A double heteroatom Mitsunobu coupling with amino hydroxybenzoic acids on solid phase: A novel application of the Mitsunobu reaction to form dendron building blocks

Article abstract of DOI:10.1016/j.tetlet.2010.08.105

A new highly efficient double heteroatom Mitsunobu coupling with amino hydroxybenzoic acids on solid phase is described. The synthetic routes reported in this work are general and applicable for the preparation of diverse building blocks, controlling protection, arm length, chirality, and peripheral functional groups. These novel units can form unusual dendritic architectures, which could be incorporated into specific complex structures, expanding the scope of dendrimer science.

Full text of DOI:10.1016/j.tetlet.2010.08.105

Tetrahedron Letters 51 (2010) 5988–5991
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Tetrahedron Letters
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A double heteroatom Mitsunobu coupling with amino hydroxybenzoic acids
on solid phase: a novel application of the Mitsunobu reaction to form
dendron building blocks
Tzachi Shalit a,b, Amnon Albeck b, Gary Gellerman a,
⇑
a Department of Biological Chemistry, Ariel University Center of Samaria, Ariel 40700, Israel
b The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar-Ilan University, Ramat Gan 52900, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 June 2010
Revised 3 August 2010
Accepted 31 August 2010
Available online 6 September 2010
A new highly efficient double heteroatom Mitsunobu coupling with amino hydroxybenzoic acids on solid
phase is described. The synthetic routes reported in this work are general and applicable for the prepa-
ration of diverse building blocks, controlling protection, arm length, chirality, and peripheral functional
groups. These novel units can form unusual dendritic architectures, which could be incorporated into
specific complex structures, expanding the scope of dendrimer science.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Dendron building block
Heteroatom Mitsunobu coupling
Azo compounds
Phosphines
Dendrimers are polymeric molecules with many arms emanat-
ing radially from a central core. High degrees of structural symme-
try and a defined number of terminal groups located at the surface
are important features of dendritic architectures. Depending on
their generation or order, dendrons not only have an impact on
the backbone conformation and flexibility, but also introduce a
large number of functional groups at the periphery. The combi-
nation of these features creates an environment within the dendri-
mer molecule, which facilitates new discoveries in many important
research areas, such as materials and biomedical sciences.1
However, most dendrimeric polymers known today are con-
structed from symmetrical dendron building blocks and possess
only one kind of functional group (usually either an amine or a
hydroxy),2 which limits the choices for ‘surface’ engineering. To
increase the options for surface chemical derivatization and
branching abilities, we decided to develop a short synthesis of
novel heteroatom dendron building blocks ‘around’ a benzoic acid
core. Coupling sites other than a typical hydroxy group can provide
dendrons with extended tunable physico-chemical properties.
We previously reported the synthesis of two types of bi-func-
tional dendron building blocks (BB) from phenolic templates via
double Mitsunobu reactions for convergent dendrimer growth on
a solid support.3 Therein, we concentrated on the 3,5-dihydroxy-
benzoic acid core and various orthogonal protection strategies of
peripheral amines. We found no evidence in the literature of any
direct Mitsunobu coupling to an amine, most probably due to its
insufficient acidity,4 although, Iranpoor et al. had reported facile
N-alkylation of aromatic amines with 1° and 2° alcohols using tri-
phenylphosphine (PPh3) and 2,3-dichloro-5,6-dicyanobenzoqui-
none (DDQ).5
The accepted strategy for derivatization of basic amines through
the Mitsunobu reaction employs a three-step approach, involving
N-nosyl protection, subsequent Mitsunobu coupling, and final
deprotection, yielding N-alkyl amines.6 The N-nosyl protection is
necessary to form a sulfonamide acidic proton that enables the
coupling. Therefore, developing a one-step direct heteroatom Mits-
unobu reaction can provide a useful method for the synthesis of
multi-substituted benzoic acid building blocks for the construction
of unusual dendritic structures. Our key hypothesis is based on the
amine protons on the aminobenzoic acid core being sufficiently
acidic to enable Mitsunobu coupling, due to the presence of an
electron-withdrawing (EW) ester group on the benzene ring. Solid
phase synthesis was chosen as our synthetic method, being advan-
tageous over solution chemistry, mostly by allowing the use of
large excess of reagents and avoiding problems associated with
purification.
Herein, we report a novel double heteroatom Mitsunobu cou-
pling on solid phase to prepare diverse dendron building blocks
containing an aminohydroxybenzoic acid core. Mitsunobu cou-
pling in the presence of unprotected peripheral secondary amines
is also discussed.
⇑
Corresponding author. Tel.: +972 3 9371442; fax: +972 3 9066634 (G.G.).
E-mail address: garyg@ariel.ac.il (G. Gellerman).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.105

T. Shalit et al. / Tetrahedron Letters 51 (2010) 5988–5991
5989
H
N
amino- and hydroxybenzoic acids 6a–d (Scheme 3). These benzoic
acids were loaded on Cl-Trt resin as usual (NMM, DMF). Subse-
quently, in the same manner as for 7, preloaded 8a–d were submit-
ted to heteroatom couplings with functionalized alcohols, yielding
a collection of double armed dendron BBs 3a–d, 4 and 5.8 These
BBs vary in the nature of the alkylated atom (oxygen or amine),
arm position on the benzene ring, arm length, peripheral func-
tional groups, protection, and chirality.
NH2
NHAlloc
HO
NHAlloc
PPh3, DBAD,
CH2Cl2, rt
MeO2C
MeO2C
1 (38%)
Alloc = CO2CH2CHCH2
Scheme 1. Mono-Mitsunobu solution phase synthesis of methyl 4-aminobenzoate
1.
In particular, the reaction of 8a–d with AllocNH(CH2)3OH affor-
ded, after cleavage (3% TFA in CH2Cl2) and RP-18 solid phase
extraction, the corresponding acids 3a–d in 75–98% yield from
Initially, we reacted Alloc-protected 3-aminopropanol with
methyl 4-aminobenzoate (Scheme 1) in solution, to examine
whether the corresponding aromatic amine can undergo Mitsun-
obu reaction. The Mitsunobu product 1 was indeed obtained after
flash chromatography purification (SiO2 gel, chloroform) but in
poor yield.
6a–d. Similarly, 8b was reacted with commercial Boc-(L)-alaninol
to yield 4 in 80% yield. Chiral 4 is of particular interest, demonstrat-
ing the extended chiral diversification abilities of diamino and
hydroxybenzoic acids from easily accessible protected amino
alcohols.
We also applied this method for synthesis of 5 via reaction of 8b
with 1-phenylpropan-1-ol. In this case, product 5 was obtained,
after cleavage and RP-18 pack solid phase extraction, in satisfac-
tory overall yield (58%), despite the possible steric hindrance.
We also examined the tolerance of the Mitsunobu coupling
reaction of preloaded 3,5-dihydroxybenzoic acid (6e) toward
unprotected aliphatic primary and secondary amines, located on
the alcohol synthons (Scheme 4). Such tolerance would simplify
the synthetic process, avoiding additional linker protection and
subsequent deprotection steps. Unfortunately, all our attempts to
obtain 10 with primary amines at the periphery under standard
Mitsunobu reaction conditions failed. On the other hand, unpro-
tected secondary amines were compatible with these conditions.
Compound 6e underwent smooth double coupling with N-methyl-
aminoethanol and with allyl 3-(3-hydroxypropylamino)propylcar-
bamate,3 to afford, after standard cleavage procedure, unprotected
9a and partially unprotected 9b dendrons in satisfactory yields
(72% for 9a and 53% for 9b from 6e).
In summary, the fast solid phase heteroatom Mitsunobu reac-
tion described in this Letter yields pure and diverse doublyarmed
benzoic acid dendron building blocks for the generation of more
complex dendritic architectures by solid phase organic chemistry
(SPOC). These building blocks are characterized by well-controlled
protection groups, arm length, chirality, and peripheral functional
groups. The successful Mitsunobu coupling in the presence of
unprotected peripheral secondary amines is also important for
Encouraged by this result, we investigated the mono-Mitsun-
obu reaction of preloaded 4-aminobenzoic acid on acid-sensitive
Cl-Trt resin (Scheme 2). Successful reaction would pave the way
to more complex double heteroatom coupling. Thus, after loading
4-aminobenzoic acid on the Cl-Trt resin (0.64 mmol/g) in anhy-
drous DMF/NMM (N-methylmorpholine) followed by capping with
methanol, the resulting amine 7 was reacted successfully with rep-
resentative hydroxy linkers bearing different functional groups un-
der standard Mitsunobu conditions [linker (3 equiv), dibenzyl
azodicarboxylate (DBAD) (3 equiv), Ph3P (3 equiv) in CH2Cl2 at
room temperature].7 After cleavage (3% TFA in CH2Cl2) and rapid
purification by solid phase extraction pack (RP-18, first washed
with water and then extracted with acetonitrile) products 2a–e
were obtained in good yields. Apparently, classical amine-protect-
ing groups, such as Alloc (2a and 2d) and Boc (2c), as well as the
thioether functional group (2b), tolerated the reaction conditions
well, yielding the corresponding alkylated aminobenzoic acids in
84–93% yields. Compounds 2c and 2d, which bear alaninol and
phenylalaninol optically active moieties, respectively, allow chiral
peripheral engineering in dendrimers. Compound 2e, the result
of coupling with 1-phenylpropan-1-ol was also obtained in reason-
able yield (78%), demonstrating the ability of aminobenzoic esters
to undergo Mitsunobu coupling with secondary alcohols.
In the next step, we explored the double heteroatom Mitsunobu
reaction with a variety of commercially available disubstituted
NH
HOOC
S
NHAlloc
2b (93%)
S
a
HO
HN
NH2
HO2C
O
O
HO
NHAlloc
1.
NH2
a
Cl
NMM, DMF
a
7
(L)
CO2H
2a (92%)
R
Chlorotrityl resin
=
HO
OH
a
HN
PG
(L)
R
HN
HN
HN
PG
CO2H
CO2H
2c R = Me, PG = Boc (90%)
2d R = Bn, PG = Alloc (84%)
2e (78%)
Scheme 2. Mono-Mitsunobu solid phase synthesis of 4-aminobenzoic acids 2a–e. Reagents and condition: a (1) PPh3, DBAD, CH2Cl2, rt; (2) 3% TFA/CH2Cl2.

5990
T. Shalit et al. / Tetrahedron Letters 51 (2010) 5988–5991
O
5 (58% from 8b)
HO2C
NH
R
HN
R
NH
OH
HO2C
a
O
HO2C
R
HN
R
Trt-Cl resin,
NMM, DMF
3b (88%)
3a (93%)
X
X
HO
NHAlloc
a
O
O
HO2C
Y
Y
R
R
O
8a-d
HN
6a 3,5-diamino-
H
HO2C
6b 3-amino-4-hydroxy-
6c 2-amino-5-hydroxy-
6d 4-amino-2-hydroxy-
(L)
N
HO2C
a
NHBoc
HO
R
O
R
3c (86%)
3d (75%)
NHBoc
NHBoc
(L)
O
R = (CH2)3NHAlloc
NH
HO2C
(L)
4 (80% from 8b)
Scheme 3. Double-Mitsunobu solid phase synthesis of amino- and hydroxy benzoic acids 3–5. Reagents and condition: a (1) PPh3, DBAD, CH2Cl2, rt; (2) 3% TFA/CH2Cl2.
R
O
OH
HO R
a
O
O
R
O
HO2C
OH
6e
H
N
(72%)
(53%)
9a R =
9b R =
a
HO
NH2
N
H
NHAlloc
O
NH2
NH2
HO2C
O
10
Scheme 4. Double-Mitsunobu solid phase synthesis of 9a,b using unprotected 2° amine hydroxy linkers. Reagents and condition: a (1) PPh3, DBAD, CH2Cl2, rt; (2) 3% TFA/
CH2Cl2.
Ed. Engl. 1990, 102, 130–141; (c) Al-Jamal, K. T.; Ramaswamy, C.; Florence, A. T.
Adv. Drug Deliv. Rev. 2005, 57, 2238–2270; (d) Kumara Swamy, K. C.; Bhuvan
Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551–
simplifying the synthesis of polyamine dendrimers. Attempts to
optimize the reaction conditions, including microwave-assisted
chemistry, as well as implementation of our dendron building
blocks in convergent dendrimer evolution on a solid support are
in progress.
2651; (e) Yuen Sze But, T.; Toy, P. H. Chem. Asian J. 2007, 2, 1340–1355.
2. (a) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.;
Ryder, J.; Smith, P. Polym. J. 1985, 17, 117–132; (b) Tomalia, D. A.; Baker, H.;
Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.; Smith, P.
Macromolecules 1986, 19, 2466–2468; (c) Tomalia, D. A.; Hall, M.; Hedstrand, D.
J. Am. Chem. Soc. 1987, 109, 1601–1603; (d) Tomalia, D. A.; Berry, V.; Hall, M.;
Hedstrand, D. M. Macromolecules 1987, 20, 1164–1167.
Acknowledgment
3. Gellerman, G.; Shitrit, S.; Shalit, T.; Ganot, O.; Albeck, A. Tetrahedron 2010, 66,
878–886.
4. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Hughes, D. L. Org. React. 1992, 42,
335–656; (c) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639–
1642.
We thank Dr. Hugo Gotlib from Bar Ilan University for analytical
assistance and helpful advice.
5. Iranpoor, N.; Firouzabadi, H.; Khalili, H. Tetrahedron 2009, 65, 3893–3899.
6. Barnett, C. J.; Grubb, L. M. Tetrahedron 2000, 56, 9221–9225.
7. General procedure for the synthesis of mono-Mitsunobu products 2a–e: To 2-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.105.
chlorotrityl resin (0.2 g, 0.28 mmol loading) was added
aminobenzoic acid (0.034 g, 0.26 mmol) in dry DMF (3.5 mL) and NMM
(140 l, 1.04 mmol). The reaction mixture was shaken for 1.5 h. After
a solution of 4-
l
completion of the loading, dry MeOH (1.5 mL) was poured into the reactor
and shaking was continued for an additional 20 min. The solvent was removed
by filtration and the following washings sequentially performed: 2 Â CH2Cl2/
MeOH/DIEA (17:2:1), 2 Â CH2Cl2, 2 Â DMF, 2 Â CH2Cl2, 2 Â CH2Cl2/DMF (1:1).
To the resin-loaded 7 was added, under N2 atmosphere, the hydroxy linker
References and notes
1. (a) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A., III Angew. Chem., Int. Ed. Engl.
1990, 102, 119–128; (b) D.A.; Naylor, A. M.; Goddard, W. A., III Angew. Chem., Int.

T. Shalit et al. / Tetrahedron Letters 51 (2010) 5988–5991
5991
(0.78 mmol) in dry CH2Cl2 (5.2 mL), DBAD (0.192 mL, 0.78 mmol) and PPh3
(0.198 g, 0.78 mmol). After shaking overnight, the solution was filtered and the
following washings sequentially performed: 1 Â THF, 1 Â CH2Cl2, 1 Â 10% DIEA/
DMF, 1 Â DMF, 3 Â MeOH, 3 Â DMF, 3 Â CH2Cl2. The resin was transferred to a
vial and a cooled solution of 3% TFA in CH2Cl2 (2 mL) was added. After shaking
for 30 min, the solution was collected and the resin was washed several times
with CH2Cl2. The combined organic solution was evaporated initially under an
N2 stream and then in vacuo to give 2a–e. Data for 2a: off-white oil (0.062 g,
yield 92%). HRMS: found m/z 279.131 (MH+), calcd: 279.126 for C14H19N2O4,
NMR (CDCl3, 75 MHz): d 166.9 (C), 157.1 (C), 132.8 (C), 131.5 (CH), 117.2 (CH),
116.4 (C), 65.4 (CH2), 62.2 (CH2), 37.7 (CH2), 28.9 (CH2).
8. Products 3–5 were prepared from acids 6a–d (0.26 mmol) in the same manner
as for 2,7 with 1.33 mmol of the hydroxy linkers, and DBAD and PPh3. Data for
3a: off-white oil (0.13 g, yield 93%). HRMS: found m/z 435.049 (MH+), calcd:
435.224 for
C21H31N4O6, mmax (KBr): 3350–3020 br s, 1700, 1655, 1410,
1070 cmÀ1 1H NMR (CDCl3, 300 MHz): d 6.92 (br s, 2Y), 6.43 (br s, 1Y), 5.92
.
(ddt, J = 16.7, 10.4, 5.3 Hz, 2H), 5.30 (d, J = 16.7, 2H), 5.20 (d, J = 10.7, 2H), 4.56 (d,
J = 5.3 Hz, 4H), 4.34 (t, J = 5.3 Hz, 4H), 3.32 (t, J = 5.3 Hz, 4H), 1.94 (quint,
J = 5.3 Hz, 4H). 13C NMR (CDCl3, 75 MHz): d 166.3 (C), 156.6 (C), 133.0 (C), 131.3
(CH), 129.8 (CH), 127.9 (C), 116.6 (CH), 116.0 (C), 64.7 (CH2), 62.0 (CH2), 37.3
(CH2), 29.1 (CH2).
mmax (KBr): 3310–3070 br s, 1705, 1650, 1340, 1120 cmÀ1 1H NMR (CDCl3,
;
300 MHz): d 7.94 (d, J = 7.5 Hz, 2Y), 6.76 (d, J = 7.5 Hz, 2Y), 5.93 (ddt, J = 16.7,
10.4, 5.3 Hz, 1H), 5.30 (d, J = 16.7 Hz, 1H), 5.20 (d, J = 10.7, 1H), 4.54 (d, J = 5.3 Hz,
2H), 4.32 (t, J = 5.3 Hz, 2H), 3.37 (t, J = 5.3 Hz, 2H), 1.98 (quint, J = 5.3 Hz, 2H). 13
C