determined at 3.19 Å. This intermolecular dis-
tance along the z-axis lies within the narrow range (3.1 Å
to 3.4 Å) typically observed between two phenyl groups
in the solid state.
In summary, this method provides a convenient route to
various aliphatic and aromatic TRIS carboxamides with-
out side reactions, and thus obviates the need to protect
hydroxylfunctionality prior to the amide-coupling reac-
tion.1 Such advantages in the use of EEDQ over DCC
coupling conditions are possible since the reactive inter-
mediate, a mixed anhydride forms slowly while its con-
0,11
2e
sumption by the amine is fast. Tables 1 and 2 indicate the
versatility of this reaction and the yields obtained during
this study. Lastly, the facility and mild conditions of the
reaction make it suitable for large scale preparations.
The general reaction performed in this study where R rep-
resents either an aliphatic or aromatic group is shown in
the Scheme. An equivalent amount of EEDQ upon disso-
lution in refluxing pyridine with mono-, di-, or tricarbox-
ylic acids and TRIS delivers the desired carboxamides in
moderate to good yields. Yields of these polyhydroxylat-
ed compounds are sufficient to allow for simple purifying
procedures through recrystallization of the obtained crude
solid. The byproducts of the reaction, quinoline, ethanol
and CO are all easily removed. For the removal of excess
2
TRIS, water was required as the rinse solvent and, in cer-
tain cases, the moderate yields reported in Tables 1 and 2
were a consequence of enhanced water solubility of the fi-
nal product.
Figure X-Ray Structuere of N-tris(hydroxymethyl)methyl-4-tert-
butylbenzenecarboxamide
All experiments were conducted under N . All glassware was
2
Scheme
washed with acetone and dried. TLC was performed using JT Baker
pre-coated hard layer silica gel plates and/or Whatman adsorption
silica gel plates: 60Å, F254, 2.50 mm thickness. H and C NMR
1
13
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PAPER
One-Step Coupling of Tris(hydroxymethyl)aminomethane to Aliphatic and Aromatic Carboxylic Acids
1437
-
1
spectra were recorded on a JEOL Eclipse 300 MHz NMR. The
chemical shifts for the H spectra are reported in ppm on the δ scale
from TMS internal reference. IR spectra were recorded on a Perkin-
Elmer FT/IR-1710 spectrophotometer. Melting points are uncor-
rected. Elemental analyses were obtained from Sandia National
Laboratory using a CHNS/O analyzer.
IR (KBr): ν = 1514, 2906, 3377 cm .
1
Anal. calcd for C H NO : C 63.58, H 8.89, N 4.94. Found: C
1
5
25
4
6
3.01, H 8.70, N 5.58.
trans-N,N’-Bis[tris(hydroxymethyl)methyl]-1,4 cyclohexanedi-
carboxamide (Table 1, Entry 5)
Yield: 47%; mp 238−239 °C.
1
N-Tris(hydroxymethyl)methylhexanecarboxamides; General
Procedure
H NMR (300 MHz, DMSO-d ): δ = 1.31 (m, 4 H), 1.74 (d, J = 7.2
6
Hz, 4 H), 2.18 (s, 2 H), 3.51 (d, J = 5.5 Hz, 12 H), 4.75 (t, J = 5.8
The appropriate carboxylic acid (1.0 g, 8.6 mmol) and an equivalent
amount of TRIS (2.08 g, 17.17 mmol), EEDQ (3.2 g, 12.9 mmol),
and pyridine (50 mL) were introduced to a 100 mL round-bottom
flask, equipped with a Dean−Stark receiver and condenser. The
mixture was heated and allowed to reflux (5 h). The solution was
concentrated by rotary evaporation and the remaining pyridine was
removed under high vacuum. The remaining solid was washed and
filtered with CH Cl (5 mL) to extract excess EEDQ. The crude
Hz, 6 H), 7.05 (s, 2 H).
13
C NMR (75 MHz, DMSO-d ): δ = 29.2, 36.8, 64.7, 70.7, 76.5,
6
1
69.7.
-
1
IR (KBr): ν = 1601, 1648, 2922, 3320 cm .
Anal. calcd for C H N O : C 50.79, H 7.99, N 7.40. Found: C
1
6
30
2
8
5
0.90, H 7.90, N 7.45.
2
2
cis-N,N’,N”- Tris[tris(hydroxymethyl)methyl]-1,3,5-cyclohex-
anetricarboxamide (Table 1, Entry 6)
Yield: 30%; mp 198−204 °C.
product was dissolved in H O and extracted with Et O (3 × 50 mL).
2
2
Rotary evaporation of Et O solution yielded a white solid.
2
N-Tris(hydroxymethyl)methylhexanecarboxamide (Table 1,
Entry 1)
Yield: 57%; mp 95−100 °C.
1
H NMR (300 MHz, DMSO-d ): δ = 1.4 (m, 3 H), 1.75 (m, 3 H), 2.3
6
(
m, 3 H), 3.52 (s, 18 H), 4.75 (br, s, 9 H), 7.0 (s, 3 H).
13C NMR (75 MHz, DMSO-d
): δ = 32.5, 61.2, 62.5, 176.2.
1
6
H NMR (300 MHz, CD COCD ): δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.3
3
3
-
1
(
(
1
m, 4 H), 1.58 (m, 2 H), 2.25 (t, J = 7.4 Hz, 2 H), 3.6 (s, 6 H), 6.8
s, 1 H).
IR (KBr): ν = 1648, 2922, 3406 cm .
Anal. calcd for C H N O : C 47.99, H 7.48, N 7.99. Found: C
2
1
39
3
12
3
C NMR (75 MHz, CD COCD ): δ = 13.4, 22.3, 25.4, 31.2, 36.3,
47.10, H 7.48, N 7.30.
3
3
6
2.4, 174.8.
N-Tris(hydroxymethyl)methyl-4-tert-butylbenzenecarboxam-
ide (Table 2, Entry 1)
-
1
IR (KBr): ν = 1602, 2922, 3273 cm .
Yield: 57%; mp 139−142 °C.
Anal. calcd for C H NO : C 54.78, H 9.65, N 6.38. Found: C
10
21
4
1
5
4.69, H 9.60, N 6.40.
H NMR (400 MHz, CD COCD ): δ = 1.32 (s, 9H), 3.77 (d, J = 5.5
3
3
Hz, 6H), 4.57 (t, J = 5.5 Hz, 3H), 7.33 (s, 1H), 7.51 (d, J = 8.4 Hz,
N-Tris(hydroxymethyl)methyldodecanecarboxamide (Table 1,
Entry 2)
Yield: 78%; mp 106−109 °C.
2
H), 7.76 (d, J = 8.4 Hz, 2H).
1
3
C NMR (100 MHz, CD SOCD ): δ = 31.5, 35.1, 61.1, 63.1, 125.5,
3
3
1
127.7, 133.0, 154.5, 167.8.
H NMR (300 MHz, DMSO-d ): δ = 0.85 (t, J = 6.3 Hz, 3 H), 1.24
6
-
1
(
s, 16 H), 1.47 (m, 2 H), 2.12 (t, J = 7.2 Hz, 2 H), 3.51 (d, J = 5.8
IR (KBr): ν = 772, 1636, 2946 cm .
Hz, 6 H), 4.75 (t, J = 5.8 Hz, 3 H), 7.08 (s, 1 H).
Anal. Calcd for C H O N:C (64.04), H (8.24), N (4.98). Found: C
(63.72), H (8.19), N (5.09).
1
5
23
4
1
3
C NMR (75 MHz, CD COCD ): δ = 14.5, 22.7, 25.9, 29.5, 31.9,
3
3
3
6.4, 61.4, 62.8, 174.4.
N-Tris(hydroxymethyl)methyl-4-phenylbenzenecarboxamide
(Table 2, Entry 2)
-
1
IR (KBr): ν = 1620, 2919, 3284 cm .
Yield: 72%; mp 147−148 °C.
Anal. calcd for C H NO : C 63.34, H 10.96, N 4.60. Found: C
1
6
33
4
1
6
3.44, H 10.71, N 4.72.
H NMR (400 MHz, DMSO-d ): δ = 3.83 (d, J = 6 Hz, 6 H), 4.52 (t,
6
J = 6.4 Hz, 3 H),), 7.3 (s, 1 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.50 (t,
J = 7.3 Hz, 2 H), 7.73 (d, J = 8.8 Hz, 2 H), 7.77 (d, J = 8.6 Hz, 2 H),
N-Tris(hydroxymethyl)methylcyclohexanecarboxamide (Ta-
ble 1, Entry 3)
Yield: 67%; mp 165−170 °C.
7
.9 (d, J = 8.3 Hz, 2 H).
13C NMR (100 MHz, CD
COCD
): δ = 63.4, 63.5, 127.8, 128.0,
1
3
3
H NMR (300 MHz, CD OD): δ = 1.34 (m, 5 H), 1.79 (m, 5 H), 2.25
3
1
28.8, 129.0, 129.9, 134.7, 140.8, 145.0, 168.7.
(
m, 1 H), 3.72 (s, 6 H).
-
1
1
3
IR (KBr): ν = 742, 1641, 2946 cm .
C NMR (75 MHz, DMSO-d ): δ = 25.4, 25.6, 29.5, 45.5, 61.8,
6
1
78.9.
Anal. calcd for C H O N: C 67.76, H 6.35, N 4.65. Found: C
1
7
19
4
-
1
67.74, H 6.50, N 4.49.
IR (KBr): ν = 1646, 2919, 3284 cm .
N,N’-Bis-[tris(hydroxymethyl)methyl]-5-tert-butyl-1,3-ben-
zenedicarboxamide (Table 2, Entry 3)
Yield: 72%; mp 147−153 °C.
Anal. calcd for C H NO : C 57.40, H 8.75, N 6.08. Found: C
11
21
4
5
7.26, H 8.95, N 6.15.
N-Tris(hydroxymethyl)methyl-1-adamantanecarboxamide
Table 1, Entry 4)
1
H NMR (300 MHz, CD OD): δ = 1.38 (s, 9 H), 3.93 (d, J = 5.5 Hz,
3
(
1
2 H), 8.03 (d, J = 4.9 Hz, 3 H).
13C NMR (75 MHz, CD
OD): δ = 30.2, 34.7, 61.4, 62.8, 122.9,
27.3, 135.1, 152.1, 169.4.
Yield: 45%; mp 193−195 °C.
1
3
H NMR (300 MHz, DMSO-d ): δ = 1.7 (m, 12 H), 1.97 (s, 3 H),
6
1
3
.49 (s, 6 H), 4.9 (br, s, 3 H), 6.39 (s, 1 H).
-
1
1
3
IR (KBr): ν = 1049, 1646, 2959 cm .
C NMR (75 MHz, pyridine-d ): δ = 28.5, 36.8, 39.7, 40.8, 58.4,
5
6
4.7, 180.6.
Anal. calcd for C H N O : C 56.07, H 7.54, N 6.54. Found: C
2
0
32
2
4
5
6.24, H 7.44, N 6.35.
Synthesis 2000, No. 10, 1435–1438 ISSN 0039-7881 © Thieme Stuttgart · New York

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438
I. Villanueva et al.
PAPER
Oxybis[N-tris(hydroxymethyl)methyl]-4,4’-benzenedicarboxa-
mide (Table 2, Entry 4)
Acknowledgement
Support for this project was provided by the Sandia-University Re-
search Project contract. M.D.H. wishes to thank Ms. Sara C. Vick
and Dr. Mark A. Rodriguez for obtaining the crystal structure data
and Dr. Timothy J. Boyle of the Advanced Materials Laboratory for
the collaborative effort that this project has initiated.
Yield: 57%; mp 158−164 °C.
1
H NMR (300 MHz, DMSO-d ): δ = 3.68 (d, J = 5.8 Hz, 12 H), 4.77
6
(
t, J = 5.8 Hz, 6 H), 7.11 (d, J = 8.5 Hz, 4 H), 7.28 (s, 2 H), 7.86 (d,
J = 8.8 Hz, 4 H).
1
3
C NMR (75 MHz, DMSO-d ): δ = 60.9, 63.2, 118.8, 130.2, 131.2,
6
1
58.9, 167.0.
References
-
1
IR (KBr): ν = 765, 1627, 2880 cm .
(
1) For reviews, see:
a) Beckwith, A. L. J., In Zabicky, The Chemistry of the
Amides, pp. 73−186, Interscience: New York, 1970.
b) Whittaker, R. G.; Hayes, P. J.; Bender, V. J. Peptide
Research, 1993, 3, 125.
2) (a) Banks, G. R.; Cohen, D.; Pattenden, G. E. J. Chem. Soc.
[C] 1967, 126.
Anal. calcd for C H N O : C 56.89, H 6.08, N 6.03. Found: C
22
28
2
9
(
5
6.21, H 5.89, N 5.75.
N,N’,N’’-Tris[tris(hydroxymethyl)methyl]-1,3,5-benzenetri-
carboxamide (Table 2, Entry 5)
Yield: 58%; mp >300 °C.
(
(
1
H NMR (300 MHz, DMSO-d ): δ = 3.32 (s, 4 H), 3.72 (d, J = 3 Hz,
6
(
1
(
b) Sheehan, J. C.; Hess, G. P.; J. Am. Chem. Soc. 1955, 77,
067.
c) Sheehan, J. C.; Goodman, M.; Hess, G. P. J. Am. Chem.
Soc. 1956, 78, 1367.
1
8 H), 4.73 (t, J = 5.8 Hz, 9 H), 7.54 (s, 3 H), 8.26 (s, 3 H).
1
3
C NMR (75 MHz, DMSO-d ): δ = 60.8, 63.5, 123.9, 135.9, 167.1.
6
-
1
IR (KBr): ν = 801, 1652, 2961 cm .
(d) Stevens, C. L.; Munk, M. E. J. Am. Chem. Soc. 1968, 4069.
(e) Buyle, R.; Viehe, G. H. Angew. Chem. 1964, 76, 572.
(f) Klausner, Y. S.; Bodansky, M. Synthesis 1972, p.453.
Anal. calcd for C H N O : C 48.55, H 6.40, N 8.09. Found: C
2
1
33
3
12
4
8.57, H 6.37, N 8.59.
(
3) Tomalia, D. A.; Durst, H. D. Top. Curr. Chem. 1993, 165,
93.
X-Ray Structure Determination of N-Tris(hydroxymethyl)me-
thyl-4-tert-butylbenzenecarboxamide (Table 2, Entry 1)
A colorless crystal was mounted on a thin glass fiber using fluorol-
ube. The crystal, which was mounted from a pool of silicone oil,
1
(
4) (a) Newkome, G. R.; Moorefield, C. N.; Vögtle, F. Dendritic
Molecules, Concepts, Syntheses, Perspectives; VCH:
Weinheim, 1996.
was immediately placed under a liquid N stream on a Bruker AXS
2
(b) Newkome, G. R.; Yao, Z.-Q.; Baker, G. R.; Gupta, J. J.
diffractometer. The lattice parameters were optimized from a least-
squares calculation on 106 carefully centered reflections. Lattice
determination and data collection were carried out using SMART
Version 5.054 software. The compound, C H NO , crystallizes in
Org. Chem. 1985, 50, 2003.
(
5) Tris(hydroxymethyl)aminomethane has been shown to form
TRIS carboxamides with carboxylic esters, see: Skarzewski,
J. Synthesis, 1990, 1125.
1
5
22
4
triclinic space group P-1; a = 6.2515(9), b = 8.6633(12),
(
(
(
6) Boyle, T. J.; Clem, P. G.; Rodriguez, M. A.; Tuttle, B. A.;
Heagy, M. D. J. Sol-Gel Sci. Tech. 1999, 16, 47.
7) Hernandez, B. A.; Chang, V.; Villanueva, I.; Heagy, M. D.;
J. Org. Chem. 1999, 64, 6905.
o
3
c = 14.045(2) Å, b = 91.186(3) . At Z = 2, V = 740.84(18) Å and
3
FW = 280.34 the calculated density is r = 1.257 Mg/m . The struc-
ture was solved by means of direct methods using SHELXTL 5.1
software. A total number of 4679 reflections were collected at
8) Vaino, A. R.; Depew, W. T.; Szarek, W. A. Chem. Commun.
1
68(2)K. Rint = 0.016(3) MoKα radiation (λ = 0.71073 Å),
1997, 1871.
-
1
µ = 0.091 mm no absorption correction. 3241 reflections with
I>2σ(I) were used in the final full-matrix least squares process. The
final refinement included anisotropic thermal parameters on all
Belleau, B.; Malek, G. J. Am. Chem. Soc. 1968, 90, 1651.
9) Desiraju. G. R. Crystal Engineering; The Design of Organic
Solids, Elsevier; New York, 1989.
(
non-hydrogen atoms and converged to R1 = 0.0518 and
(
(
10) Ashton, P. R.; Hounsell, E. F.; Jayaraman, N.; Nilsen, T. M.;
2
(
R2 = 0.1423, w = 1/σ F). Hydrogen atoms were fixed in positions
w
Spencer, N.; Stoddart, J. F.; Young, M. J. Org. Chem. 1998,
6
of ideal geometry and refined within the XSHELL software. These
idealized hydrogen atoms had there isotropic temperatures fixed at
3, 3429.
11) Jayaraman, N.; Stoddart, J. F. Tetrahedron Lett. 1997, No. 38,
767.
1
.2 or 1.5 times the equivalent isotropic U of the C atoms they were
6
bonded prior to the final refinement.
Article Identifier:
437-210X,E;2000,0,10,1435,1438,ftx,en;M03699SS.pdf
1
Synthesis 2000, No. 10, 1435–1438 ISSN 0039-7881 © Thieme Stuttgart · New York