Efficient synthesis of isoxazolidine-tethered monolayer-protected gold nanoparticles (MPGNs) via 1,3-dipolar cycloadditions under high-pressure conditions

Article abstract of DOI:10.1021/jo702398r

(Chemical Equation Presented) A maleimide-modified 2.5 ± 0.5 nm mixed monolayer protected gold nanoparticle (2-C₁₂MPGN) containing approximately 30% maleimide-terminated dodecanethiolate/dodecanethiolate ligands was prepared. The 2-C₁₂MPGN was reacted with a series of nitrones (a-i) at both atmospheric and hyperbaric (11 000 atm) conditions to form the corresponding isoxazolidine-modified nanoparticles (3-C₁₂MPGN) via an interfacial 1,3-dipolar cycloaddition. At atmospheric pressures, the reaction proceeds slowly (if at all) and makes this reaction impractical for the synthetic modification of the nanoparticles. However, by performing the reaction under the high-pressure conditions, the reaction proceeds efficiently and quantitatively. TEM shows that the use of high pressure does not affect the size of the gold nanoparticle core. The 3-C₁₂MPGNs were characterized by ¹H NMR spectroscopy by comparing the spectra obtained with those of model reactions utilizing N-dodecylmaleimide (4) with the same nitrones (a-i) to form 5. Additionally, the cycloaddition reaction also occurs more readily with 4 than with 2-C₁₂MPGN with all nitrones, indicating that the environment of the latter affects the cycloaddition reaction.

Full text of DOI:10.1021/jo702398r

Efficient Synthesis of Isoxazolidine-Tethered Monolayer-Protected
Gold Nanoparticles (MPGNs) via 1,3-Dipolar Cycloadditions under
High-Pressure Conditions
Jun Zhu, Brandon M. Lines, Michael D. Ganton, Michael A. Kerr, and Mark S. Workentin*
Department of Chemistry, The UniVersity of Western Ontario, London, ON, Canada N6A 5B7
mworkent@uwo.ca
ReceiVed NoVember 12, 2007
A maleimide-modified 2.5 ( 0.5 nm mixed monolayer protected gold nanoparticle (2-C12MPGN)
containing approximately 30% maleimide-terminated dodecanethiolate/dodecanethiolate ligands was
prepared. The 2-C12MPGN was reacted with a series of nitrones (a-i) at both atmospheric and hyperbaric
(11 000 atm) conditions to form the corresponding isoxazolidine-modified nanoparticles (3-C12MPGN)
via an interfacial 1,3-dipolar cycloaddition. At atmospheric pressures, the reaction proceeds slowly (if at
all) and makes this reaction impractical for the synthetic modification of the nanoparticles. However, by
performing the reaction under the high-pressure conditions, the reaction proceeds efficiently and
quantitatively. TEM shows that the use of high pressure does not affect the size of the gold nanoparticle
1
core. The 3-C12MPGNs were characterized by H NMR spectroscopy by comparing the spectra obtained
with those of model reactions utilizing N-dodecylmaleimide (4) with the same nitrones (a-i) to form 5.
Additionally, the cycloaddition reaction also occurs more readily with 4 than with 2-C12MPGN with all
nitrones, indicating that the environment of the latter affects the cycloaddition reaction.
Introduction
generate the isoxazolidines with a high degree of regio- and
stereochemical control. Perhaps more important than this is the
access they provide to a wide variety of 1,3-aminoalcohols via
reductive scission of the NO bond.
Controlling the surface chemical structure and thus the
interactions between monolayer-protected gold nanoparticles
Cycloaddition is one of the most efficient and reliable
synthetic transformations for the rapid, predictable, and reliable
assembly of molecular complexity. While the bulk of the
attention directed toward this reaction has centered about the
Diels-Alder reaction, other cycloadditions have established their
place in the toolbox of the synthetic chemist. 1,3-Dipolar
cycloadditions, for example, are some of the most useful ways
(MPGNs) and solutes is a major challenge for their potential
applications in device fabrications, detection systems, or drug
delivery, and so developing efficient methods for preparing
1
to construct heterocyclic rings. Often, simple variation of the
2
MPGNs remains a useful synthetic endeavor. Because of the
dipolar or dipolarophilic partners offers a method for incorpora-
tion of a large degree of structural diversity. Nitrones may be
the most studied of the dipolar species owing to their ability to
complex structures that can be introduced using cycloaddition
reactions, they have been used for the synthetic modification
(2) (a) Katz, E.; Willner, I. Angew. Chem., Int. Ed. 2004, 43, 6042-
*
To whom correspondence should be addressed. Phone: 519-661-2111
86319). Fax: 519-661-3022. E-mail: mworkent@uwo.ca.
1) (a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
6108. (b) Love, J. C.; Estroff, L. A.; Kriebel, J. K.; Nuzzo, R. G.; Whitesides,
G. M. Chem. ReV. 2005, 105, 1103-1170. (c) Daniel, M.; Astruc, D. Chem.
ReV. 2004, 104, 293-346. (d) Dreschler, U.; Erdogan, B.; Rotello. V. M.
Chem.sEur. J. 2004, 10, 5570-5579. (e) You, C.-C.; Verma, A.; Rotello,
V. M. Soft Mater. 2006, 2, 190-204. (f) Rosi, N. L.; Mirkin, C. A. Chem.
ReV. 2005, 105, 1547-1562. (g) Li, X.-M.; Huskens, J.; Reinhoudt, D. N.
J. Mater. Chem. 2004, 14, 2954-2971.
(
(
Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; Wiley: New York, 2003. (b) Gothelf, K. V.; Jørgensen, K. A. Chem.
ReV. 1998, 98, 863-909. (c) Bonin, M.; Chauveau, A.; Micouin, L. Synlett
2
006, 15, 2349-2363.
1
0.1021/jo702398r CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/09/2008
J. Org. Chem. 2008, 73, 1099-1105
1099

Zhu et al.
SCHEME 1. Preparation of 2-C12MPGN from 1-C12MPGN and the Reaction of 2-C12MPGN via a 1,3-Dipolar Cycloaddition
with Nitrones a-i to Form the Corresponding Isoxazolidine-Modified 3-C12MPGN under Ambient and High-Pressure
Conditions
of self-assembled monolayers on gold (SAMs) and MPGNs.3,4
Due to the vast structural diversity offered by the 1,3-dipolar
cycloaddition of a nitrone with an alkene and the potential to
further elaborate it by reduction of the N-O bond of the product
isoxazolidine, we investigated this reaction type for the synthetic
modification of MPGNs.
acceleration in solution. Additionally, this reaction type has been
studied on polymer solid supports. Kuster and Scheeren were
6
the first to report the successful promotion of this reaction type
proceeding on Wang resin solid supports under high-pressure
7
conditions, and they have continued to expand the usefulness
of high-pressure-promoted cycloadditions on resin-bound re-
8
We have previously developed a method to prepare a mixed
maleimide/dodecanethiolate-modified monolayer-protected gold
nanoparticle (2-C12MPGN) and showed that it could serve as a
dienophile to react via interfacial Diels-Alder reactions with a
series of dienes of varying steric and electronic demand. The
Diels-Alder reactions that did not proceed, or proceeded only
after days, on the MPGN at ambient temperature and pressure
actants on solid-phase supports. Prompted by these promising
studies and our own success on using high pressures to promote
the Diels-Alder reaction on metal nanoparticles, in this report,
we examine for the first time the interfacial 1,3-dipolar nitrone/
alkene cycloaddition under ambient and high pressures on
MPGN. We utilized the maleimide-tethered MPGN, prepared
4
,9
as we described previously, as the dipolarophile and studied
the cycloaddition reaction with a series of structurally diverse
nitrones to prepare isoxazolidine-modified MPGN, 3-C12MPGN
(see Scheme 1). The maleimide was a useful model alkene to
study this interfacial chemistry because it is a doubly activated
alkene and simplifies the analysis of the products because it
eliminates complications due to regioselectivity of the cycload-
dition reaction because it is a symmetric alkene. The results of
this study show that the slow and inefficient 1,3-dipolar
4
were completed in less than 10 min at 25 °C at 11 000 atm.
1
,3-Dipolar cycloadditions of nitrones with alkenes, like Diels-
5
Alder reactions, possess a negative volume activation reaction.
As such, they have shown to be subject to hyperbaric rate
(
3) (a) Gawalt, E. S.; Mrksich, M. J. Am. Chem. Soc. 2004, 126, 15613-
1
5617 and references therein. (b) Dillmore, W. S.; Yousaf, M.; Mrksich,
M. Langmuir 2004, 20, 7223-7231 and references therein. (c) Fleming,
D. A.; Thode, C. J.; Williams, M. E. Chem. Mater. 2006, 18, 2327-2334.
(d) Kell, A. J.; Montcalm, C. C.; Workentin, M. S. Can. J. Chem. 2003,
8
1, 484-494. (e) Collman, J. P.; Devaraj, N. K.; Eberspacher, T. P. A.;
(6) R u¨ ck-Braun, K.; Freysoldt, T. H. E.; Wierschem, F. Chem. Soc. ReV.
2005, 34, 507-516.
(7) (a) Kuster, G. J.; Scheeren, H. W. Tetrahedron Lett. 1998, 39, 3613-
3616. (b) Kuster, G. J.; Scheeren, H. W. Tetrahedron Lett. 2000, 41, 515-
519.
Chidsey, C. E. D. Langmuir 2006, 22, 2457-2464. (f) Sommer, W. J.;
Weck, M. Langmuir 2007, 23, 11991-11995. (g) Binder, W. H.; Patraru,
L.; Sachenshofer, Zirbs, R. Monatsh. Chem. 2006, 137, 835-841.
(4) Zhu, J.; Ganton, M. D.; Kerr, M. A.; Workentin, M. S. J. Am. Chem.
Soc. 2007, 129, 4904-4905.
5) Isaacs, N. S. In High Pressure Techniques in Chemistry and Physics;
Holzapfel, W. W., Isaacs, N. S., Eds.; Oxford University Press: New York,
997; Chapter 7. Unfortunately, there is no systematic activation volume
data for the reactions studied herein. From the available references about
,3-dipolar cycloadditions and Diels-Alder reactions, the activation volume
(8) See for example: (a) van Berkom, L. W. A.; Kuster, G. T. J.;
Scheeren, H. W. Mol. DiVersity 2003, 6, 271-282. (b) Kuster, G. J. T.;
van Berkom, L. W. A.; Kalmoua, M.; van Loevezijn, A.; Sliedregt, L. A.
J. M.; van Steen, B. J.; Kruse, C. G.; Rutjes, F. P. J. T.; Scheeren, H. W.
J. Comb. Chem. 2006, 8, 85-94.
(
1
1
(9) Zhu, J.; Kell, A. J.; Workentin, M. S. Org. Lett. 2006, 8, 4993-
4996.
3
for the former reaction is usually 10 cm /mol smaller than that of the latter.
1100 J. Org. Chem., Vol. 73, No. 3, 2008

Hyperbaric Synthesis of Isoxazolidine-Tethered MPGNs
FIGURE 1. 1H NMR spectra of 2-C12MPGN (A) and representative 3-C12MPGN formed in 1,3-dipolar cycloaddition of 2-C12MPGN with nitrones
c, e, and f: (B) 3c-C12MPGN; (C) 3e-C12MPGN; (D) 3f-C12MPGN. Solvent C D .
6 6
SCHEME 2. Model Reaction of 4 with Nitrones to Form
Isoxazolidine Product 5
cycloaddition reactions of 2-C12MPGNs with various nitrones
under ambient pressure are greatly accelerated under hyperbaric
conditions, making it a synthetically viable reaction for the
modification of these nanoparticles.
Results and Discussion
The dipolarophile MPGN, 2-C12MPGN, was prepared using
the method reported before.4 Dodecanethiolate-modified nano-
particles (C12-MPGN) were prepared following the Brust-
Schiffrin method using a 1:1 ratio of dodecanethiol/hydrogen
,9
smaller broad signal at 0.9 ppm. The MPGN contains ca. 30%
maleimide compared to C12.
10
4,9
tetrachloroaurate with TOAB and a 10-fold excess of NaBH4.
The Diels-Alder-protected furan maleimide dodecyl thiol (1)
was then incorporated onto the C12-MPGN using C12-MPGN/1
To probe the synthetic utility of the nitrone cycloaddition,
2-C MPGN was mixed with a 15 times molar excess of each
12
1
1
in a 1:1.5 ratio by the standard place-exchange method, and
then the maleimide-containing MPGN (2-C12MPGN) is liberated
by heating the 1-C12MPGN in toluene to initiate the release of
furan off of the MPGN and into solution. Compound 2-C12-
MPGN (Scheme 1) with an average core size of 2.5 ( 0.5 nm
is then isolated pure after removal of the liberated furan by
2 2
of the nitrones dissolved in CH Cl as the solvent. Half of each
solution was purged with argon and left at ambient conditions
(1 atm, 25 °C), and the other half was placed in a Teflon tube,
argon-purged, sealed, and placed in a high-pressure reactor and
subjected to pressures of 11 000 atm at room temperature
(Scheme 1). Because of the breadth of the NMR signals of the
substrates on a MPGN, it was important to gain information as
to what chemical shifts to expect for the isoxazolidine products
formed on reaction of each nitrone with 2-C MPGN. Therefore,
1
washing with 95% ethanol. The H NMR spectrum of 2-C12-
MPGN dissolved in C6D6 exhibits the characteristic broad NMR
signals observed for substrates immobilized on a MPGN;
however, importantly, the chemical shifts (and integration) allow
for the structural characterization of the functionality on the
MPGN (Figure 1A). Diagnostic in the spectrum of 2-C12MPGN
are the olefinic protons arising from the maleimide moiety at
12
model reactions were also carried out. Namely, each nitrone
(a-i) was mixed with N-dodecylmaleimide (4) in a 5:1 ratio in
CD Cl , argon-purged, and subjected to atmospheric and high-
2
2
pressure conditions (Scheme 2). The progress of the 1,3-dipolar
1
5
3
.80 ppm (labeled a) and the methylene protons R to the N at
.40 ppm (labeled b). The broad signals from ca. 1.1-2.0 ppm
cycloaddition reactions was monitored by H NMR spectroscopy
following the disappearance of the olefinic protons of the
are due to CH2 resonances in the alkyl chains of the ligands,
and the terminal CH3 group of the C12 ligand appears as the
maleimide moiety on 2-C MPGN (and 4) and by the concomi-
12
tant appearance of signals that could be assigned to the
corresponding isoxazolidine cycloadducts (3-C12MPGN and 5,
respectively).
Figure 1B-D shows representative NMR spectra of the 3-C12-
MPGN obtained from the reaction of 2-C12MPGN with nitrones
c, e, and f, respectively, after completion of the reaction and
(
10) Brust, M.; Walker, M.; Bethell, D.; Schiffrin, D. J.; Whyman, R. J.
Chem. Commun. 1994, 801-802.
11) (a) Hostetler, M. J.; Templeton, A. C.; Murray, R. W. Langmuir
(
1
999, 15, 3782-3789. (b) Brust, M.; Kiely, C. J. Colloids Surf. A 2002,
02, 175-186.
2
J. Org. Chem, Vol. 73, No. 3, 2008 1101

Zhu et al.
TABLE 1. Times for Quantitative Formation of Isoxazolidines
(
3a-i-C12MPGN and 5a-i) from the 1,3-Cycloaddition Reactions
between 2-C12MPGN or 4 with Nitrones a-i under Ambient
Atmospheric Pressures (1 atm, 25 °C) and Hyperbaric Pressures
(
11 000 atm, 25 °C)a
4
2-C12MPGN
1 atm 11000 atm
1 day
product
1 atm, 25 °C
11000 atm
3
3
3
3
3
3
3
3
3
a, 5a
b, 5b
c, 5c
d, 5db
e, 5e
f, 5f
g, 5g
h, 5h
i, 5i
10 h
30 h
20 h
10 min
10 min
10 min
10 min
10 min
10 min
10 min
30 min
30 min
10 min
10 min
10 min
30 min
10 min
10 min
10 min
60 min
60 min
3 days
2 days
>2 weeks
7 days
c
50% in 14 days
3 days
2 h
7 days
12 days
14 days
2 h
17 days
>2 weeks
c
>2 weeksc
a
Times indicate to reaction completion (or as indicated) as determined
1
b
by H NMR spectroscopy. Due to the poor solubility of d in CD2Cl2, the
ratio of 4/d is 1:1.5. c Less than 50% conversion after 14 days.
1
FIGURE 2. Representative H NMR spectra of the products from 1,3-
dipolar cycloaddition reaction of (A) 2-C12MPGN with nitrone a to
yield 3a-C12MPGN as a mixture of the diastereomers and 4 with nitrone
a to yield (B) 5a-exo and (C) 5a-endo, respectively. Solvent C D .
6 6
disulfides are now in solution, the proton NMR signals for the
isoxazolidines can be resolved. The ratio of exo/endo cleaved
off the 3-C12MPGN was the same as the ratio determined for
the model reaction (4 f 5, i.e., 5:3; see the Supporting
Information for an example).
removal of the excess nitrone. The broad signals assigned to
the various isoxazolidine protons on the 3-C12MPGN are
indicated in the figure and were confirmed by assigning the
spectra of 5 obtained in the model reactions. Full characteriza-
tion, including NMR spectral assignments of the products for
the model reactions and comparisons to those on the MPGN, is
provided in the Experimental Section and Supporting Informa-
tion for all the reactions. Of course, there are two diastereomers,
the exo and endo products, expected to be formed in these
cycloadditions. For the model 1,3-dipolar cycloaddition reac-
tions, these diastereomers were separated by preparative TLC
and characterized; their structures were determined with the aid
of 1-D NOESY experiments. By knowing the chemical shifts
of the relevant protons of the exo and endo diastereomers, we
were able to examine the reactions on 3-C12MPGN. A repre-
sentative example showing the comparison of the products from
the model reaction (4 f 5) to that on the particle (2-C12MPGN
f 3-C12MPGN) is shown in Figure 2 for the reaction of 2-C12-
MPGN (and 4) with nitrone a to form 3a-C12MPGN (or 5a exo
and endo). Similar figures for reactions of 2-C12MPGN with
the other nitrones are in the Supporting Information. The exo/
endo ratio of the products from reaction of 4 under the ambient
and high-pressure conditions was able to be determined as 5:3
For each reaction, the time taken to convert completely the
maleimide moiety to the isoxazolidine was determined by
1
following the reaction by H NMR spectroscopy and monitoring
the complete loss of the signals due to the maleimide olefinic
protons. The results indicating these times are summarized in
Table 1. Table 1 shows that under hyperbaric conditions the
1,3-dipolar cycloaddition reactions are quantitative and occur
in reaction times that are remarkably shorter than those under
ambient pressure (compare results for conditions a and b for
2-C12MPGN). Reactions that take days or even weeks are all
complete in less than 60 min at 11 000 atm and most in 10 min
or less. The minimum reaction time in the high-pressure reactor
is 10 min because this is the time it takes to pressurize and
depressurize the reaction vessel. Comparing reaction conditions
at 1 atm for the reactions of 4 and 2-C12MPGN, it is not
surprising that all the nitrones (a-i) react more readily with 4,
even with a lower concentration of nitrone. This is likely because
the MPGN offers a unique environment providing steric effects
to the reaction.
Although the reactions summarized were all performed on a
small scale (because of the cost of the MPGN), the reactions
are scalable. For example, similar reactions carried out at the
50 mg scale proceed rapidly and quantitatively at high pressure
(see Supporting Information for details). In fact, the reactor used
will allow these reactions on the several gram scale, making
the use of hyperbaric reactions on MPGN practical for applica-
tions and further synthetic elaborations.
1
from H NMR integration of the product mixture. Because of
the inherent breadth of the signals of the isoxazolidine ligands
on 3-C12MPGN, the exo/endo ratio could not be as easily
determined, although it is clear that both isomers are formed
(see Figure 2). Because there is no obvious bias in the broad
signal in the NMR spectrum toward any one diastereomer that
is not expected from the result with the model compound, the
results suggest that under high-pressure conditions the reactions
on the MPGN do not show a significant difference in diaste-
reoselectivity. There is no noticeable change in the exo/endo
ratio in 3-C12MPGN, and it appears that they are formed in
Examining Table 1 more carefully, there are differences in
the reactivity of various nitrones with both 4 and 2-C MPGN
12
under ambient pressures, and this is presumably determined by
the different electronic and steric demands of the substituents
R and R′ on the nitrone. The inductive effect of a N-aryl
substitute group (R) increases the dipolar nature of the nitrone
(a, b, c, and e), and as a result, N-aryl nitrones generally reacted
faster than the N-alkyl-substituted nitrones (g-i). For nitrone
d, its larger steric demand resulted in the much lower apparent
reactivity compared to that of other N-aryl nitrones. The
difference in reactivity between nitrones g and h can likely be
explained through the smaller steric effect of N-CH3 in g
12
roughly the same ratio as in the model reaction. In several
cases, the 3-C12MPGN was reduced using iodine reduction with
the result that the ligands come off as disulfides. Because the
(12) The issues of exo/endo selectivity in 1,3-dipolar cycloadditions is
still a matter of discussion, and we make no attempt to rationalize the ratio.
For examples of reactions of N-substituted maleimides with nitrones, see:
(
a) Cokun, N.; Mert, H.; Arikan, N. Tetrahedron 2006, 62, 1351-1359.
(b) Cokun, N.; O¨ zt u¨ rk, A. Tetrahedron 2007, 63, 1402-1410.
1102 J. Org. Chem., Vol. 73, No. 3, 2008

Hyperbaric Synthesis of Isoxazolidine-Tethered MPGNs
procedures.13 Other general information can be found in the
Supporting Information.
General Procedure for the 1,3-Dipolar Cycloaddition Reac-
tions of 2-C12MPGN with Nitrones a-i at High Pressure and
Ambient Conditions. Typically, 10 mg of 2-C12MPGN was
compared to that of the N-benzyl in h. Nitrone f has small steric
demands on the carbon terminus of the nitrone, making it the
most efficient nitrone under ambient pressure. The stronger
electron-donating substituents on nitrone i compared to g affects
the dipole and nearly doubles the reaction time for the former.
It is also worth pointing out that, for nitrone e, even though it
contains both a nitrone group and a furan diene, no Diels-
Alder adducts of furan with the maleimide were detected from
this reaction. This may be attributed to a more negative
activation volume expected for the 1,3-cycloaddition than for
the Diels-Alder reaction.
2 2
dissolved in 2.0 mL of CD Cl then mixed with 15 equiv of the
nitrones (a-i). The mixture was then separated into two parts. One
portion was transferred into a brass-clamp sealed PTFE tube under
argon and placed in the high-pressure reactor at 11 000 atm. The
other portion was purged with argon and left to react under ambient
conditions (1 atm, 25 °C) for comparison. The products, 3(a-i)-
C
3
12MPGN, were purified by washing with 95% ethanol and CH -
1
CN to remove excess nitrone. H NMR spectroscopy was used to
check the completion and purity of 3(a-i)-C12MPGNs. The
disappearance of the peak at 5.80 ppm, which was due to the
olefinic protons of the maleimide moiety, was used to determine
the completion of these reactions. In a few cases, the reactions were
also performed at higher concentrations (50 mg) of 2-C12MPGN.
General Procedure for the 1,3-Dipolar Cycloaddition Reac-
tions of N-Dodecylmaleimide (4) with Nitrones a-i at High
Pressure and Ambient Conditions. Typically, 10 mg of N-
dodecylmaleimide and 5 equiv of the nitrone (a-i), except for
In general, the 1,3-dipolar cycloaddition reactions of various
nitrones with 4 or 2-C12MPGNs take from hours to weeks at
ambient conditions. After applying a high pressure of 11 000
atm, all these reactions are greatly accelerated and complete
within 1 h, and for most cases, within 10 min. Importantly, TEM
analysis of particles before and after exposure to hyperbaric
conditions shows that, even after applying 11 000 atm on 2-C12-
MPGNs for 24 h, their core size is not affected (Supporting
Information). Thus the only effect of the high pressure is a
significant acceleration of the cycloaddition.
nitrone d, were dissolved in 2.0 mL of CD
2 2
Cl . Due to the poor
solubility of nitrone d in CD Cl , the ratio of N-dodecylmaleimide/d
2
2
used was 1:1.5. The mixture was separated into two portions. One
portion was purged with argon in a NMR tube and left to react
under ambient conditions (1 atm, 25 °C). The other portion was
transferred into a brass-clamp sealed PTFE tube under argon and
placed in the high-pressure reactor at 11 000 atm. The reactions
Conclusions
We demonstrate for the first time that by using hyperbaric
conditions we are able to introduce complex isoxazolidine
functionality at the interface of a nanoparticle via 1,3-dipolar
cycloaddition of a nitrone with an alkene. Such synthetic
transformations at ambient conditions on these particles are
impractical because they are so slow and proceed to poor
conversions. Of particular note is that the use of high-pressure
reaction conditions does not alter the integrity of the metal core
of the MPGN. Although the maleimide-tethered MPGN was
used as the dipolarophile for this proof of concept, in practice,
any suitably activated alkene-tethered MPGN and indeed
nitrone-modified MPGN could be used as the reaction template
for the preparation of isoxazolidine-modified MPGNs which
can be further elaborated synthetically by cleavage of the N-O
bond to yield gold-supported aminoalcohol moieties which in
turn could be further derivatized. This aspect to incorporate
synthetic diversity for the modification of MPGNs is currently
under investigation. Besides being a useful approach to acceler-
ate cycloaddition reactions in solution, our work illustrates that
hyperbaric chemistry is a useful tool to be exploited generally
for the efficient and rapid synthetic surface modification of
MPGNs (and perhaps other nanoparticles) using reactions that
are subject to such acceleration.
1
were monitored by H NMR spectroscopy. The product was then
separated by preparative TLC and characterized. Two diastereomers
were generated, and their conformations were confirmed by 1-D
NOESY. The exo/endo ratio was determined as 5:3 from the crude
1
H NMR spectra.
N-Dodecylmaleimide (4). Maleimide (4.00 g, 41.2 mmol) and
furan (4.20 g, 62.0 mmol) were dissolved in 30 mL of diethyl ether
in a sealed tube and heated to 90-100 °C for 12 h. The 3,6-endoxo-
4
∆
-tetrahydrophthalhide (furan-masked maleimide) precipitated as
a white solid after cooling the mixture to room temperature. The
product was then filtered and washed with 3 × 10 mL of cold
diethyl ether to remove the unreacted maleimide, giving rise to a
4
yield of 6.0 g (89%). The NMR spectrum of 3,6-endoxo-∆
-
tetrahydrophthalhide indicates that the product is exclusively the
exo isomer: 1H NMR (CDCl
, 600 MHz) δ 8.10 (br s, H), 6.52
d, J ) 0.782 Hz, 2H), 5.31 (d, J ) 0.782 Hz, 2H), 2.89 (s, 2H);
3
1
3
(
1
C NMR (CDCl
dropcast on NaCl plate, cm ) ν 3185, 3089, 3029, 2995, 1705,
356, 1258, 1189, 856, 822. MS (EI); m/z (%) 165.1(4.9), 138-
3.6), 121(2), 68(100); exact mass (C N) calcd 165.0426, found
65.0422. The 3,6-endoxo-∆ -tetrahydrophthalhide (6.0 g, 36.6
3
, 600 MHz) δ 175.9, 136.5, 80.9, 48.7; IR
-
1
(
1
(
1
8 7 3
H O
4
mmol) and 1-dibromododecane (26.6 mL, 146.4 mmol) were
dissolved in 70 mL of dry DMF. K CO (6.0 g, 43.9 mmol) was
2
3
added, and the mixture was heated to 50 °C for 3 h. The mixture
was then dissolved in 200 mL of diethyl ether and washed with
5
% HCl, followed by water to remove DMF. The organic layer
Experimental Section
was then dried with magnesium sulfate and evaporated to dryness.
The crude product was purified by liquid column chromatography
General. The compounds dodecanethiol, hydrogen tetrachloro-
aurate(III), tetraoctylammoniun bromide, 1,12-dibromododecane,
benzene-d , chloroform (CDCl ), and dichloromethane (CD Cl )
6 3 2 2
(10% EtOAc/hexane) to isolate the furan-protected dodecylmale-
imide (10.25 g, white crystal, 84% yield). This product was then
heated at reflux in 200 mL of toluene overnight to effect a retro-
Diels-Alder reaction. After removal of toluene, the crude product
was subjected to column chromatography (10% EtOAc/hexane) to
yield 6.69 g (81% yield) of N-dodecylmaleimide as a white
were used as received from suppliers. The high-pressure reactions
were carried out on a commercially available reactor at 11 000 atm
at room temperature. Proton NMR and 13C NMR spectra were
recorded on either a 600 or a 400 MHz spectrometer (as noted) in
deuterated chloroform, deuterated methylene chloride, or deuterated
benzene solutions and are reported in parts per million (ppm), with
the solvent resonance used as a reference. Compound 2-C12MPGN
was prepared using a protocol we previously reported.4 The
nitrones a-i used in this study were prepared following reported
1
crystalline solid: mp 57.7-58.2 °C; H NMR (CDCl , 400 MHz)
3
δ 6.67 (s, 2H), 3.50 (t, J ) 7.27 Hz, 2H), 1.56 (quintet, 2H), 1.1-
1.3 (br, 18H, a quintet at 1.26 ppm was merged with the broad
,9
(13) Ganton, M. D.; Kerr, M. A. J. Org. Chem. 2004, 69, 8554-8557
and reference therein.
J. Org. Chem, Vol. 73, No. 3, 2008 1103

Zhu et al.
peak), 0.87 (t, J ) 6.70 Hz, 3H); 13C NMR (CDCl
, 100 MHz) δ
3.02 (dd, J ) 9.0, 7.8 Hz, 1H), 1.28-1.10 (br, 20H), 0.91 (t, J )
3
1
2
2
70.8 (2C), 134.0 (2C), 37.9, 31.8, 29.6 (2C), 29.5, 29.4, 29.3, 29.1,
7.1 Hz, 3H); 13C NMR (400 MHz, C
6 6
D ) δ 173.8, 171.8, 160.1,
8.5, 26.7, 22.7, 14.1; IR (dropcast on NaCl, cm-1) ν 3078, 2919,
816, 1698, 1465, 1446, 1403, 1371, 1124, 692; MS (EI) exact
148.5, 129.2 (2C), 128.9 (2C), 127.1, 124.4, 119.1 (2C), 114.4 (2C),
77.0, 70.9, 54.68, 54.59, 39.0, 32.3, 30.08 (2C), 30.03, 29.89, 29.80,
-
1
mass (C16
Isoxazolidine 5a-exo: H NMR (C
H
27
O
2
N) calcd 265.2042, found 265.2046.
29.52, 28.0, 27.2, 23.1, 14.4; FT-IR (dropcast on NaCl, cm ) ν
1
6
6
D , 400 MHz) δ 7.35 (m,
2921, 2852, 1711, 1613, 1598, 1513, 1491, 1467, 1453, 1401, 1250,
2
1
2
H), 7.10 (m, 2H), 7.05-6.97 (m, 3H), 6.92 (m, 2H), 6.68 (m,
H), 5.42 (s, 1H), 4.29 (d, J ) 7.4 Hz, 1H), 3.14 (t, J ) 7.3 Hz,
H), 3.06 (d, J ) 7.4 Hz, 1H), 1.28-1.08 (br, 18H), 0.95-0.91
40 2 4
1173, 1072, 1033, 821, 759, 692; HRMS calcd m/z for C30H N O
492.2988, found 492.2996.
1
3c-C12MPGN: H NMR (C
6
D
6
, 600 MHz) δ 7.28, 7.10 (merge
13
(m, 3H, a quintet merge together with a triplet, J ) 7.0 Hz);
C
with solvent), 7.02, 6.74, 5.42, 4.38, 3.25, 1.38, 0.97.
Isoxazolidine 5d-exo: H NMR (C D , 400 MHz) δ 8.03 (m,
6 6
1
NMR (C
D
6 6
, 400 MHz) δ 174.5, 172.9, 148.8, 139.3, 128.9 (2C),
1
3
28.7 (2C), 126.8 (3C), 122.4, 114.6 (2C), 77.1, 69.8, 57.2, 39.1,
2.1, 29.8 (2C), 29.7, 29.5, 29.6, 29.3, 26.7, 26.8, 22.9, 14.1; FT-
1H), 7.24-7.22 (m, 2H), 7.04-7.02 (m, 3H), 6.90 (m, 1H), 6.81
(s, 1H), 6.76 (d, J ) 8.18 Hz, 2H), 5.84 (s, 1H), 4.39 (d, J ) 7.5
Hz, 1H), 3.37 (d, J ) 7.5 Hz, 1H), 3.18 (t, J ) 7.9 Hz, 3H), 1.98
-1
IR (dropcast on NaCl, cm ) ν 3069, 3036, 2924, 1734, 1480, 1457,
1
3
1163, 1024, 715; HRMS calcd m/z for C29
H N O
38 2 3
462.2882, found
(s, 3H), 1.29-0.98 (br, 20H), 0.92 (t, J ) 7.0 Hz, 3H); C NMR
(C , 400 MHz) δ 175.1, 173.8, 147.2, 136.9, 131.7, 129.8 (2C),
4
62.2895.
6 6
D
1
Isoxazolidine 5a-endo: H NMR (C
6
6
D , 400 MHz) δ 7.27 (m,
125.9, 122.7 (2C), 120.5, 119.1, 115.2 (2C), 114.1, 111.7, 77.6,
64.8, 56.4, 39.2, 32.3, 30.1 (2C), 30.0, 29.9, 29.8, 29.6, 27.1, 27.0,
2
9
3
7
1
7
2
2
4
H), 7.10-7.00 (m, 5H), 6.94 (m, 2H), 6.79 (m, 1H), 4.36 (d, J )
.1 Hz, 1H), 4.27 (d, J ) 7.8 Hz, 1H), 3.27 (t, J ) 7.9 Hz, 2H),
.0 (dd, J ) 7.8, 9.1 Hz, 1H), 1.28-1.08 (br, 18H), 0.91 (t, J )
-1
23.1, 20.5, 14.4; FT-IR (dropcast on NaCl, cm ) ν 3440 (br), 3091,
3072, 3036, 2925, 2854, 1960, 1713, 1616, 1507, 1465, 1248, 1036,
.0 Hz, 3H); 13C NMR (C
D
, 400 MHz) δ 173.4, 171.3, 148.0,
6
6
41 3 3
1018, 821, 749, 676; HRMS calcd m/z for C32H N O 515.3148,
35.2, 128.6 (2C), 128.5 (2C), 128.3, 124.2 (2C), 121.8, 118.8 (2C),
6.8, 70.9, 54.4, 38.8, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.2, 27.7,
found 515.3163.
Isoxazolidine 5d-endo: H NMR (C
1
6
D
6
, 400 MHz) δ 7.79 (m,
-
1
6.9, 22.9. 14.1; FT-IR (dropcast on NaCl, cm ) ν 3070, 3050,
1H), 7.23-7.17 (merged in the C
D
6 6
solvent peak, 2H), 7.13 (m,
926, 1713, 1479, 1265, 1031, 740; HRMS calcd m/z for C29
H
38
N
2
O
3
1H), 6.98 (m, 1H), 6.91 (s, 1H), 6.73-6.71 (m, 3H), 4.83 (d, J )
8.6 Hz, 1H), 4.40 (d, J ) 7.8 Hz, 1H), 3.37-3.28 (m, 2H), 3.15 (t,
J ) 8.6, 7.8 Hz, 1H), 1.91 (s, 3H), 1.29-1.08 (br, 20H), 0.92 (t, J
62.2882, found 462.2878.
1
3
a-C12MPGN: H NMR (C
6
6
D , 600 MHz) δ 7.38, 7.15-7.02
(merge with solvent), 6.78, 5.45, 4.37, 4.28, 3.19, 1.39, 0.98.
) 7.0 Hz, 3H); 13C NMR (C
6 6
D , 400 MHz) δ 174.2, 171.9, 145.9,
1
Isoxazolidine 5b-exo: H NMR (C
6
D
6
, 600 MHz) δ 7.80 (d, J
136.3, 133.9, 129.2 (2C), 126.4, 123.3, 122.4, 120.0 (2C), 119.8,
119.5, 111.4, 109.5, 76.8, 65.7, 53.8, 38.8, 32.1, 29.9 (2C), 29.8,
29.7, 29.6, 29.3, 27.6, 26.9, 22.9, 20.4, 14.1; FT-IR (dropcast on
)
8.7 Hz, 2H), 7.00 (d, J ) 8.7 Hz, 2H), 6.9 (m, 4H), 6.70 (m,
1
2
6
1
7
2
1
7
5
H), 5.23 (s, 1H), 4.16 (d, J ) 7.5 Hz, 1H), 3.15 (t, J ) 7.5 Hz,
-
1
H), 2.75 (d, J ) 7.5 Hz, 1H), 1.29-1.20 (br, 20H), 0.92 (t, J )
NaCl, cm ) ν 3442, 3104, 2954, 2918, 2850, 1706, 1617, 1457,
.9 Hz, 3H); 13C NMR (600 MHz, C
6
6
D ) δ 174.0, 172.7, 148.4,
41 3 3
1374, 1265, 1023, 1019, 742; HRMS calcd m/z for C32H N O
47.8, 145.5, 129.3 (2C), 127.5 (2C), 123.9 (2C), 123.2, 114.8 (2C),
7.1, 69.1, 56.9, 39.4, 32.3, 30.1, 30.0 (2C), 29.8, 29.7, 29.5, 27.1,
7.0, 23.1, 14.4; FT-IR (dropcast on NaCl, cm-1) ν 2917, 2850,
709, 1517, 1488, 1468, 1353, 1224, 1198, 1141, 1024, 838, 767,
515.3148, found 515.3157.
1
3d-C12MPGN: H NMR (CD
2
Cl
2
, 600 MHz) δ 7.38, 6.99, 6.87,
6.31, 6.24, 5.03, 3.95, 3.81, 3.46, 3.27, 2.24, 1.26, 0.88.
Isoxazolidine 5e-exo: H NMR (C D , 400 MHz) δ 6.99 (s, 1H),
6 6
1
51, 719, 700, 689, 614; HRMS calcd m/z for C29
H N
37 3
O
5
6.88 (d, J ) 8.1 Hz, 2H), 6.74 (d, J ) 8.1 Hz, 2H), 6.01 (s, 1H),
5.93 (s, 1H), 5.40 (s, 1H), 4.45 (d, J ) 7.4 Hz, 1H), 3.34 (d, J )
7.4 Hz, 1H), 3.21 (t, J ) 7.4 Hz, 2H), 1.96 (s, 3H), 1.26-1.08 (br,
07.2733, found 507.2729.
1
Isoxazolidine 5b-endo: H NMR (C
6 6
D , 600 MHz) δ 7.79 (d,
J ) 8.6 Hz, 2H), 7.04 (d, J ) 8.6 Hz, 2H), 6.99 (t, J ) 7.8 Hz,
H), 6.91 (dd, J ) 8.6, 7.8 Hz, 2H), 6.83 (t, J ) 7.8 Hz, 1H), 4.22
m, 2H), 3.20 (t, J ) 7.4 Hz, 2H), 2.89 (dd, J ) 7.8, 9.0 Hz, 1H),
.30-1.20 (br, 18H), 1.02 (quintet, 2H), 0.92 (t, J ) 7.0 Hz, 3H);
18H), 0.90 (t, J ) 6.7 Hz, 3H); 13C NMR (C
6 6
D , 400 MHz) δ
2
(
1
174.5, 173.4, 151.2, 145.6, 142.6, 132.3, 129.6(2C), 115.9(2C),
110.7, 108.7, 76.8, 64.4, 53.9, 39.2, 32.3, 30.1 (2C), 30.0, 29.9,
29.8, 29.5, 27.3, 27.0, 23.1, 20.5, 14.4; FT-IR (dropcast on NaCl,
1
3
-1
C NMR (400 MHz, C
6
D
6
) δ 173.0, 171.2, 148.1, 147.3, 141.9,
cm ) ν 2924.41,2854.04, 1713.59, 1616.98, 1507.08, 1465.21,
1
5
1
1
7
5
29.1 (2C), 128.6 (2C), 125.1, 123.8 (2C), 119.1 (2C), 77.0, 69.9,
4.4, 39.1, 32.3, 30.1 (2C), 30.0, 29.9, 29.8, 29.4, 27.9, 27.0, 23.1,
4.3; FT-IR (dropcast on NaCl, cm ) ν 2919, 2851, 1710, 1594,
522, 1489, 1466, 1454, 1350, 1259, 1094, 1071, 868, 853, 767,
52, 722, 693; HRMS calcd m/z for C29H N O 507.2733, found
37 3 5
07.2729.
1399.94, 1345.94, 1149.64, 1016.79, 741.33; HRMS calcd m/z for
28 38 2 4
C H N O 466.2832, found 466.2839.
-
1
1
6 6
Isoxazolidine 5e-endo: H NMR (C D , 400 MHz) δ 7.08 (dd,
J ) 1.8, 0.8 Hz, 1H), 6.99 (d, J ) 8.5 Hz, 2H), 6.80 (d, J ) 8.5
Hz, 2H), 6.08 (d, J ) 3.25 Hz, 1H), 5.97 (dd, J ) 3.25, 1.8 Hz,
1H), 4.34 (d, J ) 8.6 Hz, 1H), 4.22 (d, J ) 7.6 Hz, 1H), 3.45 (t,
J ) 7.4 Hz, 2H), 2.99 (dd, J ) 8.6, 7.6 Hz, 1H), 1.96 (s, 3H), 1.56
1
3
b-C12MPGN: H NMR (C
6
6
D , 600 MHz) δ 7.84, 7.05-7.02
1
3
(merge with solvent), 6.79, 5.28, 4.25, 3.32, 3.22, 1.38, 0.97.
(quintet, 2H), 1.27-1.23 (br, 18H), 0.91 (t, J ) 7.0 Hz, 3H);
C
1
Isoxazolidine 5c-exo: H NMR (C
8.6 Hz, 2H), 7.02 (d, J ) 8.6 Hz, 2H), 6.94 (t, J ) 7.3 Hz, 2H),
6
6
D , 600 MHz) δ 7.24 (d, J
NMR (C , 400 MHz) δ 143.0, 134.0, 129.5 (2C), 119.9 (2C),
6 6
D
)
110.8, 110.3, 76.6, 66.7, 52.8, 39.2, 32.3, 30.1, 30.07, 30.03, 29.97,
29.81, 29.58, 28.0, 27.1, 23.1, 20.7, 14.4. Two carbonyl carbon
signal were not observed. However, the presence of the carbonyl
group was verified by the strong carbonyl absorption peaks from
6
4
3
0
1
.73 (d, J ) 8.6 Hz, 2H), 6.69 (t, J ) 7.3 Hz, 1H), 5.39 (s, 1H),
.32 (d, J ) 7.4 Hz, 1H), 3.24 (s, 3H), 3.20 (t, J ) 7.3 Hz, 2H),
.08 (d, J ) 7.4 Hz, 1H), 1.29-1.02 (br, 18H), 1.02 (quintet, 2H),
.92 (t, J ) 7.1 Hz, 3H); 13C NMR (600 MHz, C
-1
6
D ) δ 174.8,
FT-IR spectra: FT-IR (dropcast on NaCl, cm ) ν 2917, 2903,
6
73.2, 159.7, 148.9, 131.2, 129.1 (2C), 128.4 (2C), 122.6, 115.2
2849, 1918, 1844, 1700, 1506, 1457, 1275, 1267, 1261, 1124, 764,
(
2
2C), 114.4 (2C), 77.2, 69.8, 57.5, 54.8, 39.3, 32.3, 30.10, 30.08,
38 2 4
749, 668; HRMS calcd m/z for C28H N O 466.2832, found
9.99, 29.86, 29.00, 29.5, 27.2, 27.0, 23.1, 14.4; FT-IR (dropcast
466.2825.
3e-C12MPGN: H NMR (C
-1
1
on NaCl, cm ) ν 2925, 2854, 1710, 1597, 1514, 1492, 1463, 1400,
1
HRMS calcd m/z for C30
D
6 6
, 600 MHz) δ 7.02 (merge with
371, 1347, 1305, 1251, 1160, 1033, 832, 803, 755, 693, 621;
solvent), 6.91, 6.82, 6.05, 5.93, 5.43, 4.36, 3.48, 3.30, 1.38, 0.98.
1
H
40
1
N
2
O
4
492.2988, found 492.3002.
, 600 MHz) δ 7.21 (d, J
Isoxazolidine 5f: H NMR (C D , 400 MHz) δ 7.0 (d, J ) 8.5
6
6
Isoxazolidine 5c-endo: H NMR (C
6
D
6
Hz, 2H), 6.74 (d, J ) 8.5 Hz, 2H), 4.05 (d, J ) 7.3 Hz, 1H), 3.91
(d, J ) 13.2 Hz, 1H), 3.49 (d, J ) 13.2 Hz, 1H), 3.42 (t, J ) 7.2
Hz, 2H), 3.26 (s, 3H), 3.16 (d, J ) 8.6 Hz, 1H), 2.57 (t, J ) 7.3
Hz, 1H), 2.06 (br, 1H), 1.585 (quintet, 2H), 1.26-1.20 (br, 18H),
)
8.7 Hz, 2H), 7.10 (d, J ) 8.7 Hz, 2H), 6.98 (t, J ) 7.4 Hz, 2H),
.80 (t, J ) 7.4 Hz, 1H), 6.71 (d, J ) 8.7 Hz, 2H), 4.38 (d, J ) 9.0
Hz, 1H), 4.29 (d, J ) 7.8 Hz, 1H), 3.32 (m, 2H), 3.20 (s, 3H),
6
1104 J. Org. Chem., Vol. 73, No. 3, 2008

Hyperbaric Synthesis of Isoxazolidine-Tethered MPGNs
0
1
4
2
1
1
.91 (t, J ) 6.9 Hz, 3H); 13C NMR (400 MHz, C
6
D
6
) δ 175.8,
Hz, 1H), 3.54-3.34 (t, a doublet at 3.54, J ) 15.4 Hz, 1H, merged
with another doublet 3.52, J ) 8.5 Hz, 1H), 3.34 (t, J ) 7.7 Hz,
59.7, 130.2 (2C), 128.1, 127.9, 114.1 (2C), 75.9, 60.5, 57.7, 54.7,
8.4, 38.9, 32.3, 30.10, 30.08, 30.06, 29.96, 29.80, 29.55, 27.93,
6.99, 23.1, 14.3; FT-IR (dropcast on NaCl, cm-1) ν 2925, 2854,
785, 1709, 1685, 1613, 1514, 1465, 1457, 1438, 1400, 1368,
349.33, 1303, 1248, 1174, 1036, 860, 822, 803, 668, 627; HRMS
2H), 2.74 (dd, J ) 7.4, 8.5 Hz, 1H), 1.24 (br, 20H), 0.88 (t, J )
13
6.9 Hz, 3H); C NMR (400 MHz, C
6
6
D ) δ 174.5, 172.2, 136.4,
134.6, 128.87 (4C), 128.77, 128.42 (2C), 127.90 (2C), 127.48, 76.4,
74.2, 58.3, 53.8, 38.9, 32.3, 30.1, 30.1, 30.0, 29.98, 29.81, 29.59,
-
1
calcd m/z for C25
H
38
N
2
O
4
430.2832, found 430.2836.
28.2, 27.3, 23.1, 14.4; FT-IR (dropcast on NaCl, cm ) ν 2926,
1
3
f-C12MPGN: H NMR (C , 600 MHz) δ 7.06 (merge with
D
6 6
2855, 1714, 1499, 1956, 1437, 1399, 1373, 1347, 1261, 1162, 1082,
solvent), 6.76, 3.90, 3.50, 3.36, 3.16, 2.60, 2.17, 1.39, 0.97.
40 2 3
1030, 870, 756, 732, 698; HRMS calcd m/z for C30H N O
1
Isoxazolidine 5g-exo: H NMR was collected at 70 °C (600
476.3039, found 476.3038.
1
MHz, C
6 6
D ) δ 7.12-7.10 (m, 4H), 7.08 (m, 1H), 4.34 (d, J ) 7.3
3h-C MPGN: H NMR (C D , 600 MHz) δ 7.26-7.00 (merge
1
2
6
6
Hz, 1H), 3.95 (br, 1H), 3.46 (t, J ) 7.3 Hz, 2H), 3.03 (dd, J ) 7.3,
with solvent), 4.45, 4.30, 3.97, 3.74, 3.58-3.34, 3.03, 1.39, 0.97.
Isoxazolidine 5i-exo: H NMR was collected at 70 °C (C D ,
1
3
0
.3 Hz, 1H), 2.26 (s, 3H), 1.61 (quintet, 2H), 1.28-1.25 (br, 18H),
6
6
1
.89 (t, J ) 7.0 Hz, 3H). H NMR in C
D
6 6
was also provided here
600 MHz) δ 6.71 (br, 1H), 6.56 (d, J ) 7.8 Hz, 1H), 6.62 (d, J )
7.8 Hz, 1H), 5.37 (d, J ) 1.3 Hz, 1H), 5.34 (d, J ) 1.3 Hz, 1H),
4.29 (d, J ) 7.2 Hz, 1H), 3.84 (br, 1H), 3.45 (t, J ) 7.3 Hz, 2H),
2.99 (dd, J ) 7.2, 4.0 Hz, 1H), 2.27 (s, 3H), 1.61 (quintet, 2H),
for comparison. One key proton was missing and the other peaks
1
were generally broad: H NMR (600 MHz, C
6
D
6
) δ 7.10-7.08
(br, 4H), 4.27 (br, 1H), 3.46 (br, 2H), 2.95 (dd, J ) 7.3, 3.6 Hz,
1
1H), 2.20 (br, 3H), 1.6 (br, 2H), 1.27-1.22 (br, 18H), 0.90 (t, J )
.3 Hz, 3H); 13C NMR (400 MHz, C
7 ) δ 175.2, 175.1, 128.8,
128.5 (2C), 128.1, 127.9, 76.3 (2C), 57.5 (br), 39.0, 32.3, 30.08
1.28-1.25 (br, 18H), 0.90 (t, J ) 7.0 Hz, 3H). For comparison, H
1
6
D
6
NMR data at room temperature 25 °C are also provided here:
H
NMR (C D , 600 MHz) δ 6.56 (d, J ) 7.8 Hz, 1H), 5.31 (d, J )
6
6
(2C), 29.99, 29.92, 29.8, 29.5, 27.9, 27.0, 23.1, 14.3, one carbon
1.3 Hz, 1H), 5.27 (d, J ) 1.3 Hz, 1H), 4.20 (br, 1H), 3.45 (br,
2H), 2.90 (dd, J ) 7.3, 3.6 Hz, 1H), 2.22 (br, 3H), 1.60 (br, 2H),
of the isoxazoline was too weak to be observed; FT-IR (dropcast
-1
13
on NaCl, cm ) ν 3091, 3072, 3037, 2953, 2854, 1717, 1465, 1036,
74; HRMS calcd m/z for C24 400.2725, found 400.2714.
Isoxazolidine 5g-endo: 1H NMR (C
, 400 MHz) δ 7.13
merged in the solvent peak, 2H), 7.09 (m, 3H), 4.10 (d, J ) 7.4
1.28-1.22 (br, 18H), 0.90 (t, J ) 7.0 Hz, 3H); C NMR (600
6
H
36
N O
2 3
MHz, C D ) δ 175.15, 175.10, 148.50, 148.17, 122.4, 108.4 (br,
6
6
6 6
D
2C), 101.22 (2C), 76.1 (br, 2C), 57.3 (br, 2C), 39.0, 32.3, 30.1
(2C), 29.99, 29.92, 29.80, 29.48, 27.94, 27.03, 23.1, 14.4; FT-IR
(
-
1
Hz, 1H), 3.38 (t, J ) 7.3 Hz, 2H), 3.24 (d, J ) 8.6 Hz, 1H), 2.83
(dropcast on NaCl, cm ) ν 2925, 2854, 1711, 1505, 1491, 1445,
1400, 1370, 1348, 1251, 1191, 1099, 1039, 932, 840, 810, 788,
718, 668, 606, 562; HRMS calcd m/z for C H N O 444.2624,
(
(
dd, J ) 8.6, 7.4 Hz, 1H), 2.34 (s, 3H), 1.55 (m, 2H), 1.27-1.21
br, 18H), 0.91 (t, J ) 7.0 Hz, 3H); 13C NMR (400 MHz, C
) δ
74.6, 172.3, 134.6, 128.7 (2C), 128.1 (2C), 127.9, 76.4, 75.5, 54.4,
6 6
D
25
36
2
5
1
4
1
2
4
found 444.2615
Isoxazolidine 5i-endo: H NMR (C D , 600 MHz) δ 6.71 (d, J
1
2.4, 39.0, 32.3, 30.1, 30.0 (2C), 29.9, 29.7, 29.5, 28.2, 27.2, 23.1,
6
6
4.3; FT-IR (dropcast on NaCl, cm-1) ν 3091, 3071, 3058, 2953,
) 1.6 Hz, 1H), 6.65 (dd, J ) 1.6, 7.9 Hz, 1H), 6.54 (d, J ) 1.6,
7.9 Hz, 1H), 5.21 (2d, J ) 4.8 Hz, 2H), 4.06 (d, J ) 7.4 Hz, 1H),
3.39 (t, J ) 7.3 Hz, 2H), 3.14 (d, J ) 8.6 Hz, 1H), 2.76 (dd, J )
7.4, 8.6 Hz, 1H), 2.35 (s, 3H), 1.59 (quintet, 2H), 1.27 (br, 18H),
0.91 (t, J ) 6.9 Hz, 3H); 13C NMR (400 MHz, C D ) δ 174.6,
36 2 3
850, 1714, 1465, 1437, 1036, 673; HRMS calcd m/z for C24H N O
00.2725, found 400.2710.
1
3
g-C12MPGN: H NMR (C
6 6
D , 600 MHz) δ 7.15-7.02 (merge
with solvent), 4.32, 3.49, 3.02, 2.23, 1.40, 0.99.
6
6
1
Isoxazolidine 5h-exo: H NMR was collected at 70 °C (C
6 6
D ,
172.4, 148.5, 148.3, 121.7, 114.1, 108.5, 108.3, 101.2, 76.4, 75.3,
54.4, 42.3, 39.0, 32.3, 30.10, 30.08, 30.03, 29.92, 29.80, 29.54,
6
7
4
1
1
3
00 MHz) δ 7.16-7.09 (merged with solvent peak), 7.12 (m, 1H)
-
1
.09 (m, 2H), 7.03 (t, J ) 7.2 Hz, 1H), 4.31 (d, J ) 7.3 Hz, 1H),
.21 (d, J ) 3.4 Hz, 1H), 3.77 (d, J ) 14.3 Hz, 1H), 3.58 (d, J )
4.3 Hz, 1H), 3.47 (t, J ) 7.3 Hz, 2H), 3.02 (dd, J ) 7.3, 3.4 Hz,
H), 1.63 (quintet, 2H), 1.29-1.27 (br, 18H), 0.90 (t, J ) 7.0 Hz,
28.3, 27.3, 23.1, 14.4; FT-IR (dropcast on NaCl, cm ) ν 2924,
2854, 1710, 1505, 1489, 1465, 1445, 1369, 1348, 1251, 1173, 1099,
1038, 934, 861, 811, 718, 627; HRMS calcd m/z for C H N O
2
5
36
2
5
444.2624, found 444.2619.
1
H). For comparison, H NMR data at room temperature are also
1
3
6 6
i-C12MPGN: H NMR (C D , 600 MHz) δ 6.69, 6.56, 5.33,
1
provided here: H NMR (C
with solvent peak), 7.10 (m, 5H), 7.03 (t, J ) 7.3 Hz, 1H), 4.23
6 6
D , 600 MHz) δ 7.16-7.12 (merged
4
.27, 3.51, 3.14, 2.40, 2.25, 1.39, 0.98.
(
br, 1H), 3.73 (d, J ) 14.4 Hz, 1H), 3.50-3.47 (a doublet at 3.50,
Acknowledgment. We thank The Natural Science and
Engineering Research Council (NSERC) of Canada and The
University of Western Ontario for support of this work.
1
J ) 14.4 Hz, H merged together with a triplet, J ) 6.4 Hz, 2H),
2
0
.93 (dd, J ) 7.3, 3.4 Hz, 1H), 1.63 (br, 2H), 1.28-1.25 (br, 18H),
.91 (t, J ) 7.1 Hz, 3H); 13C NMR (600 MHz, C
D
6
) δ 175.1
6
(
1
(
2C), 137.3, 136.9, 128.9 (2C), 128.7 (2C), 128.5 (2C), 128.4 (2C),
27.9, 127.5, 76.2, 71.7 (br), 57.1 (br, 2C), 39.1, 32.3, 30.10, 30.08
2C), 30.05, 29.9, 29.6, 27.9, 27.1, 23.1, 14.4; FT-IR (dropcast on
Supporting Information Available: General experimental
details, details of the synthesis and characterization of C12MPGN,
1
1
-C12MPGN and 2-C12MPGN and 4, H NMR spectra of C12
-
-
1
NaCl, cm ) ν 2926, 2854, 1711, 1496, 1455, 1438, 1399, 1366,
156, 1069, 1044, 850, 760, 745, 730, 698, 626; HRMS calcd m/z
for C30 476.3039, found 476.3043.
Isoxazolidine 5h-endo: H NMR (C
J ) 7.6 Hz, 2H), 7.14-7.10 (merged in the solvent peak, 6H),
.05-7.00 (m, 2H), 4.01 (d, J ) 7.4 Hz, 1H), 3.93 (d, J ) 15.4
1
MPGN, 1-C12MPGN and 2-C12MPGN, 3(a-i)-C12MPGN and H
and 13C NMR spectra 5(a-i). Other characterization details such
as TEM. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
40 2 3
H N O
1
6 6
D , 600 MHz) δ 7.28 (d,
7
JO702398R
J. Org. Chem, Vol. 73, No. 3, 2008 1105