Carbosilane dendrimeric carbodiimides: Site isolation as a lactamization tool

Article abstract of DOI:10.1021/jo052027c

The convergent syntheses of three generations of carbosilane dendrimeric carbodiimides are described. The wedge-type building blocks were synthesized in a divergent way, starting from allyl chloride and a repetitive sequence of hydrosilylation with HSiCl₃ and a Grignard reaction with allylmagnesium bromide. Hydrogenation of the terminal double bonds led to inert and stable wedges. The chloride substitutent at the focal point was transformed into several functional groups that eventually led to dendrimeric structures with a carbodiimide core. The extent of the site isolation effect of the dendrimers was studied with dilution experiments monitored by FT-IR spectroscopy on the corresponding dendrimeric ureas. These studies showed that only the first generation self-aggregates via hydrogen bonding, while the second and the third do not, implying isolation of core-bound moieties. The dendrimeric carbodiimides mediated lactamization reactions to obtain homodiketopiperazines.

Full text of DOI:10.1021/jo052027c

Carbosilane Dendrimeric Carbodiimides:
Site Isolation as a Lactamization Tool
†
†
‡
‡
†
Alessia Amore, Rieko van Heerbeek, Niek Zeep, Jan van Esch, Joost N. H. Reek,
†
,†
Henk Hiemstra, and Jan H. van Maarseveen*
Van ’t Hoff Institute for Molecular Sciences, UniVersity of Amsterdam, Nieuwe Achtergracht 129,
1
018 WS Amsterdam, The Netherlands, and Stratingh Institute, UniVersity of Groningen, Nijenborgh 4,
9
747 AG Groningen, The Netherlands
jVm@science.uVa.nl
ReceiVed September 27, 2005
The convergent syntheses of three generations of carbosilane dendrimeric carbodiimides are described.
The wedge-type building blocks were synthesized in a divergent way, starting from allyl chloride and a
repetitive sequence of hydrosilylation with HSiCl and a Grignard reaction with allylmagnesium bromide.
3
Hydrogenation of the terminal double bonds led to inert and stable wedges. The chloride substitutent at
the focal point was transformed into several functional groups that eventually led to dendrimeric structures
with a carbodiimide core. The extent of the site isolation effect of the dendrimers was studied with
dilution experiments monitored by FT-IR spectroscopy on the corresponding dendrimeric ureas. These
studies showed that only the first generation self-aggregates via hydrogen bonding, while the second and
the third do not, implying isolation of core-bound moieties. The dendrimeric carbodiimides mediated
lactamization reactions to obtain homodiketopiperazines.
Introduction
research fields, especially homogeneous catalysis. Properties of
dendrimers such as reactivity were, in some cases, different from
those of the nondendrimeric analogues. For example, dendritic
nickel catalysts used in the oligomerization of ethylene showed
higher activity compared with their parent complex due to
Dendrimers are well-defined macromolecules with a regular
and highly branched three-dimensional structure. These mac-
romolecules possess internal cavities that can exhibit site-
isolation effects, as the branches shield the core to create a
distinct nanoenvironment isolated from the bulk solution. This
1
3
dendritic site isolation. The ability of dendrimers to alter the
2
local environments has seen application in other research fields,
peculiar feature of dendrimers has been explored in different
including material science and biology (drug delivery).4
Surprisingly, only a few applications of dendrimers are known
*
To whom correspondence should be addressed. Phone: +31205255671.
5
in organic synthesis, none of which utilize core-functionalized
Fax: +31205255670.
6
†
‡
dendrimers. For example, Kim and co-workers reported the
University of Amsterdam.
University of Groningen.
(
1) (a) Newkome, G. R.; Moorefield, C. N.; V o¨ gtle, F. Dendrimers and
(3) Muller, C.; Ackerman, L.; Reek, J. N. H.; Kamer, P. C. J.; Leeuwen,
P. W. N. M. J. Am. Chem. Soc. 2004, 126, 14960-14963.
(4) For recent reviews, see: (a) Bosman, A. W.; Janssen, H. M.; Meijer,
E. W. Chem. ReV. 1999, 99, 1665-1688. (b) van Heerbeek, R.; Kamer, P.
C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. ReV. 2002, 102,
3717-3756. (c) Preston, A. C.; Klein Gebbink, R. J. M.; van Koten, G. J.
Organomet. Chem. 2004, 24, 4016-4054.
Wedges: Concept, Synthesis and Application; Wiley-VCH: Weinheim,
001. (b) Dendrimers and Other Dendritic Polymers; Fr e´ chet, J. M. J.,
Tomalia, D. A., Eds.; Wiley: Chichester, 2001.
2) (a) Hawker, C. J.; Wooley, L. K.; Fr e´ chet, J. M. J. J. Am. Chem.
2
(
Soc. 1993, 115, 4375-4376. (b) Hecht, S.; Fr e´ chet, J. M. J. Angew. Chem.,
Int. Ed. 2001, 40, 74-91.
1
0.1021/jo052027c CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/01/2006
J. Org. Chem. 2006, 71, 1851-1860
1851

Amore et al.
SCHEME 1. Encapsulation of the Linear Precursor Prevents Intermolecular Processes, Enabling the Intramolecular Reaction
To Occur (Third Generation Carbosilane Dendrimer Is Shown)
use of periphery functionalized PAMAM dendrimers as a
soluble support for the Fisher indole synthesis. Van Koten et
al. used the periphery of carbosilane dendrimers to synthesize
encapsulation of the activated ester generates a “pseudo-high-
dilution” environment in the dendritic structure. Therefore,
intermolecular processes (to give oligomers) are impaired, and
the reaction can take place preferentially in an intramolecular
fashion to give the desired monocyclic product.
Herein, we report the divergent synthesis of three different
generations of carbosilane wedges having a primary chloride
as focal point and the subsequent transformation into other
functional groups. These wedges were employed to construct,
in a convergent manner, dendrimers possessing a carbodiimide
core. The (dendrimeric) peptide coupling reagents were inves-
tigated to mediate the ring-closure reaction providing seven-
membered bis-lactams (homodiketopiperazines), which are
difficult to access using traditional methods.
7
a small library of â-lactams. Both groups demonstrated the value
of dendrimers as soluble supports by the synthesis of a small
8
set of compounds.
Our group is interested in the development of new strategies
toward the ring closure of medium-sized lactams. Head-to-tail
cyclization of ω-amino acids and peptides suffers from compet-
ing intermolecular reactions yielding linear and cyclic oligo-
9
mers. Synthetic strategies toward macrolactams using classical
peptide coupling reagents generally lead to poor results, unless
high dilution conditions are employed. Even then, in many cases
10
the cyclized product can only be obtained in poor yield. Many
approaches to perform head-to-tail lactamizations have been
1
1
12
14
proposed and explored, including cyclization on solid phase,
Results and Discussion
1
3
use of auxiliaries, cyclization via the Staudinger ligation,
and chemoenzymatic cyclization.15 However, we anticipated that
dendrimeric site isolation could provide a tool to perform
difficult cyclization reactions, which would be a novel applica-
tion for dendrimer, as is depicted schematically in Scheme 1.
At the core of a diimide-containing dendrimer, a linear
lactamization precursor is trapped via the C-terminus. The
Carbosilane dendrimers possess excellent characteristics for
our purposes: a straightforward synthesis, stability to a variety
of conditions, and facile functionalization both at the periphery
(to alter their physical properties) and in the core. Since the
first report in 1992, much work has been done to synthesize
carbosilane dendrimers with modified structures and properties.17
The flexibility of the route to construct these dendrimers in a
convergent way from carbosilane wedges was demonstrated for
1
6
(5) Reviews: (a) Klein Gebbink, R. J. M.; Kruithof, C. A.; van Klink,
G. P. M.; van Koten, G. Mol. Biotechnol. 2002, 90, 183-193. (b) van
Heerbeek, R.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H.
Chem. ReV. 2002, 102, 3717-3756.
(13) (a) Meutermans, W. D. F.; Golding, S. W.; Bourne, G. T.; Miranda,
L. P.; Dooley, M. J.; Alewood, P. F.; Smythe, M. L. J. Am. Chem. Soc.
1999, 121, 9790-9796. (b) Bier a¨ ugel, H.; Schoemaker, H. E.; Hiemstra,
H.; van Maarseveen, J. H. Org. Biomol. Chem. 2003, 1, 1830-1832. (c)
Meutermans, W. D. F.; Bourne, G. T.; Golding, S. W.; Horton, D. A.;
Campitelli, M. R.; Craik, D.; Scanlon, M.; Smythe, M. L. Org. Lett. 2003,
7, 2711-2714.
(14) David, O.; Meester, W.; Bier a¨ ugel, H.; Schoemaker, H. E.; Hiemstra,
H.; van Maarseveen, J. H. Angew. Chem., Int. Ed. 2003, 42, 4373-4375.
(15) (a) Bordusa, F. ChemBioChem 2001, 2, 99-107. (b) Kohli, R. M.;
Walsh, C. T.; Burkart, M. D. Nature 2002, 418, 658. (c) Sieber, S. A.;
Tao, J.; Walsh, C. T.; Marahiel, M. A. Angew. Chem., Int. Ed. 2004, 43,
493-498.
(6) Kim, R. M.; Manna, M.; Hutchins, S. M.; Griffin, P. R.; Yates, N.
A.; Bernik, A. M.; Chapman, K. T. Proc. Natl. Acad. Sci. U.S.A. 1996, 93,
0012-10017.
7) (a) Hovestad, N. J.; Jastrzebski, J. T. B. H.; van Koten, G. Polym.
1
(
Mater. Sci. Eng. 1999, 80, 53-54. (b) Hovestad, N. J.; Ford, A.; Jastrzebski,
J. T. B. H.; van Koten, G. J. Org. Chem. 2000, 65, 6338-6344.
(8) Le N oˆ tre, J.; Firet, J. J.; Sliedregt, L. A. J. M.; van Steen, B. J.; van
Koten, G.; Klein Gebbink, R. J. M. Org. Lett. 2005, 7, 363-366.
9) (a) Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 126-193. (b)
Schmidt, U.; Langner, J. J. Pept. Res. 1997, 49, 2481-2495.
10) (a) Lambert, J. N.; Mitchell, J. P.; Roberts, K. D. J. Chem. Soc.,
(
(
Perkin Trans. 1 2001, 471-484. (b) Sewald, N.; Jakubke, H.-D. Peptides:
Chemistry and Biology; Wiley-VCH: Weinheim, 2002.
(16) (a) van der Made, A. Chem. Commun. 1992, 1400-1401. (b) van
der Made, A. AdV. Mater. 1993, 5, 466-467. (c) Roovers, J.; Toporowski,
P. M.; Zhou, L. Polym. Prepr. 1992, 182-183. (d) Zhou, L.; Roovers, J.
Macromolecules 1993, 26, 963-968. (e) Muzafarov, A. M.; et al. Polym.
Sci. 1993, 35, 1575-1580.
(
11) For a recent review about cyclization methodologies, see: Davies,
J. S. J. Pept. Sci. 2003, 9, 471-501.
12) Alsina, J.; Jensen, K. J.; Albericio, F.; Barany, G. Chem.-Eur. J.
999, 5, 2787.
(
1
1852 J. Org. Chem., Vol. 71, No. 5, 2006

Site Isolation as a Lactamization Tool
SCHEME 2. General Route to the Dendrimeric
Carbodiimides
SCHEME 3. Synthesis of the Dendritic Carbosilane Wedges
1-3a
a
Reaction conditions: (a) HSiCl3, (Bu4N)2PtCl6 (10-4 mol catalyst per
mol of allyl end group), CH2Cl2/Et2O, room temperature; (b) (allyl)MgBr,
Et2O, room temperature, 5-16 h.
the first time in 1999 by van Leeuwen et al.18 They used the
divergent route consisting of sequential hydrosilylation and
Grignard alkenylation to obtain carbosilane wedges up to the
third generation possessing 3-bromopropyl at the focal point.
The same synthetic strategy was employed to synthesize
carbosilane wedges with an aryl bromide as the focal point
lyst) gave clean product formation,23 while other platinum
catalysts used in previous work gave substantial amounts of
24
side products (such as the branched adduct). After an induction
period of 30 min to 6 h, the reaction became exothermic, which
was crucial for a successful outcome of the reaction. Reaction
1
9
group.
With the aim of constructing dendrimers possessing a diimide
moiety as the core, we focused on a synthesis starting from
carbosilane wedges with the appropriate electrophilic and
nucleophilic focal points. By connecting the single wedges via
the mutually reactive focal point functional groups to a
multivalent centerpiece, core-functionalized dendrimers are
obtained in a convergent way.20,21 This approach to synthesize
dendrimers presents two noteworthy advantages: (i) access to
a variety of core moieties and (ii) synthesis of dendrimers
possessing a reactive core moiety (e.g., carbodiimide). The
dendrimeric diimides have been prepared using two different
strategies (Scheme 2). For both strategies, the key starting
materials are carbosilane dendrimeric wedges with an azide as
the focal point, allowing facile further transformation into an
amine and isocyanate. Reaction of the amine and isocyanate
wedges provides dendrimers with a urea in the core that
subsequently can be dehydrated to give the final dendrimeric
diimides (route A, Scheme 2). As an alternative, dendrimeric
diimides were prepared in one step from the azide wedges by
a Staudinger reaction with isocyanide-functionalized wedges
1
progress was assessed by H NMR, and after typically 16 h
disappearance of the allylic signals indicated complete conver-
sion for the first generation, while longer reaction times were
necessary for the higher generations (e.g., 5 days for multigram
1
scale synthesis of the third generation). From H NMR analysis,
traces of a side product resulting from dechlorination during
the hydrosilylation step were observed for all generations. For
the first generation, the side product (n-propyltrichlorosilane)
could be removed via distillation, however, only at the expense
of product yield, unfortunately. Allylmagnesium bromide was
used to substitute the chloride atoms of the trichlorosilane end
groups for allylic groups. The reaction mixture was stirred for
5
-24 h, depending on the generation. Higher generation
dendritic wedges were synthesized, in a multigram scale, by
repeating the hydrosilylation and Grignard alkylation steps.
Wedges 2 and 3 were obtained in high yields (90 and 83%,
respectively) after purification by flash column chromatography.
The structure of the third generation wedge Cl[G3](allyl)27
3
was confirmed by MALDI-TOF mass spectrometry. The
dominant peak (2121.92 m/z) results from the addition of silver
ions (silver nitrate was used for the ionization of the molecules)
and the loss of one allyl end group of the formed wedge 3.
While allylic end groups present at the periphery of the
(route B, Scheme 2).
Divergent Synthesis of 3-Chloropropyl Wedge Building
Blocks. The 3-chloropropyl wedges were synthesized analo-
18
gously to the 3-bromopropyl wedges. Allyl chloride was used
as the starting material for the platinum-catalyzed hydrosilylation
with trichlorosilane (Scheme 3).22 Excess of trichlorosilane was
required to drive the reaction to completion. Hydrosilylation
with tetrabutylammonium hexachloroplatinate (Lukevics’ cata-
25
wedges can be used to modify the surface of the dendrimers,
the stability of allylsilane containing dendrimers is reduced due
to their reactivity toward acids and acetone and their sensitivity
to light. We expected that the hydrogenation of the allylic groups
would provide us with inert wedges suitable for the application
described herein. Catalytic hydrogenation of Cl[G1](allyl)3 1
and Cl[G2](allyl)9 2 was achieved using a Pd(C) in a hydrogen
atmosphere. Cl[G3](allyl)27 3, having 27 terminal double bonds,
required the use of the more active PtO2 catalyst and prolonged
reaction times (Scheme 4). The saturated wedges 4-6 were all
obtained in excellent yields.
(
17) (a) Kim, C.; Park, E.; Kang, E. J. Korean Chem. Soc. 1995, 39,
7
1
1
99-805. (b) Kim, C.; Park, E.; Kang, E. Bull. Korean Chem. Soc. 1996,
7, 419-424. (c) Kim, C.; An, K. Bull. Korean Chem. Soc. 1997, 18, 164-
70. (d) Kim, C.; Sung, D.-D.; Chung, D.; Park, E.; Kang, E. J. Korean
Chem. Soc. 1995, 39, 789-798. (e) Seyferth, D.; Kugita, T.; Rheingold,
A. L.; Yap, G. P. A. Organometallics 1995, 14, 5362-5366. (f) Gossage,
R. A.; Mu n˜ oz-Mart ´ı nez, E.; Frey, H.; Burgath, A.; Lutz, M.; Spek, A. L.;
van Koten, G. Chem.-Eur. J. 1999, 1, 2191-2197.
Indeed, the saturated wedges showed no decomposition upon
storage over prolonged periods or exposure to light and moisture.
Furthermore, they showed a remarkable stability toward a variety
of reaction conditions (vide infra).
(
18) van Heerbeek, R.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen,
P. W. N. M. Tetrahedron Lett. 1999, 40, 7127-7130.
19) Oosterom, G. E.; van Haaren, R. J.; Reek, J. N. H.; Kamer, P. C.
J.; van Leeuwen, P. W. N. M. Chem. Commun. 1999, 1119-1120.
20) Gossage, R. A.; Mu n˜ oz-Mart ´ı nez, E.; Frey, H.; Burgath, A.; Lutz,
M.; Spek, A. L.; van Koten, G. Chem.-Eur. J. 1999, 5, 2191-2196.
21) Botman, P. N. M.; Amore, A.; van Heerbeek, R.; Black, J. W.;
Hiemstra, H.; Reek, J. N. H.; van Maarseveen, J. H. Tetrahedron Lett. 2004,
5, 5999-6002.
22) For an extensive study on the Pt(0)-catalyzed hydrosilylation, see:
Stein, J.; Lewis, L. N.; Gao, Y.; Scott, R. A. J. Am. Chem. Soc. 1999, 121,
693 and references therein.
(
(
(23) Iovel, I. G.; Goldberg, Y. S.; Shymanska, M. V.; Lukevics, E.
Organometallics 1987, 6, 1410-1413.
(24) de Groot, D. Ph.D. Thesis, University of Amsterdam, The Nether-
lands, 2001.
(25) (a) Lorenz, K.; M u¨ lhaupt, R.; Frey, H.; Rapp, H.; Mayer-Posner,
F. J. Macromolecules 1995, 28, 6657-6661. (b) Krska, S. W.; Seyferth,
D. J. Am. Chem. Soc. 1998, 120, 3604-3612.
(
4
(
3
J. Org. Chem, Vol. 71, No. 5, 2006 1853

Amore et al.
SCHEME 4. Synthesis of the Saturated Wedgesa
the core more accessible to the nucleophile. In addition, sodium
azide dissolves well in these mixtures, ensuring a high concen-
tration of the nucleophile. When 6 was stirred with an excess
(
°
10 equiv) of NaN3 and a stoichiometric amount of KI at 110
C using THF as the solvent for 3 days in a sealed tube, the
desired 3-azidopropyl wedge 9 was obtained in 90% yield
Scheme 5). A two-step route was also possible: substitution
(
of the chloride in wedge 6 for iodide, followed by azide
introduction. The first transformation is easily performed by
reaction of the chloride wedge 6 with an excess of NaI using a
mixture of THF/DMA (3:1) at 110 °C for 12 h. The resulting
iodo wedge I[G3](propyl)27 10 could be converted into the
desired azide N3[G3](propyl)27 9 by reaction with NaN3 in a
mixture of THF/DMA (3:1) and stirring at 110 °C for 40 h.
Both approaches resulted in an overall yield of 90%.
a
Reaction conditions: (a) H2 balloon, 10% Pd/C, EtOAc/MeOH (3:1),
1
(
6 h for 1 (81%) and 2 (93%); PtO2, EtOAc/MeOH (10:1), 48 h for 3
81%).
SCHEME 5. Focal Point Modification Starting from the
Saturated Chloro Wedgesa
1
H NMR analysis of N3[G3](propyl)27 9 indicated, by the
diagnostic signal shift of the CH2 group flanking the focal point
functional group, complete conversion of the chloride atoms
into azides and no detectable structural defects. The high purity
of 9 was also confirmed by the GPC trace.
n
The azido wedges N3[Gn](propyl)3 (n ) 1, 2, 3) 7-9 were
reduced into the corresponding amine wedges NH2[Gn]-
n
(
propyl)3 (n ) 1, 2, 3) 11-13 by Pd(C)-catalyzed hydrogena-
tion at atmospheric pressure in a mixture of EtOAc/MeOH (10:
) for 16 h. Purification was performed by simple filtration over
Celite, yielding the amine wedges 11-13 in good yields (55-
1%) (Scheme 5). In the case of the third generation wedge
a
Reagents and conditions: (a) NaN3 (10 equiv), THF, 90 °C, 6 h, for 4;
1
THF/DMF (3:1), 90 °C, 16 h for 5; THF/DMA (3:1), 115 °C, 3 days, for
; quantitative; (b) Only for 6: NaI (10 equiv) THF/DMA (3:1), 110 °C,
6 h, 95%; (c) NaN3 (10 equiv), THF/DMA (3:1), 110 °C, 16 h, 95%. (d)
6
1
7
For 7-9: H2 balloon, 10% Pd(C), EtOAc/MeOH (10:1), 56-71%. For 9:
a) PPh3 (1 equiv), THF, 70 °C, 16 h; (b) H2O, 60 °C, 2 h, 95%; (e)
phosgene/toluene (1.57 M, 2 equiv), toluene/ NaHCO3 (aq), 0 °C, 2 h, 85-
7%.
N3[G3](allyl)27 9, the catalytic reduction required very long
reaction times and a higher catalyst loading.
(
Alternatively, reduction of N3[G3](allyl)27 9 could be achieved
by treatment with triphenylphoshine in THF at 70 °C for 16 h.
Subsequent hydrolysis of the intermediate iminophosphorane
by adding water provided NH2[G3](allyl)27 wedge 13 in 95%
9
Focal Point Modification. Wedges with a 3-aminopropyl
focal point group and allylic end groups have been previously
synthesized by van Leeuwen and co-workers.18 In their ap-
proach, the amino wedges were obtained by reaction of the
2
7,28
yield.
The reaction was monitored using IR spectrometry
to observe the disappearance of the strong azide absorption at
-
1
2
096 cm . Taking advantage of the lipophilic character of the
3
-bromopropyl-functionalized wedges with a large excess of
wedges, we accomplished purification of the amino wedge 13
by precipitation of triphenylphosphine oxide with hexanes or
washing of the wedge with MeOH.
liquid ammonia at 70 °C under 15 bar of pressure in an
autoclave. The formation of unwanted secondary amine-
functionalized wedges could be avoided by using low concen-
trations. However, under these conditions it was hard to obtain
large quantities of the wedges, making this approach not suitable
for our purposes. As an alternative, a stepwise procedure by
conversion of the bromine into a masked amino moiety such
as an azide and subsequent transformation to the amine should
enable the formation of large quantitites.
The 3-chloropropyl focal points of the saturated wedges 4
and 5 were converted into the desired azido wedges 7 and 8 in
almost quantitative yields by reaction with an excess of sodium
azide in DMF at 90 °C for 3-7 h (Scheme 5).
The amino group at the focal point of the wedges was
converted into the corresponding isocyanate (Scheme 5) by
reacting 11-13 with an excess of phosgene in a mixture of
toluene and water for 2 h using NaHCO3 as a base. The desired
n
products OCN[Gn](propyl)3 (n ) 1, 2, 3) 14-16 were obtained
in near quantitative yield, and no purification was necessary.
The reaction was monitored by TLC for the first generation
wedges, but for the higher generations, IR spectroscopy (ap-
pearance of the typical absorption band of isocyanate at 2266
-1
1
cm ) and H NMR in particular (variation of the protons
adjacent to the focal point) provided more information.
Unfortunately, employing the same conditions for 6 failed
to provide any product, and only starting material was recovered.
Increasing either temperature or reaction time led to the product,
albeit in poor yields (a mixture of products and starting material
was usually observed). Since the poor solubility of the third
generation wedges in DMF likely slowed the reaction, the use
of different solvent mixtures was explored. Mixtures of THF/
DMF or THF/DMA (DMA ) N,N-dimethylacetamide) in a ratio
of 3:1 were the most suitable solvent combinations. These
solvent systems probably induce a more open structure of the
wedges, as has been observed for other dendrimers,2 making
All the wedges were characterized by 1H NMR, 13C NMR,
and IR spectroscopy. FAB and MALDI-TOF analysis was only
possible for the amine wedges that were ionizable under mild
conditions.
Synthesis of Urea Core-Functionalized Carbosilane Den-
drimers. The dendrimeric carbodiimides were obtained con-
vergently from the wedges described above possessing a variety
of focal points. The most common method to prepare diimides
29
is via dehydration of ureas. The urea wedges 17-19 were
obtained in good yields (60-93%) by reacting the amino-
6
(
27) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635-646.
(28) Vaultier, M.; Knouzi, N.; Carrie, R. Tetrahedron Lett. 1983, 8, 763-
764.
(26) De Backer, S.; Prinzie, Y.; Verheijen, W.; Smet, M.; Desmedt, K.;
Dehaen, W.; De Schryver, F. C. J. Phys. Chem. A 1998, 102, 5451-5155.
1854 J. Org. Chem., Vol. 71, No. 5, 2006

Site Isolation as a Lactamization Tool
SCHEME 6. Dendrimeric Urea Synthesis
functionalized wedges 11-13 with an equimolar amount of the
corresponding isocyanate 14-16 in refluxing THF (Scheme 6).
Simple filtration over a short silica pad furnished the pure
compounds. The third generation urea 19 could also be purified
using size exclusion chromatography. The integrity of 19 was
mM solution, two N-H and two amide I bands are observed at
-
1
3433 and 1690 cm corresponding to non-hydrogen-bonded
-
1
-1
urea moieties and signals at 3370 cm (broad) and 1628 cm
corresponding to hydrogen-bonded urea moieties. Increasing the
concentration to 120 mM solution gives two main bands at 3370
1
13
-1
-1
confirmed by H-, C NMR, and MALDI-TOF analysis.
The first generation dendrimeric urea 17 is a solid (mp 66
cm (N-H) and at 1628 cm (amide I), indicating that at
high concentrations the first generation dendrimer 17 self-
associates (Figure 2, only N-H shown).
3
2
°
C) and dissolves in most organic solvents (toluene, CHCl3,
EtOAc, MeOH, etc.). The second generation dendrimeric urea
8 is an oil showing poor solubility in polar solvents such as
The FT-IR experiments for the second generation urea 18
were conducted at concentrations of 24, 60, and 90 mM (see
Supporting Information). At these concentrations, only two
stretching vibrations were observed, which are associated with
1
MeOH. The third generation urea 19 is a viscous oil that phase
separates in polar solvents (e.g., MeOH).
Dendrimeric Ureas: Aggregation Properties. We envi-
sioned that the self-aggregation properties of a series of urea-
functionalized dendrimers could provide information on the
extent of the site-isolation effect, a relevant property for core-
functionalized dendrimers. It is well-known that urea groups
can form strong bifurcated hydrogen bonds to form linear chains
as shown in Figure 1.30 The strength (and the mode) of
association of the aggregates is influenced by the electronic and
steric properties of the substituents (R).
-1
-1
the free N-H (3437 cm ) and CdO (1690 cm ) groups, and
they indicate that the urea moieties have a trans-trans confor-
mation. Thus, already in the second generation urea 18, the
wedges shield the core and inhibit the formation intermolecular
hydrogen bonds.
The different aggregation properties of the first and second
generation dendrimeric urea compounds 17 and 18 were
1
confirmed by measuring their H NMR spectra at different
concentrations. It is known that upon aggregate formation the
chemical shift of the NH varies with the concentration. In the
The hydrogen-bonding interactions of the three generations
of dendrimeric urea were studied with FT-IR spectroscopy using
toluene-d8 as the solvent. FT-IR spectra of a solution of the
first generation urea dendrimer 17 at low concentration (12 mM)
1
H NMR of 17 at low concentrations (i.e., solutions under 11
mM), the chemical shift of the NH does not change significantly
(
NH is at 3.75 ppm), but an increase in the concentration resulted
in a clear upfield shift. This indicates that at low concentration
7 is mainly present as a monomer, whereas at higher
-
1
showed two absorptions for the urea moiety: one at 3439 cm
(
N-H) and another at 1691 cm- (amide I). The same
1
31
1
absorption bands were found when the concentration was
increased to 22 mM. These bands are characteristic for non-
hydrogen-bonded urea groups with a trans-trans conformation,
pointing to self-aggregation as depicted in Figure 1. For a 60
33
concentrations the equilibrium is shifted in favor of aggregates.
The H NMR spectrum of the second generation urea 18 shows
1
little sensitivity to changes in concentration (see Supporting
Information). The very small variation in chemical shift at
different concentrations results from the steric bulk in the
dendrimeric branches, which probably allows the formation of
dimers, but not of higher oligomers.
As expected, the third generation urea 19 did not show any
hydrogen bonding. At 50 and 100 mM, only non-hydrogen-
bonded species were present, as indicated by the weak stretching
FIGURE 1. Association pattern of N,N′-disubstituted ureas.
-
1
-1
vibrations at 3439 cm for N-H and 1690 cm for CdO
1
(
Figure 3, only N-H shown). In addition, H NMR analysis at
various concentrations of 19 in toluene-d8 showed no change
in the chemical shifts of the NH-CH2 protons.
The absence of any concentration dependence in the IR and
H NMR spectra of 19 indicates the lack of hydrogen-bonding
1
interactions and therefore of core-core interactions. These
results suggest that shielding of the core unit occurs also for
the dendrimeric carbodiimides. In accordance with the hydrogen-
(
29) Review: Mikolajczyk, M.; Kielbasinski, P. Tetrahedron 1981, 37,
2
33-284.
(
30) (a) Mohmeyer, N.; Schmidt, H-W. Chem.-Eur. J. 2005, 11, 863-
8
3
73. (b) Lortie, F.; Boileau, S.; Boutellier, L. Chem.-Eur. J. 2003, 9, 3008-
014.
(
31) Dobrowolski, J. Cz.; Jamroz, M. H.; Mazurek, A. P. Vib. Spectrosc.
994, 8, 53-60.
32) (a) Hanasuba, K.; Yamada, M.; Kimura, M.; Shirai, H. Angew.
1
(
Chem., Int. Ed. Engl. 1996, 35, 1949-1951. (b) Schoonbeck, F. S.; de Loos,
M.; Kooijman, H.; Kellogg, R. M.; Feringa, B. L. Chem.-Eur. J. 1999, 5,
9
37-950.
FIGURE 2. Normalized FT-IR spectra of the first generation urea 17
(33) Haushalter, K. A.; Lau, J.; Roberts, J. D. J. Am. Chem. Soc. 1996,
at different concentrations.
118, 8891-8896.
J. Org. Chem, Vol. 71, No. 5, 2006 1855

Amore et al.
SCHEME 7. Synthesis of the First and Second Generation
Dendrimeric Carbodiimidesa
a
Reagents and conditions: PPh3 (1.1 equiv), Br2 (1.1 equiv), Et3N (2.5
equiv), CH2Cl2, from 0 °C to room temperature, 16 h; DCG1 63% and
DCG2 74%.
These carbodiimides proved to be stable under basic conditions,
allowing purification via filtration over a short basic alumina
pad to give the pure products DCG1 and DCG2.
Surprisingly, application of the same conditions to the
1
dehydration of 19 gave, according to H NMR of the reaction
mixture, some DCG3, despite longer reaction times. Although
urea and carbodiimide functionalities typically have considerably
different properties, this large difference in physical properties
was not observed for urea 19 and carbodiimide DCG3. In this
case, the carbosilane dendritic bulk determines the physical
properties (e.g., polarity). As a result, purification of DCG3 by
column chromatography was troublesome. Moreover, the similar
molecular weights of urea 19 and carbodiimide DCG3 preclude
the use of size exclusion chromatography as a means of
purification. As a result, the separation of the third generation
dendrimeric carbodimiide DCG3 and its urea 19 congener was
only partially successful, making this route unappealing. We
therefore turned to the Staudinger reaction, which has been
reported to be useful in the synthesis of carbodiimides.34 The
highly nucleophilic iminophosphorane species (R-N3 + PPh3
f R-NdPPh3 + N2) can be “trapped” by isocyanates to yield
a carbodiimide and triphenylphosphine oxide. We anticipated
that use of the third generation azidopropyl wedge could be
the key intermediate in our synthetic strategy.
N3[G3](propyl)27 9 was reacted at 65 °C in THF with 1 equiv
of triphenylphosphine for 6 h to ensure quantitative formation
of the iminophosphorane. Gratifyingly, subsequent addition of
an equimolar amount of OCN[G3](propyl)27 16 followed by
refluxing in THF for 16 h afforded the desired dendrimeric
carbodiimide DCG3 in a yield of 72% (Scheme 8).
Clearly, the advantage of this route is that no urea is involved.
The byproducts, unreacted wedges and triphenylphosphine
oxide, can be separated easily from the product DCG3 by size
exclusion chromatography or column chromatography on basic
alumina. Further, this convergent approach to obtain DCG3 also
opens up the possibility for a straightforward synthesis of
asymmetric dendrimeric carbodiimides.
FIGURE 3. Normalized FT-IR spectra of the third generation urea
9 at different concentrations.
1
TABLE 1. Dehydrating Reagents Evaluated on 17a
dehydrating agent
base
carbodiimide
COCl2
Cl3CCOCCl3
SOCl2
TosCl
PPh3Br2
DBU or NH3
pyridine or DiPEA
Et3N
K2CO3 or pyridine
Et3N
none
none
none
low
yes
a
DiPEA ) N,N-diisopropylethylamine.
bonding studies performed on the dendrimeric ureas, the CPK
models (Figure 4) of the three generation dendrimeric carbo-
diimides DCG1, DCG2, and DCG3 also show that core
encapsulation becomes more efficient as generations increase.
Synthesis of Diimide Core-Functionalized Carbosilane
Dendrimers. To achieve dehydration of the urea to furnish a
carbodiimide, the first generation urea 17 was subjected to
various conditions (i.e., dehydrating reagents in combination
with different bases).29 Reaction of 17 with phosgene, trispho-
sgene, thionyl chloride, or tosyl chloride either failed to furnish
the desired product or provided only trace amounts. Gratifyingly,
triphenylphosphine dibromide proved to be an efficient dehy-
drating agent (Table 1).
Reaction of the dendrimeric ureas 17 and 18 with a stoichio-
metric amount of triphenylphosphine dibromide (prepared in
situ) in the presence of triethylamine as the base gave the desired
carbodiimides DCG1 and DCG2 in good yields (Scheme 7).
FIGURE 4.
1856 J. Org. Chem., Vol. 71, No. 5, 2006

Site Isolation as a Lactamization Tool
SCHEME 8. Two-Step One-Pot Convergent Synthesis of
Dendrimeric Carbodiimide DCG3a
FIGURE 5. Dipeptides utilized as cyclization precursors.
1
Because H NMR or HPLC proved inapplicable to monitor
the reactions for all generations, the yield of the desired
monocyclic product was determined after purification by column
chromatography. In addition to the desired cyclo[-âAla-(NBn)-
Phe-] 22, a side product was formed during cyclization mediated
by DCG1, insoluble in solvents such as CHCl3 and MeOH and
most likely emerging from oligomerization. In the crude reaction
mixture of the DCG2-mediated cyclization, the cyclic dimer
(616 m/e, LC-MS) was observed. Interestingly, reaction with
the first generation dendrimer generated a higher yield than
DCC. This result is an accordance with literature precendent
describing that a good solubility of the ureas formed may
3
7,38
improve the coupling yield.
The second generation showed
a yield comparable to the first generation, while the yield of
the DCG3-mediated reaction was slightly lower (20%) than that
of DCG2. Neither changing the solvent (CH2Cl2, mixture of
DMF/THF) nor heating the reaction mixture improved the
results. In apolar solvents such as hexanes, only starting material
a
Reagents and conditions: (a) PPh3 (1 equiv), THF, 65 °C, 6 h; (b)
OCN[G3](propyl)27 16 (1 equiv), reflux, 16 h, 72%.
Lactamization Reactions. The dendrimeric analogue of the
classical carbodiimides (e.g., dicyclohexylcarbodiimide) was
explored in the ring closure of homodiketopiperazines (seven-
membered cyclodipeptides). These compounds can be obtained
via lactamization of their linear dipeptide precursors, but this
is known to be very difficult using traditional solution carboxylic
acid activating agents. Dipeptides H-âAla-(NBn)Phe-OH 20 and
H-Phe-(NBn)âAla-OH 21, consisting of an R- and a â- amino
acid35 and possessing a tertiary amide bond in the backbone,
were used in our lactamization studies (Figure 5). Substitution
at the amide promotes the population of the cisoid amide bond
conformation and thus facilitates ring closure. Dipeptides 20
and 21 were chosen to study the influence of steric congestions
at the C- or N-terminus, respectively, on the cyclization
efficiency.
As a control experiment, the head-to-tail ring closure of the
N-substituted dipeptide 20 was also performed using the
common dicyclohexylcarbodiimide (DCC) peptide coupling
reagent. Compound 20 was reacted with DCC in 0.01 M THF
in the presence of 1 equiv of DiPEA (to liberate the trifluoro-
acetic acid salt). Under these conditions, the cyclized product
was obtained in a maximum of 12% yield. Next, the linear
precursor 20 was reacted under the same conditions employing
DCG1, DCG2, and DCG3 as dendrimeric carbodiimides (Table
(DCG3) was recovered. We attribute the low yield obtained
with the highest generation dendrimeric diimide DCG3 to steric
hindrance of the C-terminus of 20 hampering the activation step
leading to the intermediate O-acylurea species. As a result of
this steric interference, the concentration of the O-acylurea is
low compared to that of free dipeptide, leading to side product
formation via unwanted intermolecular pathways.
36
Consequently, the less hindered dipeptide 21 with respect to
the C-terminus should give rise to a faster activation and thus
higher cyclization yield. Initially, a blank experiment was
conducted by reacting 21 with DCC using the standard
cyclization conditions (THF, 0.01 M). The cyclized product 23
was obtained in 30% yield (vs 12% obtained with 20),
suggesting that a substrate with a less hindered C-terminus
indeed results in fewer side reactions (oligomer formation).
Dipeptide 21 was then subjected to cyclization mediated by the
DCG1, DCG2, and DCG3 dendrimeric carbodiimides (see
3
9
Table 2). Ring closure of 21 mediated by DCG1 afforded the
desired cyclo[-Phe-(NBn)âAla-] 23 in yields almost twice as
high as that found for the dipeptide 20. Again, LC-MS analysis
of the crude reaction mixtures of all dendrimer generations
indicated the presence of linear (635 m/e) and ring-closed (617
m/e) dimers. However, a small but significant positive trend
toward the formation of lactam 23 was observed going from
DCC to DCG3. In fact, once the O-acylurea species is formed,
the dendritic wedges can, especially for DCG3, hamper the side
reactions.
2
).
(
34) (a) Katritzky, A. R.; Jiang, J.; Urogdi, L. Synthesis 1990, 565-
5
3
67. (b) Ding, M.-W.; Tu, H.-Y.; Liu, Z.-J. Synth. Commun. 1997, 27,
657-3662. (c) Heras, M.; Ventura, M.; Linden, A.; Villalgordo, J. M.
Tetrahedron 2001, 57, 4371-4388.
A further advantage of employing dendrimeric carbodiimides
is the ease of product purification. Whereas using DCC as the
coupling reagent leads to a very tedious separation of the urea
(
35) Synthesized according to: Bier a¨ ugel, H.; Schoemaker, H. E.;
Hiemstra, H.; van Maarseveen, J. H. Org. Biomol. Chem. 2003, 1, 1830-
832.
36) Initially, it was our intention to cyclize unfunctionalized ω-amino
1
(
acids, leading to 7-, 9-, 11-, and 13-membered lactams. These linear
precursors can be excellent substrates since they present no conformational
bias, and therefore the dendrimeric effect could be maximized. Unfortu-
nately, they could not be used since they are not soluble in any of the
solvents screened (THF, CH2Cl2, CHCl3, MeOH) due to their dominating
zwitterionic nature.
(37) Izdebski, J.; Kunce, D. J. Pept. Sci. 1997, 3, 141-144.
(38) Tartar, A.; Gesquiere, J. C. J. Org. Chem. 1979, 44, 5000-5001.
(39) It was noticed that the cyclization experiments required the addition
of DiPEA prior to the addition of the carbodiimide to obtain reproducible
results.
J. Org. Chem, Vol. 71, No. 5, 2006 1857

Amore et al.
TABLE 2. Yields of the Lactamization Reactionsa
a
Reaction conditions: DiPEA (1 equiv), THF (0.01 M), rt, 16 h. Isolated yields after column chromatography. b Recovered via column chromatography.
byproduct from the product, with dendrimeric carbodiimides
such a process proved much easier and the dendrimers were
recovered quantitatively (Table 2). In fact, the lipophilic
properties of the ureas 18 and 19 permit facile separation of
the dendrimers from the bulk solution by stirring with MeOH,
which dissolves the peptide-based compounds but not the
dendrimeric products. Additionally, the urea byproducts derived
from DCG1 and DCG2 can be converted to the active
carbodiimide easily and can therefore be reused.
from sodium with benzophenone as indicator. Dry DMF and CH
2
-
Cl were distilled from CaH . Triethylamine was dried and distilled
2
2
from KOH pellets. All commercially available reagents were used
as received, unless indicated otherwise.
CAUTION: Hydrosilylation reactions are highly exothermic, and
good care should be taken. As a precaution, a dry ice/acetone bath
should be kept at hand when adding the trichlorosilane.
First Generation Carbosilane Wedges Cl[G1](allyl)
3
(1).40
Freshly distilled allyl chloride (60 mL, 0.74 mol) was divided into
two portions and transferred in two dry Schlenk vessels under a
nitrogen atmosphere; to each of them the cosolvents CH
mL for 1 g of allyl chloride) and Et O (1.0 mL for 1 g of allyl
chloride) were added. A freshly prepared solution of [Bu N] -
2 2
Cl (1.5
Conclusions
2
In conclusion, the divergent synthesis of carbosilane wedges
up to the third generation on a multigram scale having a versatile
primary chloride as focal point moiety and allylic end groups
was reported. Hydrogenation of the terminal allylic groups led
to saturated dendrimers that were much more stable and inert.
Efficient synthetic strategies were developed to convert the focal
point into several reactive groups, both having electrophilic and
nucleophilic properties ultimately leading to dendrimers contain-
ing a carbodiimide in the core in a convergent way. The
Staudinger reaction proved to be a highly efficient route to
obtain the third generation dendritic diimide DCG3. Such
dendritic carbodiimides are stable and highly soluble in many
organic solvents. Further, dendrimeric ureas 17-19 were
analyzed for their tendency to aggregate via hydrogen bonding.
FT-IR measurements showed that intermolecular hydrogen
bonding occurs for the first generation dendrimer, but not for
higher generations. This indicates that core-bound moieties are
isolated from the bulk solution in higher generation carbosilane
dendrimers. We exploited this shielding effect to enforce
intramolecular reactions and thus explored the application of
the dendrimeric carbodiimides to lactamization reactions. DCG1,
DCG2, and DCG3 successfully mediated cyclization of dipep-
tides that are difficult to ring-close with traditional methods.
Although a positive dendritic effect was observed, the formation
of side products could not be completely suppressed. Overall,
it can be concluded that core-functionalized dendrimers have
considerable potential in facilitating difficult cyclization reac-
tions. We are currently developing a recyclable dendrimeric
carboxylic acid-activating reagent with a more controllable
mechanism to broaden the scope and utility of this new concept.
4
2
[PtCl6]23 in dichloromethane was added (10 mol catalyst per mol
of allyl end group). After the solution was stirred for 10 min, HSiCl
was added (1.5 equiv based on the amount of allyl end groups).
Subsequently, a CaCl tube was placed on the flask, and the nitrogen
-4
3
2
1
inlet was removed. The reactions were followed by H NMR
spectroscopy. If no more progress was observed, fresh catalyst was
added. When conversion was complete (disappearance of allyl
groups, usually observed after 16 h) the solvents were evaporated
1
in vacuo. Distillations: membrane pump 110 °C product H NMR
(
CDCl
product not isolated.) The hydrosilylation product of the two
reactions were combined and diluted with Et O (40 mL) and added
dropwise to a cooled 2 M allylmagnesium bromide solution in Et
1.1 equiv per chlorine end group). The reaction mixture was stirred
3
): 3.60 (t, 2H), 2.09-2.02 (m, 2H), 1.57 (t, 2H). (Side
2
2
O
(
for 5 h at room temperature. Excess allylmagnesium bromide was
quenched by the addition of 10% NH Cl at 0 °C. The aqueous
4
(aq)
layer was extracted with diethyl ether (3×), and the combined
organic layers were washed with water (1×) and brine (1×), dried
4
over MgSO , and concentrated in vacuo. The crude product was
2
filtered over a short silica column (pentane/Et O 10:1) to afford
1
the product 1 (90 g, 52%) as a colorless oil. H NMR (CDCl
3
):
5
1
.83-5.73 (m, 3H), 4.91-4.85 (m, 6H), 3.36 (t, J ) 6.9 Hz, 2H),
1
3
.88-1.85 (m, 2H), 1.58 (d, 6H), 0.72-0.66 (m, 2H). C NMR
21
): 133.6, 113.7, 47.3, 27.0, 19.4, 9.0. FAB-MS for C12H -
(CDCl
3
ClSi: 186.9 [M - allyl], 144.9 [M - 2allyl].
Second Generation Carbosilane Wedges Cl[G2](allyl) (2).
9
The first generation carbosilane wedge Cl[G1](allyl)
mol) was transferred in a dry Schlenk vessel under a nitrogen
atmosphere; the cosolvents CH Cl (30 mL) and Et O (20 mL) were
added. A freshly prepared solution of [Bu N] [PtCl
romethane was added (10-4 mol catalyst per mol of allyl end group).
After the solution was stirred for 10 min, HSiCl was added (39.5
mL, 0.39 mol). Subsequently, a CaCl tube was placed on the flask,
3
1 (20 g, 0.087
2
2
2
23
4
2
6
]
in dichlo-
3
Experimental Section
2
All manipulations involving air- or water-sensitive compounds
were performed using standard Schlenk techniques under a nitrogen
atmosphere. Tetrahydrofuran and diethyl ether were freshly distilled
(40) This method has been developed by Van Leeuwen/Van der Made
at Shell (Amsterdam).
1858 J. Org. Chem., Vol. 71, No. 5, 2006

Site Isolation as a Lactamization Tool
and the nitrogen inlet was removed. The reaction was followed by
H NMR spectroscopy. If no more progress was observed, fresh
catalyst was added. When conversion was complete (disappearance
of allyl groups, usually observed after 2 or 3 days), the solvents
were evaporated in vacuo. The hydrosilylation product was diluted
3 9
N [G2](propyl) (8). This compound was prepared according to
1
the procedure described for the first generation starting from 5 (1
g, 1.4 mmol), stirring at 90 °C for 16 h, and yielding 8 (1 g, 99%)
1
as a colorless oil. H NMR: 3.22 (t, J ) 6.9 Hz, 2H), 1.60-1.53
(m, 2H), 1.21-1.17 (m, 24H), 0.83 (t, J ) 7.2 Hz, 27H), 0.50-
with Et
nesium bromide solution in Et
The reaction mixture was stirred for 6 h at room temperature. Excess
allylmagnesium bromide was quenched by the addition of 10% NH
Cl(aq) at 0 °C. The aqueous layer was extracted with diethyl ether
2
O and was added dropwise to a cooled 2.2 M allylmag-
0.35 (m, 32H). 13C NMR (CDCl
3
): 54.7, 23.9, 18.6, 17.9, 17.7,
2
O (1.1 equiv per chlorine end group).
17.6, 15.4, 9.9. IR (NaCl): ν 2955 to 2869 (CH
2 3
, CH stretch),
2096, 1461 (CH deformation).
2
4
-
I[G3](propyl)27 (10). To a solution of Cl[G3](propyl)27 6 (2 g,
0.95 mmol) in THF/DMF (80 mL, 3:1 v/v) was added NaI (1.42 g,
9.5 mol). The resulting mixture was warmed to 110 °C and stirred
for 16 h. Then, most of the solvents were evaporated; the remaining
(
3×), and the combined organic layers were washed with water
(
1×) and brine (1×), dried over MgSO , and concentrated in vacuo.
4
The crude product was filtered over a short silica column (pentane/
Et O 95:5) to afford the pure product 2 as a colorless oil (54 g,
mixture was diluted with water (50 mL) and extracted with Et O
2
2
(2 × 100 mL). The combined organic layers were washed with
1
9
3
1
1
0%). H NMR (CDCl
.49 (t, J ) 6.9 Hz, 2H), 1.75-1.60 (m, 2H), 1.58 (d, 18H), 1.37-
.31 (m, 6H), 0.68-0.56 (m, 14H). 13C NMR (CDCl
): 134.1,
13.4, 47.6, 27.6, 19.7, 17.3, 17.2, 16.4, 9.9. MALDI-TOF MS
3
): 5.83-5.73 (m, 9H), 4.91-4.85 (m, 18H),
water (1 × 20 mL) and aqueous saturated NaCl (20 mL), dried
over MgSO , and concentrated in vacuo to afford I[G3](propyl)
4
27
1
3
5c (2 g, 95%) as a yellow oil. H NMR (500 MHz, CDCl ): 3.17
3
(t, J ) 7.1 Hz, 2H), 1.82-1.78 (m, 2H), 1.35-1.29 (m, 78H), 0.95
+
13
calcd for C39
H69ClSi
4
, 684.42. Found, 643.3 [M - allyl] .
(t, J ) 7.2 Hz, 81H), 0.58-0.47 (m, 104H). C NMR (500 MHz,
Third Generation Carbosilane Wedges Cl[G3](allyl)27 (3).
This compound was prepared according to the procedure described
for the second generation starting from 2 (38 g, 55 mmol), stirring
the hydrosilylation reaction for 5 days, and yielding after column
3
CDCl ): 29.3, 19.0, 18.9, 18.1, 18.0, 17.8, 15.7.
3
N [G3](propyl)27 (9). To a solution of I[G3](propyl)27 10 (2 g,
0.90 mmol) in THF/DMF (20 mL, 3:1 v/v) was added NaN (0.6
3
g, 9 mmol). The resulting mixture was warmed to 110 °C and stirred
for 2 days. Then, most of the solvents were evaporated; the
remaining mixture was diluted with water (30 mL) and extracted
1
chromatography (pentane) 3 as a colorless oil (94 g, 83%). H NMR
(
CDCl
3
): 5.83-5.73 (m, 27H), 4.90-4.85 (m, 54H), 3.49 (t, J )
.9 Hz, 2H), 1.76-1.72 (m, 2H), 1.58 (d, 54H), 1.36-1.26 (m,
4H), 0.68-0.54 (m, 50H). 13C NMR (CDCl
) δ 134.3, 113.4, 47.9,
7.8, 19.6, 18.2, 17.4, 16.5. MALDI-TOF MS: calcd for C120
6
2
2
with Et
with water (1 × 20 mL) and aqueous saturated NaCl (20 mL), dried
over MgSO , and concentrated in vacuo to afford N [G3](propyl)27
9 (1.74 g, 91%) as a yellow oil. H NMR (500 MHz, CDCl ): 3.14
(t, J ) 6.8 Hz 2H), 1.60-1.57 (m, 2H), 1.28-1.22 (m, 78H), 0.88
2
O (2 × 50 mL). The combined organic layers were washed
3
H
213
-
4
3
+
1
ClSi13Ag, 2124.3. Found, 2121.9 [M - allyl + Ag] .
Cl[G1](propyl) (4). To a solution of Cl[G1](allyl)
0 mmol) in EtOAc/MeOH (60 mL, 3:1 v/v) 10% Pd/C (0.3 g)
3
3
3
1 (3.47 g,
13
1
(t, J ) 7.2 Hz, 81H), 0.51-0.40 (m, 104H). C NMR (500 MHz,
CDCl ): 54.7, 23.9, 18.7, 18.6, 17.8, 17.7, 17.5, 15.4, 1.0. IR
(NaCl): ν 2955 to 2795 (CH
deformation). Anal. calcd for C120
was added. The resulting mixture was stirred under hydrogen
pressure (1 atm, balloon) for 16 h. The reaction was filtered over
Celite, and the solvents were evaporated under reduced pressure
3
2
, CH
3
stretch), 2095, 1455 (CH
2
267 3
H N Si13: C, 68.06; H, 12.71;
1
to afford the product 4 (1.9 g, 81%) as a colorless oil. H NMR
N, 1.98. Found: C, 68.21; H, 12.75; N, 2.02.
(
(
(
CDCl
m, 6H), 0.90 (t, J ) 7.2 Hz, 9H), 0.50-0.40 (m, 6H). C NMR
CDCl ): 48.1, 27.8, 18.6, 17.4, 15.7, 10.4.
Cl[G2](propyl) (5). This compound was prepared according to
3
): 3.49 (t, J ) 6.9 Hz, 2H), 1.82-1.65 (m, 2H), 1.40-1.20
One-Pot Procedure for the Synthesis of N
Starting from Cl[G3](propyl)27. To a solution of Cl[G3](propyl)27
6 (2 g, 0.95 mmol) in THF/DMF (20 mL, 3:1 v/v) in a sealed tube
3
[G3](propyl)27
13
3
9
3
were added KI (0.16 g, 0.9 mmol) and NaN (0.6 g, 9 mmol). The
the procedure described for the first generation starting from 2 (1.94
g, 2.8 mmol) and yielding 5 (1.8 g, 93%) as a colorless oil. H
resulting mixture was warmed to 110 °C and stirred for 3 days.
Then, most of the solvents were evaporated; the remaining mixture
1
NMR (CDCl
3
): 3.44 (t, J ) 6.8 Hz, 2H), 1.78-1.74 (m, 2H), 1.41-
was diluted with water (30 mL) and extracted with Et
mL). The combined organic layers were washed with water (1 ×
20 mL) and aqueous saturated NaCl (20 mL), dried over MgSO
2
O (2 × 50
1
3
9
.32 (m, 24H), 1.01-0.97 (t, J ) 7.2 Hz, 27H), 0.65-0.53 (m,
2H). 13C NMR (CDCl
.3.
3
): 43.1, 29.5, 18.5, 17.8, 17.6, 17.3, 15.5,
4
,
3
and concentrated in vacuo to afford N [G3](propyl)27 9 (1.8 g, 90%)
as a yellow oil.
Cl[G3](propyl)27 (6). To a solution of Cl[G3](allyl)27 3 (4 g,
.9 mmol) in EtOAc/MeOH (50 mL, 10:1 v/v) 10% PtO (0.4 g)
1
2
NH
2
[G1](propyl)
3
(11). To a solution of N
3
[G1](propyl) 7 (0.5
3
was added. The resulting mixture was stirred under hydrogen
pressure (1 atm, balloon) for 2 days. The reaction was filtered over
Celite, and the solvents were evaporated under reduced pressure
g, 2.1 mmol) in EtOAc/MeOH (25 mL, 10:1 v/v) 10% Pd/C (0.05
g) was added. The resulting mixture was stirred under hydrogen
pressure (1 atm, balloon) for 16 h. The reaction was filtered over
Celite, and the solvents were evaporated under reduced pressure
1
to afford the product 6 (4.14 g, 99%) as a colorless oil. H NMR
1
(
1
(
1
1
CDCl
.35-1.28 (m, 78H), 0.97-0.93 (t, J ) 7.2 Hz, 81H), 0.57-0.47
m, 104H). 13C NMR (CDCl
, 500 MHz): 43.1, 29.5, 18.4, 17.6,
7.3, 15.2. Anal. calcd for C120 267ClSi13: C, 68.28; H, 12.75; Si,
7.30. Found: C, 68.14; H, 12.70; Si, 17.24.
[G1](propyl) (7). To a solution of Cl[G1](propyl)
mmol) in DMF (15 mL) was added NaN (1 g, 15 mmol). The
3
, 500 MHz): 3.47 (t, J ) 6.7 Hz, 2H), 1.77-1.75 (m, 2H),
to afford the product 11 (0.32 g, 71%) as a colorless oil. H NMR
(CDCl
6H), 0.95 (t, J ) 7.2 Hz, 9H), 0.57-0.49 (m, 8H). C NMR
(CDCl ): 43.4, 22.2, 18.6, 17.2, 14.8, 9.5. IR (NaCl): ν 3167 (N-H
stretch), 2728 (CH , CH stretch), 1459 (CH deformation). HRMS
(FAB ) m/e found 216.2145 (MH C12 30NSi requires 216.2148).
NH [G2](propyl) (12). To a solution of N [G2](propyl) 8 (0.5
3
): 2.94-2.90 (m, 2H), 1.74-1.70 (m, 2H), 1.30-1.26 (m,
13
3
H
3
2
3
2
+
+
N
3
3
3
4 (0.7 g,
H
3
3
2
9
3
9
resulting mixture was warmed to 90 °C and stirred for 6 h. Then,
most of the solvents were evaporated; the remaining mixture was
g, mmol) in EtOAc/MeOH (30 mL, 10:1 v/v) 10% Pd/C (0.05 g)
was added. The resulting mixture was stirred under hydrogen
pressure (1 atm, balloon) for 16 h. The reaction was filtered over
Celite, and the solvents were evaporated under reduced pressure
diluted with water (15 mL) and extracted with Et
The combined organic layers were washed with water (1 × 10 mL)
and aqueous saturated NaCl (10 mL), dried over MgSO , and
concentrated in vacuo to afford N [G1](propyl) 7 (0.62 g, 86%)
): 3.22 (t, J ) 6.8 Hz, 2H), 1.61-
.54 (m, 2H), 1.35-1.28 (m, 6H), 0.95 (t, J ) 7.2 Hz, 9H), 0.56-
.49 (m, 8H). 13C NMR (CDCl
): 54.5, 23.6, 18.4, 17.2, 14.9, 9.6.
, CH stretch), 2094, 1464 (CH
2
O (2 × 30 mL).
1
to afford the product 12 (0.42 g, 56%) as a colorless oil. H NMR
4
(CDCl
(m, 24H), 0.94 (t, J ) 7.2 Hz, 24H), 0.59-0.46 (m, 32H).
NMR (CDCl ): 42.5, 22.0, 18.5, 17.5, 16.9, 15.0, 8.0. IR (NaCl):
ν 2956 to 2870 (CH , CH stretch), 1454 (CH deformation).
NH [G3](propyl)27 (13). Method A (Catalytic Hydrogenation).
To a solution of N
3
): 2.91 (t, J ) 6.9 Hz, 2H), 1.68-1.65 (m, 2H), 1.35-1.26
3
3
1
13
as a yellow oil. H NMR (CDCl
3
C
1
0
3
3
2
3
2
IR (NaCl): ν 2955 to 2869 (CH
2
3
2
2
deformation).
3
[G3](propyl)27 9 (1 g, 0.47 mmol) in EtOAc/
J. Org. Chem, Vol. 71, No. 5, 2006 1859

Amore et al.
MeOH (50 mL, 10:1 v/v) 10% Pd/C (0.1 to 0.4 g) was added. The
resulting mixture was stirred under hydrogen pressure (1 atm,
balloon) for 16 h. The reaction was filtered over Celite, and the
Third Generation Urea (19). This compound was prepared
according to the procedure described for the first generation starting
from 12 (200 mg, 0.1 mmol) and 16 (200 mg, 0.1 mmol) and
1
solvents were evaporated under reduced pressure to afford the
yielding 19 (239 mg, 60%) as a colorless oil. H NMR (CDCl ):
3
1
product 13 (0.7 g, 70%) as a colorless oil. H NMR (CDCl
3
): 2.67
@NH 3.12 (m, 4H), 1.50-1.41 (m, 4H), 1.38-1.26 (m, 156H),
1
3
(
t, J ) 6.9 Hz, 2H), 1.53-1.27 (m, 80H), 0.97-0.94 (t, J ) 7.2
0.96 (t, J ) 7.2 Hz, 162H), 0.55-0.49 (m, 208H). C NMR
13
Hz, 81H), 0.58-0.48 (m, 104H). C NMR (CDCl
1
NSi13, 2089.811. Found, 2091.889 [M + H] .
3
): 46.0, 29.0,
(CDCl ): 157.0, 44.1, 24.7, 18.5, 18.4, 17.7, 17.5, 17.3, 15.2. IR
3
9.0, 18.9, 18.8, 14.4, 8.8. MALDI-TOF MS: calcd for C120
269
H -
(neat NaCl): ν 2957 to 2725 (CH , CH stretch), 1698, 1518 (CO
2
3
+
stretch), 1458 (CH deformation). MALDI-TOF MS: calcd for
2
Method B (Staudinger Reduction). To a solution of N
3
[G3]-
+
C H N
241 536 2
OSi26, 4207.6. Found, 4231.0 [M + Na] .
3
(propyl)27 9 (1 g, 0.47 mmol) in THF (10 mL) PPh (0.13 g, 0.47
First Generation Carbodiimide (DCG1). A solution of PPh
500 mg, 1.9 mmol) in dry CH Cl (10 mL) was cooled at 0 °C.
Bromine (99 µL, 1.9 mmol) was added dropwise followed by the
addition of Et N (0.61 mL, 4.2 mmol) in one portion. After the
3
mmol) was added. The resulting mixture was stirred at 70 °C
overnight. After this time, a few drops of water were added and
stirring was continued for 2 h. The solvent was removed under
reduced pressure, and the resulting slurry was diluted with pentane
(
2
2
3
solution was stirred for 10 min, 17 (800 mg, 1.7 mmol) was added
to the yellow suspension. The mixture was allowed to warm to
room temperature and stirred for 16 h. The resulting red slurry was
concentrated in vacuo before dilution with dry pentane (5 mL).
The solids were filtered off and washed with additional pentane.
The organic layer was evaporated, and the crude product was
3
(10 mL). The solid (PPh O) was filtered off and washed with
additional pentane. The organic layer was evaporated to afford the
product 13 (0.93 g, 95%) as a colorless oil.
OCN[G1](propyl)
g, 27 mmol) in water (18 mL), H
3
(14). To a stirred solution of NaHCO
3
(2.3
2
N[G1](propyl) 11 (1.5 g, 7 mmol)
3
in toluene (18 mL) was added. The resulting mixture was cooled
at 0 °C, and phosgene (14 mL, 27 mmol) was added in once. The
white solution was stirred for 2 h. The layers were separated, and
purified by flash column chromatography (basic alumina, 5% Et
3
N
in pentane) to afford the carbodiimide DCG1 (470 mg, 63%) as a
1
colorless oil. H NMR (CDCl
1
0
3
): 3.15 (t, J ) 6.9 Hz, 4H), 1.56-
.52 (m, 4H), 1.34-1.28 (m, 12H), 0.95 (t, J ) 7.1 Hz, 18H), 0.55-
.48 (m, 16H). 13C NMR (CDCl
): 141.0, 50.0, 25.9, 18.4, 17.2,
, CH stretch), 2120 (NdCdN
deformation). Anal. calcd for C25 Si : C,
the aqueous layer was extracted with Et
organic layers were dried over MgSO and concentrated in vacuo
to afford OCN[G1](propyl) 14 (1.57 g, 93%) as a colorless oil,
which was used without further purification. H NMR: 3.22 (t, J
2
O (5 mL). The combined
4
3
3
1
15.0, 9.7. IR (NaCl): ν 2955 (CH
stretch), 1461 (CH
2
3
2
H N
54 2
2
)
6.8 Hz, 2H), 1.61-1.56 (m, 2H), 1.34-1.27 (m, 6H), 0.95 (t, J
7.2 Hz, 9H), 0.55-0.46 (m, 8H). 1 C NMR (CDCl
3
68.42; H, 12.40; N, 6.38. Found: C, 68.33; H, 12.29; N, 6.31.
Second Generation Carbodiimide (DCG2). This compound
was prepared according to the procedure described for the first
generation starting from 18 (610 mg, 0.4 mmol) and yielding DCG2
)
3
): 122.0,
, CH
45.9, 26.1, 18.2, 17.2, 14.9, 9.4. IR (NaCl): ν 2922 (CH
2
3
stretch), 2268 (OdCdN stretch).
OCN[G2](propyl) (15). This compound was prepared according
to the procedure described for the first generation starting from
9
1
(450 mg, 74%) as a colorless oil. H NMR (CDCl
3
): 3.17 (t, J )
H
2
N[G2](propyl)
9
1
12 (2 g, 2.9 mmol) and yielding 15 (2.1 g, 97%)
): 3.24 (t, J ) 6.9 Hz, 2H), 1.55-
7.0 Hz, 4H), 1.56-1.54 (m, 4H), 1.36-1.29 (m, 48H), 0.95 (t, J
13
as a colorless oil. H NMR(CDCl
3
3
) 7.2 Hz 54H), 0.58-0.47 (m, 64H). C NMR (CDCl ): 140.5,
1
4
1
.50 (m, 2H), 1.37-1.29 (m, 24H), 0.96 (t, J ) 7.2 Hz, 27H), 0.60-
50.5, 26.4, 18.9, 18.8, 10.1, 17.9, 17.8, 15.7, 10.2. IR (NaCl): ν
2955 to 2868 (CH , CH stretch), 2130 (NdCdN stretch), 1411
8.00 (m, 32H). 13C NMR (CDCl
7.0, 16.5, 15.6, 11.1.
): 121.0, 45.0, 26.0, 18.4, 18.2,
3
2
3
+
+
(CH deformation). HRMS (FAB ) m/e found 1376.1912 (MH
2
OCN[G3](propyl)27 (16). This compound was prepared accord-
ing to the procedure described for the first generation starting from
3 (0.6 g, 0.29 mmol) and yielding 16 (0.52 g, 85%) as a colorless
79 175 2 8 78 170 2 8
C H N Si requires 1376.1910). Anal. calcd for C H N Si :
C, 68.84; H, 12.59; N, 2.06. Found: C, 69.03; H, 12.75; N, 2.01.
Third Generation Carbodiimide (DCG3). To a solution of N
G3](propyl)27 9 (850 mg, 0.40 mmol) in THF (12 mL) was added
PPh (105 mg, 0.40 mmol). The resulting mixture was stirred at
1
3
-
1
oil. H NMR (CDCl
H), 1.37-1.30 (m, 78H), 0.96 (t, J ) 7.2 Hz, 81H), 0.59-0.48
m, 104H). 13C NMR (CDCl
): 120.0, 45.0, 27.0, 19.0, 18.0, 17.0,
5.0, 7.0. IR (NaCl): ν 2953 to 2868 (CH , CH stretch), 2266
OdCdN stretch), 1455 (CH deformation).
First Generation Urea (17). A solution of OCN[G1](propyl)
4 (440 mg, 1.8 mmol) and H N[G1](propyl) 10 (340 mg, 1.6
3
): 3.21 (t, J ) 6.9 Hz, 2H), 1.55-1.52 (m,
[
2
3
(
3
65 °C for 6 h. After this time OCN[G3](propyl)27 16 (930 mg,
1
2
3
0.44 mmol) was added, and stirring was continued under reflux
(
2
for 16 h. Then, the solvent was evaporated. The crude product was
purified using column chromatography (basic alumina, hexanes)
to afford the carbodiimide DCG3 (1.2 gr, 72%) as a colorless oil.
3
1
2
3
mmol) in dry toluene (5 mL) was stirred at 90 °C for 16 h. The
solution was then concentrated in vacuo, and the crude product
was purified by flash column chromatography (PE/EtOAc 1:1) to
1
H NMR (CDCl
3
): 3.18 (t, J ) 7.0 Hz, 4H), 1.54-1.52 (m, 4H),
.37-1.28 (m, 156H), 0.98 (t, J ) 7.2 Hz, 162H), 0.58-0.48 (m,
08H). 13C NMR (500 MHz, CDCl
): 139.6, 50.3, 26.3, 18.7, 17.9,
7.8, 17.7, 15.7. IR (NaCl): ν 2954 to 2866 (CH , CH stretch),
130 (NdCdN stretch), 1411 (CH deformation). Anal. calcd for
Si26: C, 69.07; H, 12.84; N, 0.67. Found: C, 69.15; H,
1
2
1
2
1
3
afford urea 17 (900 mg, 89%) as a white solid (mp 66 °C). H
2
3
NMR (CDCl
H), 1.35-1.25 (m, 12H), 0.93 (t, J ) 7.2 Hz, 18H), 0.51-0.46
m, 16H). 13C NMR (CDCl
): 157.9, 43.9, 24.7, 18.4, 17.2, 15.0,
.6. IR (NaCl): ν 3366 (NH stretch), 2954 to 2867 (CH , CH
stretch), 1630, 1578 (CO stretch). HRMS (FAB ) m/e: found
3
): 4.20 (bs, NH), 3.13-3.10 (m, 4H), 1.48-1.44 (m,
2
4
241 534 2
C H N
(
3
12.76; N, 0.69.
9
2
3
+
+
439.3907 (MH
C
25
H
55
N
2
Si
2
requires 439.3904).
Acknowledgment. We thank Dr. J. W. Back for measure-
Second Generation Urea (18). This compound was prepared
according to the procedure described for the first generation starting
ment of the MALDI-TOF MS spectra. Victoria Bock is
acknowledged for critiquing the manuscript.
from 11 (420 mg, 0.6 mmol) and 15 (468 mg, 0.7 mmol) and
1
yielding 18 (770 mg, 93%) as a colorless oil. H NMR (CDCl
3
):
Supporting Information Available: Analytical equipment used
and procedures of the lactamization experiments toward 22 and 23
4
(
.20 (bs, NH), 3.13-3.11 (m, 4H), 1.47-1.44 (m, 4H), 1.34-1.25
m, 48H), 0.94 (t, J ) 7.2 Hz, 54H), 0.58-0.47 (m, 64H). 13
C
(
part I). Copies of the spectral data of compounds 1-23 (1-9, part
NMR (CDCl
3
): 157.8, 44.0, 29.2, 18.4, 17.7, 17.5, 15.3, 9.9. IR
, CH stretch),
deformation). HRMS (FAB )
OSi requires 1394.2015).
I; 10-16, part II; 17-23, part III). This material is available free
of charge via the Internet at http://pubs.acs.org.
(
1
NaCl): ν 3326 (NH stretch), 2954 to 2867 (CH
2
3
+
640, 1566 (CO stretch), 1464 (CH
2
+
m/e found 1394.2010 (MH
C
79
H N
177 2
8
JO052027C
1860 J. Org. Chem., Vol. 71, No. 5, 2006