Monoprotection of diols as a key step for the selective synthesis of unequally disubstituted diamondoids (Nanodiamonds)

Article abstract of DOI:10.1021/jo801321s

(Chemical Equation Presented) The monoprotection (desymmetrization) of diamondoid, benzylic, and ethynyl diols has been achieved using fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) under acidic conditions. This practical acid-catalyzed S_NI reaction opens the door for the synthesis of novel bifunctional diamondoids. With diamantane as an example, we show that the resulting monoethers can be used to prepare selectively, for instance, amino or nitro alcohols and unnatural amino acids. These are important compounds in terms of the exploration of electronic, pharmacological, and material properties of functionalized nanodiamonds.

Full text of DOI:10.1021/jo801321s

Monoprotection of Diols as a Key Step for the
Selective Synthesis of Unequally Disubstituted
Diamondoids (Nanodiamonds)†
Hartmut Schwertfeger,‡ Christian Würtele,§ Michael Serafin,§
Heike Hausmann,‡ Robert M. K. Carlson,|
Jeremy E. P. Dahl,| and Peter R. Schreiner*,‡
Institut fu¨r Organische Chemie and Institut fu¨r Anorganische
und Analytische Chemie, Justus-Liebig-UniVersita¨t,
Heinrich-Buff-Ring 58, 35392 Giessen, Germany, and
MolecularDiamond Technologies, CheVron Technology
Ventures, 100 CheVron Way, Richmond, California 94802
FIGURE 1. Examples of diamondoids: adamantane (1), diamantane
(2), triamantane (3), [121]tetramantane (4), (M)-[123]tetramantane (4a),
and [1(2,3)4]pentamantane (5).
[1(2,3)4]pentamantane (5).3-5 The synthesis of thiol derivatives6
led to the preparation of diamondoid-SAMs, which display
negative electron affinity (NEA) upon irradiation with X-rays.7
Since the selective mono- and also the difunctionalization of
diamondoids with equal substituents is now a straightforward
task, we attempted to synthesize nanodiamonds with two
different substituents. These building blocks would make the
use of diamondoids even more interesting (e.g., to control and
tune the NEA effect7 or for the preparation of polymers). In
our recent review,2 we showed that besides 1 the derivatization
of diamondoids having two different substituents at their tertiary
positions has only been achieved for 2. Burkhard, Janku, and
Vodicka studied brominations of diamantanecarboxylic acids
and their hydrolysis to hydroxy carboxylic acids.8 Although the
bromination route via the carboxylic acids leads to unequally
disubstituted diamantane derivatives, these reactions either have
low yields or the mixtures are hard to separate even with
advanced HPLC techniques.9 Recently, Padmanaban et al.
treated diamantane-4,9-diol (6, Scheme 1) with equimolar
amounts of reagent to obtain 4-hydroxy-9-diamantylmethacry-
late, but this reaction proceeded in only 5% yield.10
prs@org.chemie.uni-giessen.de
ReceiVed June 30, 2008
The monoprotection (desymmetrization) of diamondoid,
benzylic, and ethynyl diols has been achieved using fluori-
nated alcohols such as 2,2,2-trifluoroethanol (TFE) under
acidic conditions. This practical acid-catalyzed SN1 reaction
opens the door for the synthesis of novel bifunctional
diamondoids. With diamantane as an example, we show that
the resulting monoethers can be used to prepare selectively,
for instance, amino or nitro alcohols and unnatural amino
acids. These are important compounds in terms of the
exploration of electronic, pharmacological, and material
properties of functionalized nanodiamonds.
Since it is possible to prepare the bisapical diol 6 in high
yield directly from 2 using 100% nitric acid,5 this linear
(3) Fokin, A. A.; Tkachenko, B. A.; Gunchenko, P. A.; Gusev, D. V.;
Schreiner, P. R. Chem.sEur. J. 2005, 11, 7091–7101.
(4) (a) Schreiner, P. R.; Fokina, N. A.; Tkachenko, B. A.; Hausmann, H.;
Serafin, M.; Dahl, J. E. P.; Liu, S.; Carlson, R. M. K.; Fokin, A. A. J. Org.
Chem. 2006, 71, 6709–6720. (b) Fokin, A. A.; Schreiner, P. R.; Fokina, N. A.;
Tkachenko, B. A.; Hausmann, H.; Serafin, M.; Dahl, J. E. P.; Liu, S.; Carlson,
R. M. K. J. Org. Chem. 2006, 71, 8532–8540. (c) Fokin, A. A.; Butova, E. D.;
Chernish, L. V.; Fokina, N. A.; Dahl, J. E. P.; Carlson, R. M. K.; Schreiner,
P. R. Org. Lett. 2007, 9, 2541–2544.
(5) Fokina, N. A.; Tkachenko, B. A.; Merz, A.; Serafin, M.; Dahl, J. E. P.;
Carlson, R. M. K.; Fokin, A. A.; Schreiner, P. R. Eur. J. Org. Chem. 2007,
4738–4745.
The naturally occurring1 class of so-called diamondoids has
received considerable attention during the past few years.2 These
nanometer-sized diamond-like molecules (nanodiamonds) pos-
sess a variety of different shapes (e.g., stick or pyramidal), and
some of them are even chiral (Figure 1). Recently, our group
was able to synthesize not only derivatives of diamantane
(2), but also of triamantane (3), [121]tetramantane (4), and
(6) Tkachenko, B. A.; Fokina, N. A.; Chernish, L. V.; Dahl, J. E. P.; Liu,
S.; Carlson, R. M. K.; Fokin, A. A.; Schreiner, P. R. Org. Lett. 2006, 8, 1767–
1770.
(7) Yang, W. L.; Fabbri, J. D.; Willey, T. M.; Lee, J. R. I.; Dahl, J. E. P.;
Carlson, R. M. K.; Schreiner, P. R.; Fokin, A. A.; Tkachenko, B. A.; Fokina,
N. A.; Meevasana, W.; Mannella, N.; Tanaka, K.; Zhou, X. J.; van Buuren, T.;
Kelly, M. A.; Hussain, Z.; Melosh, N. A.; Shen, Z.-X. Science 2007, 316, 1460–
1462.
† Functionalized Nanodiamonds. 10. For part 9, see: Willey, T. M.; Fabbri,
J. D.; Lee, J. R. I.; Schreiner, P. R.; Fokin, A. A.; Tkachenko, B. A.; Fokina,
N. A.; Dahl, J. E. P.; Carlson, R. M. K.; Vance, A. L.; Yang, W.; Terminello,
L. J.; van Buuren, T.; Melosh, N. A. J. Am. Chem. Soc. 2008, 130, 10536-10544.
‡ Institut fu¨r Organische Chemie, Justus-Liebig-Universita¨t.
(8) (a) Burkhard, J.; Janku, J.; Vodicka, L. Sb. Vys. Sk. Chem. Techn. 1983,
D47, 73–99. (b) Janku, J.; Burkhard, J.; Vodicka, L. Sb. Vys. Sk. Chem. Techn.
1984, D49, 25–38. (c) Vodicka, L.; Janku, J.; Burkhard, J. Collect. Czech. Chem.
Commun. 1983, 48, 1162–1172.
§ Institut fu¨r Anorganische und Analytische Chemie, Justus-Liebig-Universita¨t.
| MolecularDiamond Technologies.
(1) (a) Landa, S.; Machacek, V. Collect. CzechosloV. Chem. Commun. 1933,
5, 1–5. (b) Hala, S.; Landa, S.; Hanus, V. Angew. Chem., Int. Ed. 1966, 5, 1045–
1046. (c) Dahl, J. E. P.; Liu, S.; Carlson, R. M. K. Science 2003, 299, 96–99.
(2) Schwertfeger, H.; Fokin, A. A.; Schreiner, P. R. Angew. Chem., Int. Ed.
2008, 47, 1022–1036.
(9) Schwertfeger, H. Diploma thesis, 2006.
(10) Padmanaban, M.; Chakrapani, S.; Lin, G.; Kudo, T.; Parthasarathy, D.;
Anyadiegwu, C.; Antonio, C.; Dammel, R.; Liu, S.; Lam, F.; Maehara, T.;
Iwasaki, F.; Yamaguchi, M. J. Photopol. Sci. Technol. 2007, 20, 719–728.
10.1021/jo801321s CCC: $40.75
Published on Web 08/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7789–7792 7789

TABLE 1. Yields, Temperatures, Times, and Selectivities for the
Preparation of Fluorinated Monoethers Using TFE (HFIP for Entry 8)
and Triflic Acid (3-37 mol %)a
SCHEME 1. Monoprotection of Diamantane-4,9-diol (6,
Crystal Structure Depicted), Using TFE and Catalytic
Amounts of Triflic Acid Followed by Neutralization Using
Triethylamine
dialcohol is a readily accessible precursor for the monoprotec-
tion. Even though there are many strategies for the monopro-
tection of diols, such reactions often require uncommon reagents,
polymers, and/or dry solvents.11 With regard to a suitable
solvent, we first had to overcome the problem of solubility of
the diamondoid diols. We found that 2,2,2-trifluoroethanol (TFE)
is not only a good solvent in comparison to nonfluorinated
simple alcohols but also exhibits its power as an excellent
nucleophile upon addition of catalytic amounts of a non-
nucleophilic acid such as triflic acid (Scheme 1). Therefore, we
were able to isolate 9-(2,2,2-trifluoroethoxy)-diamantan-4-ol (7)
in good yield (the crystal structure of 7 is available in the
Supporting Information).
Fluorinated alcohols have long been known for their unique
properties as solvents or cosolvents and can also be used in a
whole variety of reaction types such as epoxidations, cycload-
ditions, metathesis, reductions, ring openings, and isomerization
reactions,12 but we found that they have not been used for the
monoprotection of diols.
Encouraged by the results for the monoprotection of model
compound 6, we also examined other symmetrical diols for this
reaction. Table 1 shows that this reaction is not only applicable
to 6 but to all known symmetrical diamondoid diols. Further-
more, it can be applied to aromatic and ethynyl diols that
stabilize the incipient tertiary cation in this SN1 reaction. Other
fluorinated alcohols, which are, however, more expensive, can
also be used as shown for 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP), and they react with these diols in the same manner (entry
8, Table 1). Table 1 also shows that these results are in line
with our earlier observations and computations regarding the
reactivity of diamondoids.3 Higher diamondoids are more
reactive (decrease of reaction time and temperature) as compared
to their smaller analogues. Also, the medial positions of 2 (and
hence its corresponding diol) are more reactive than the apical
ones.
The advantage of this protocol is the low boiling points of
fluorinated alcohols in comparison to their nonfluorinated
analogues. Thus, the reaction can be stopped by the addition of
Et3N and the solvent can easily be evaporated (and recycled),
leaving the crude product behind. For the optimal quenching
times and temperatures the reactions were monitored by GC/
MS analysis. Preference for the monoether product is likely due
a All yields are preparative, and compounds are fully characterized.
For entries 1, 6, and 7, only traces of the corresponding diethers were
obtained.
(11) (a) Licence, P.; Gray, W. K.; Sokolova, M.; Poliakoff, M. J. Am. Chem.
Soc. 2005, 127, 293–298. (b) Ogawa, H.; Ichimura, Y.; Chihara, T.; Teratani,
S.; Taya, K. Bull. Chem. Soc. Jpn. 1986, 59, 2481–2483. (c) Wu, X.; Schmidt,
R. R. J. Org. Chem. 2004, 69, 1853–1857. (d) Zheng, Q.-H.; Liu, X.; Fei, X.;
Wang, J.-Q.; Ohannesian, D. W.; Erickson, L. C.; Stone, K. L.; Martinez, T. D.;
Miller, K. D.; Hutchins, G. D. J. Labelled Compd. Radiopharm. 2002, 45, 1239–
1252. (e) Phillips, D. J.; Pillinger, K. S.; Li, W.; Taylor, A. E.; Graham, A. E.
Tetrahedron 2007, 63, 10528–10533.
to the destabilization of the intermediate carbenium ion through
the trifluoroethyl group. Alternatively, the reaction can be
quenched with water, and the crude product can be extracted
with chloroform; this method requires more time and produces
slightly lower yields.
To emphasize the practicality of the synthesized monoethers,
we derivatized 7 to prepare an amino alcohol and an amino
(12) (a) Begue, J.-P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 18–29.
(b) Shuklov, I. A.; Dubrovina, N. V.; Bo¨rner, A. Synthesis 2007, 2925–2943.
7790 J. Org. Chem. Vol. 73, No. 19, 2008

SCHEME 2. Ritter Reaction of Monoether 7 with
function but also with an electron-withdrawing group. The
easiest way to reach this goal was to oxidize 24 to a nitro
alcohol. For this process, we followed a protocol by Gilbert et
al.15 and used m-CPBA in 1,2-dichloroethane to obtain the nitro
alcohol 25 in high yield (Scheme 2).
Chloroacetonitrile Followed by Either Conversion of the
Ether into the Corresponding Amino Ether or into Its Estera
The amino alcohol 24 is not only a suitable precursor for
nitro derivatives but is also ideal for the preparation of amino
acids. We found that the Koch-Haaf reaction in oleum with
HCOOH gave the corresponding amino acid as the sulfate salt.
Unfortunately, this product is insoluble in organic solvents and
not pure. A better way to the amino acid is to prepare the methyl
ester of the crude sulfate salt and to hydrolyze subsequently in
concd hydrochloric acid (Scheme 2). Since the hydrochloride
of the amino acid (28) is poorly soluble in aqueous HCl, we
were able to grow crystals for structural proof by slowly cooling
the reaction mixture (see the Supporting Information). It is very
likely that this reaction sequence is also amenable to the other
diols.
In conclusion, we have reported the first application of
fluorinated alcohols for the monoprotection of various diamon-
doid as well as aromatic and ethynyl diols. The procedure
employs only commodity chemicals and requires no special
equipment. Using diamantane as a model, we showed that
fluorinated diamondoid monoethers can be converted into
unequally disubstituted derivatives such as amino- or nitro
alcohols and even unnatural amino acids. No isomerization
reactions were observed in these transformations.
a The ester can be hydrolyzed into the amino alcohol from which the
amino acid is prepared.
Experimental Section
acid. However, we ran into the problem that all known
procedures for the preparation of diamondoid amines either have
low yields, use explosive azides, or employ the alkaline/acidic
hydrolysis of acetamides, which is also low yielding.13 Inspired
by the work of Jirgensons et al.,14 we attempted to prepare
amines via Ritter reaction using chloroacetonitrile. With this
approach, we were able to isolate the desired 2-chloro-N-[9-
(2,2,2-trifluoroethoxy)diamant-4-yl]acetamide (22) in 45% yield.
Structural proof of this compound was obtained from an X-ray
measurement (Supporting Information). Along with this desired
product, we isolated three other unequally disubstituted deriva-
tives of 2 as side products (see the Supporting Information).
Since the conversion of the chloroacetamide into an amine
is straightforward by using thiourea in acidic media,14 we first
turned our attention to converting the ether part back into an
alcohol function. We attempted to synthesize the amino alcohol
24 in one step by using Jirgensons’ protocol with acetic or
trifluoroacetic acid, trying to convert the ether into a base labile
ester, but this resulted in the preparation of the amino ether 26
(Scheme 2). Apparently, the use of thiourea with acetic or
trifluoroacetic acid suppresses the conversion of the ether
function into an ester. We bypassed the problem of the stable
ether function by refluxing 22 with trifluoroacetic acid and
obtained the corresponding trifluoroacetoxy ester 23 in high
yield (Scheme 2). The following transformation of 23 into the
amino alcohol 24 was achieved following a modified protocol
by Jirgensons et al.14 At this stage, we also attempted not only
to prepare a diamondoid alcohol with an electron-donating
General Procedure for the Preparation of Fluorinated
Monoethers. As a representative procedure, diamantan-4,9-diol (6)
(2.5 mmol, 551 mg), which was prepared according to the literature
procedure5 and recrystallized from methanol, was dissolved in 100
mL of TFE and heated to 40 °C. After the addition of 50 µL of
triflic acid, the clear solution was stirred for 4 h at the same
temperature. Thereafter, the reaction mixture was quenched with
100 µL of Et3N and the solvent was completely evaporated. Column
chromatography on silica gel (ethylacetate/hexane 8:2) gave 426.3
mg (56%) of the pure, colorless monoether 7 (Rf 0.36): mp 149
°C; IR (KBr) 3278, 2925, 2904, 2889, 2855, 1445, 1418, 1350,
1301, 1278, 1146, 1104, 1008, 962, 836, 663 cm-1; 1H NMR (400
MHz, CDCl3) δ 3.79 (2H, q, J ) 8.8 Hz), 2.01-1.90 (6H, m),
1.83-1.72 (12H, m), 1.33 (1H, OH, br s); 13C NMR (100 MHz,
CDCl3) δ 124.3 (q, J ) 277.7 Hz), 73.1, 67.1, 59.3 (q, J ) 35.2
Hz), 44.5, 40.3, 38.8, 38.3; 19F-NMR (376 MHz, CDCl3) δ -74.55;
HRMS (m/z) found 302.1489, calcd for C16H21F3O2 302.1494. Anal.
Calcd for C16H21F3O2 (302.32): C, 63.56; H, 7.00. Found: C, 63.30;
H, 6.90. Furthermore, 82.5 mg (9%) of the pure diether 8 (Rf 0.73)
and 165.9 mg (30%) of the diol 6 (Rf 0.15) were obtained.
Preparation of 2-Chloro-N-[9-(2,2,2-trifluoroethoxy)diaman-
tan-4-yl]acetamide (22). 9-(2,2,2-trifluoroethoxy)diamantan-4-ol
(7) (1.96 g, 6.48 mmol) was dissolved in a mixture of 30 mL of
acetic acid and 9 mL (0.1 mol) of chloroacetonitrile. The solution
was cooled in an ice bath, and 4.5 mL of concd H2SO4 was added.
After the solution was stirred for 30 min, the ice bath was removed
and the solution was stirred for 17 h at rt. The addition of 120 mL
of distilled water produced a white precipitate which could be
extracted with CHCl3 (4 × 50 mL). After being washed with
distilled water (2 × 75 mL), the product was dried with Na2SO4.
The obtained crude product was purified using column chroma-
tography on silica gel (DCM/ethyl acetate 85:15 (Rf 0.57) and
diethylether/pentane 2:1 (Rf 0.38), for a mixed fraction). The
combined yield was 1.11 g (45%) of 22 as a colorless solid: mp
(13) (a) Cahill, P. A. Tetrahedron Lett. 1990, 31, 5417–5420. (b) Gund, T. M.;
Nomura, M.; Schleyer, P. v. R. J. Org. Chem. 1974, 39, 2987–2994. (c) Chern,
Y.-T.; Wang, J.-J. Tetrahedron Lett. 1995, 36, 5805–5806. (d) Davis, M. C.;
Nissan, D. A. Synth. Commun. 2006, 36, 2113–2119.
(14) Jirgensons, A.; Kauss, V.; Kalvinsh, I.; Gold, M. R. Synthesis 2000,
1709–1712.
(15) Gilbert, K. E.; Borden, W. T. J. Org. Chem. 1979, 44, 659–661.
J. Org. Chem. Vol. 73, No. 19, 2008 7791

148 °C; IR (KBr) 3294, 2932, 2894, 2862, 1691, 1664, 1555, 1445,
1411, 1353, 1292, 1172, 1110, 965, 799 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.24 (1H, br s, NH), 3.94 (2H, s), 3.79 (2H, q, J ) 8.8
Hz), 2.10-2.00 (9H, m), 1.91 (3H, br s), 1.81-1.76 (6H, m); 13C
NMR (100 MHz, CDCl3) δ 164.9, 124.3 (q, J ) 277.7 Hz), 73.1,
59.3 (q, J ) 34.2 Hz), 50.8, 42.9, 40.50, 40.46, 38.4, 37.4; 19F-
NMR (376 MHz, CDCl3) δ -74.55; HRMS (m/z) found 377.1346,
calcd for C18H23ClF3NO2 377.1369. Anal. Calcd for C18H23ClF3NO2
(377.83): C, 57.22; H, 6.14; N, 3.71. Found: C, 56.91; H, 6.04; N,
3.40. For side products, see the Supporting Information.
Preparation of 9-Aminodiamantan-4-ol (24). Compound 23
(1.62 g, 4.12 mmol) was mixed with 474 mg (6.23 mmol) of
thiourea and dissolved in a mixture of 20 mL of ethanol and 15
mL of acetic acid. The solution was refluxed for 4 h and diluted
with 60 mL of a 20% aqueous NaOH solution after being cooled
to rt (caution: solution heats up very quickly upon addition).
Extraction with CHCl3 (4 × 80 mL), washing with distilled water
(2 × 80 mL), and drying over anhydrous Na2SO4 gave 781.3 mg
(86%) of a colorless solid which proved to be amino alcohol 24:
mp 240-244 °C; IR (KBr) 3241, 2920, 2887, 2849, 1584, 1470,
1439, 1352, 1254, 1122, 1082, 1045, 1032, 970, 919 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.89-1.79 (6H, m), 1.74-1.68 (6H, m),
1.61-1.55 (6H, m), 1.42 (3H, br s, OH + NH2); 13C NMR (100
MHz, CDCl3) δ 67.2, 45.8, 45.7, 44.8, 38.8, 37.9; HRMS (m/z)
found 219.1628, calcd for C14H21NO, 219.1623. Anal. Calcd for
C14H21NO (219.32): C, 76.67; H, 9.65; N, 6.39. Found: C, 76.57;
H, 9.65; N, 6.33.
Acknowledgment. This work was supported by Molecular-
Diamond Technologies, Chevron Technology Ventures. The
compounds 2, 13, and 15 have been synthesized by N. A.
Fokina, B. A. Tkachenko, and A. A. Fokin. Solvay Chemicals
is gratefully acknowledged for the donation of TFE.
Supporting Information Available: Detailed experimental
data for the remaining fluorinated monoethers and for the other
1
obtained products, including all H and 13C NMR spectra as
well as the crystallographic data (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JO801321S
7792 J. Org. Chem. Vol. 73, No. 19, 2008