4-Dihydroxyborylphenyl Analogues of 1-Aminocyclobutanecarboxylic Acids: Potential Boron Neutron Capture Therapy Agents

Article abstract of DOI:10.1021/jo990878c

A series of 4-dihydroxyborylphenyl analogues of an unnatural α-amino acid, 1-aminocyclobutanecarboxylic acid (ACBC), was synthesized. Varying numbers of methylene units were introduced between the 4-boronophenyl and ACBC moieties in order to introduce different degrees of lipophilicity into the molecules. The key step in the syntheses was the preparation of the precursor p-boronophenyl-substituted cyclobutanones which were subsequently converted to the desired amino acids via the Bucherer-Strecker reaction.

Full text of DOI:10.1021/jo990878c

J . Org. Chem. 1999, 64, 8495-8500
8495
4-Dih yd r oxybor ylp h en yl An a logu es of
1-Am in ocyclobu ta n eca r boxylic Acid s: P oten tia l Bor on Neu tr on
Ca p tu r e Th er a p y Agen ts
Rajiv R. Srivastava, Robert R. Singhaus, and George W. Kabalka*
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, Tennessee 37996-1600
Received J une 1, 1999
A series of 4-dihydroxyborylphenyl analogues of an unnatural R-amino acid, 1-aminocyclobutane-
carboxylic acid (ACBC), was synthesized. Varying numbers of methylene units were introduced
between the 4-boronophenyl and ACBC moieties in order to introduce different degrees of
lipophilicity into the molecules. The key step in the syntheses was the preparation of the precursor
p-boronophenyl-substituted cyclobutanones which were subsequently converted to the desired amino
acids via the Bucherer-Strecker reaction.
In tr od u ction
molecules have been used to deliver boron to tumor cells.
These include carbohydrates,12-14 polyamines,15 amino
acids,16,17 nucleosides,18-21 antisence agents,22 porphy-
rins,23,24 antibodies,25 and liposomes.26
Boron neutron capture therapy (BNCT) was first
proposed as a potential cancer therapy in 1936,1 but the
successful application of BNCT to the treatment of cancer
still presents a challenge in modern medical research.
Early attempts to cure cancer using BNCT were unsuc-
cessful2-5 due to vascular damage caused by the non-
selective uptake of the boronated agents. Encouraging
results obtained in J apan6 using sodium mercapto-
undecahydrodecaborate (Na2B12H11SH, BSH) and 4-di-
hydroxyborylphenylalanine (BPA, 1) have led to a resur-
gence of interest in BNCT. Current clinical trials suggest
that BNCT can play an important role in cancer therapy
(especially in the treatment of glioblastoma multiforma,
which does not respond well to conventional chemo-
therapy and radiation therapy.)7,8
Boron neutron capture therapy (BNCT) is a binary
therapy which is dependent on the selective deposition
of boron-10 in the tumor prior to irradiation by slow
(thermal) neutrons.9 The interaction of a boron-10 atom
with a thermal neutron produces an R-particle and a high
energy lithium-7 ion. The linear energy transfer (LET)
of these heavy charged particles has a range of ap-
proximately one cell diameter and thus they are lethal
to the cells in which they are generated. To minimize
damage to normal tissues, the quantity of boron in the
tumor (∼30 µg of 10B/g of tumor) must exceed that in the
surrounding normal tissues.9-11 A variety of carrier
Boron-containing amino acid derivatives16,17 have been
examined as potential agents for BNCT. It is believed
that amino acids are preferentially taken up by growing
tumor cells. In fact, the only drug (BPA) currently in
clinical trials in the United States is an amino acid.27
Carboranyl analogues of phenylalanine16,17 have also
been synthesized and are currently being evaluated as
potential BNCT agents.
Large cellular concentrations of boron are required for
successful BNCT, which makes it imperative that the
carrier molecules be nontoxic. For these reasons, we have
focused our efforts on a cyclic R-amino acid, 1-amino-
cyclobutanecarboxylic acid (ACBC), as a boron carrier.
(11) Zamenhof, R. G.; Kalend, A. M.; Bloomer, W. D. J . Natl. Cancer
Inst. 1992, 84, 1290.
(12) Tjarks, W.; Anisuzzaman, A. K. M.; Liu, L.; Soloway, A. H.;
Barth, R. F.; Perkins, D. J .; Adams, D. M. J . Med. Chem. 1992, 35,
1628.
(13) Maurer, J . L.; Berchier, F.; Serino, A. J .; Knobler, C. B.;
Hawthorne, M. F. J . Org. Chem. 1990, 55, 838.
(14) Maurer, J . L.; Serino, A. J .; Hawthorne, M. F. Organometallics
1988, 7, 2519.
(15) Zhuo, J . C.; Cai, J .; Soloway, A. H.; Barth, R. F.; Adams, D.
M.; J i, W. J . Med. Chem. 1999, 42, 1282.
(16) Radel, P. A.; Kahl, S. B. J . Org. Chem. 1996, 61, 4582.
(17) Kahl, S. B.; Kasar, R. A. J . Am. Chem Soc. 1996, 118, 1223
(18) Yong, J .-H.; Barth, R. F.; Wyzlic, I. M.; Soloway, A. H.; Rotaru,
J . H. Anticancer Res. 1995, 15, 2033.
* Corresponding author. E-mail: kabalka@utk.edu.
(1) Locher, G. L. Am. J . Roentgenol. Radiat. Ther. 1936, 36, 1.
(2) Sweet, W. H. N. Engl. J . Med. 1951, 245, 875.
(3) Sweet, W. H. N.; J avid, M. J . Neurosurgery 1952, 9, 200.
(4) Asbury, A. K.; Ojeann, R. G.; Nielsen, S. L.; Sweet, W. H. N. J .
Neuropathol. Exp. Neurol. 1972, 31, 278.
(5) Sweet, W. H. N. Proceedings of First International Symposium
on Neutron Capture Therapy. Brookehaven National Laboratory
Report No. 51730, 1983, p 376.
(19) Anisuzzaman, A. K. M.; Alan, F.; Soloway, A. H. Polyhedron
1990, 9, 891.
(20) Goudgaon, N. M.; Kattan, Fulcrand-E. G.; Liotta, D. C.;
Schinazi, R. F. Nucleosides Nucleotides 1994, 13, 849.
(21) Yamamoto, Y.; Seko, T.; Nemoto, H. J . Org. Chem. 1989, 54,
4734.
(22) Kattan, Fulcrand-E. G.; Lesnikowski, Z. J .; Yao, S.; Tanious,
F.; Wilson, W. D.; Schinazi, R. F. J . Am. Chem. Soc. 1994, 116, 7494.
(23) Kahl, S. B.; J oel, D. D.; Nawrocky, M. M.; Micca, P. L.; Tran,
K. P.; Finkel, G. C.; Slatkin, D. N. Proc. Natl. Acad. Sci. USA 1990,
87, 7265.
(6) Hatanaka, H.; Nakagawa, Y. Int. J . Radiat. Oncol. Biol. Phys.
1994, 28, No. 5, 1061.
(7) Haritz, D.; Gabel, D.; Huiskamp, R. Int. J . Radiat. Oncol. Biol.
Phys. 1994, 28, 1175.
(8) Mallesch, J . L.; Moore, D. E.; Allen, B. J .; McCarthy, W. H.;
J ones, R.; Stening, W. A. Int. J . Radiat. Oncol. Biol. Phys. 1994, 28,
1183.
(9) Barth, R. F.; Soloway, A. H.; Goodman, J . H.; Gahbauer, R. A.;
Gupta, N.; Blue, T. E.; Yang, W.; Tjarks, W. Neurosurgery 1999, 44,
433.
(24) Miura, M.; Micca, P. L.; Fisher, C. D.; Gordon, C. R.; Heinrichs,
J . C.; Slatkin, D. N. Br. J . Radiol. 1998, 71(847), 773.
(25) Guan, L.; Wims, L. A.; Kane, R. R.; Smuckler, M. B.; Morrison,
S. L.; Hawthorne, M. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 13206.
(26) Shelly, K.; Feakes, D. A.; Hawthorne, M. F.; Schmidt, P. G.;
Krisch, T. A.; Bauer, W. F. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 9039.
(27) Coderre, J .; Elowitz, E. H.; Chadha, M.; Bergland, R.; Capala,
J .; J oel, D. D.; Liu, H. B.; Slatkin, D. N.; Chanana, A. D. J . Neuro-
Oncology 1997, 33, 141.
(10) Hawthorne, M. F. Mol. Med. Today 1998, 4, 174.
10.1021/jo990878c CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/27/1999

8496 J . Org. Chem., Vol. 64, No. 23, 1999
Srivastava et al.
Sch em e 1
This unnatural amino acid is known to be preferentially
retained in intracerebral tumors. In fact, carbon-11-
labeled ACBC is used for imaging brain tumors at the
University of Tennessee Medical Center.28,29
We recently reported the syntheses of a m-carborane-
containing ACBC derivative and a more lipophilic ana-
logue.30,31 We now wish to report the syntheses of a new
series of boron-containing ACBC molecules, 2-5. These
novel boronated unnatural amino acids contain a 4-
boronophenyl moiety as the boron source. The syntheses
of these molecules were undertaken because of the tumor
selectivity of ACBC29 and their structural similarity to
BPA, 1, a boron-containing amino acid currently in phase
II clinical trials in the United States.27 We introduced
varying numbers of methylenes between the borono-
phenyl and ACBC moieties, 2-5, to create different
degrees of lipophilicity in the molecules. It is known that
lipophilicity plays an important role in the transport of
biologically active molecules.
butanones 10-13) obtained from the ketene additions
were subjected to a reductive dechlorination with zinc
and acetic acid. The resultant p-bromophenyl-substituted
cyclobutanones 14-17 were then protected as ethylene
ketals 18-21 by reaction with ethylene glycol.35 The
ethylene ketals were then sequentially reacted with
butyllithium and triisopropylborate.36 The reaction mix-
tures were quenched by dilute sulfuric acid to obtain
ethylene ketal boronic acids 22-25. The ketal group was
removed by the action of dilute hydrochloric acid in
methanol to regenerate the desired ketones 26-29, which
were reacted with ammonium carbonate and potassium
cyanide in a pressure tube. Hydantoins 30-33 were
formed in excellent yields. In the final step of the
syntheses, the hydantoins were heated in the presence
of sodium hydroxide to generate the desired amino acids
2-5 in good yields.
Resu lts a n d Discu ssion
The key synthetic step in the formation of the desired
amino acids involves the preparation of appropriately
substituted cyclobutanones followed by a Bucherer-
Strecker amino acid synthesis.32 The syntheses of the
boron-containing amino acids were initiated starting with
alkenes 6-9 (Scheme 1). While alkene 6 is commercially
available, alkenes 7-9 were prepared by an SN2 dis-
placement reaction using 4-bromobenzyl bromide and the
appropriate Grignard reagent (eq 1). For the syntheses
As anticipated, the introduction of varying numbers
of methylene groups between the cyclobutane and the
aromatic rings influenced the lipophilicities of the result-
ant boronated amino acids, as reflected in their Rf values.
The most lipophilic product, 5, exhibited an Rf value of
0.61 using acetonitrile:methanol:water as the mobile
phase. Whereas, 2 was found to be the least lipophilic
with an Rf value of 0.32 in the same mobile phase. Amino
acids 3 and 4, in which the number of methylene units
fell between 0 and 7, exhibited intermediate Rf values.
of alkene 8 and 9, a catalytic amount of lithium tetra-
chlorocuprate(II) was required (eq 1).33 Cyclobutanones
were obtained (Scheme 1) via a 2 + 2 cycloaddition of
the precursor alkenes with dichloroketene, which was
generated in situ from the reaction of trichloroacetyl
chloride and phosphorus oxychloride in the presence of
a Zn-Cu couple.34 The crude products (dichlorocyclo-
Con clu sion
We report the syntheses of novel boronic acid-contain-
ing analogues of a tumor-seeking unnatural cyclic R-ami-
no acid, 1-aminocyclobutanecarboxylic acid. Boronic acid-
containing analogues of ACBCs with varying degree of
lipophilicities were synthesized, and the agents are being
evaluated as potential BNCT agents.
(28) Washburn, L. C.; Sun, T. T.; Byrd, B. L.; Hayes, R. L.; Butler,
T. A. J . Nucl. Med. 1980, 20, No. 10, 1055.
(29) Hubner, K. F.; Thie, J . A.; Smith, G. T.; Kabalka, G. W.; Keller,
I. B.; Ciefoth, A. B.; Campbell, S. K.; Buonocore, E. Clin. Positron Imag.
1998, 1, 165.
(30) Srivastava. R. R.; Singhaus, R. R.; Kabalka, G. W. J . Org. Chem.
1997, 62, 4476.
(31) Srivastava. R. R.; Kabalka, G. W. J . Org. Chem. 1997, 62, 8730.
(32) Henz, H. R.; Speer, R. J . J . Org. Chem. 1942, 7, 522.
(33) Tolstikov, G. A.; Odinokov, V. N.; Galeeva, R. I.; Bakeeva, R.
S. Tetrahedron Lett. 1978, No 1, 1857.
(35) Crimmins, M. T.; DeLoaza, J . A. J . Am. Chem. Soc. 1986, 108,
800
(34) Krepski, L. R.; Hassner, A. J . Org. Chem. 1978, 43, 2879.
(36) Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316.

Boron Neutron Capture Therapy Agents
J . Org. Chem., Vol. 64, No. 23, 1999 8497
1 mmHg) to obtain a colorless liquid (3.6 g). The crude reaction
mixture was purified using chromatography (silica gel, hexane)
to obtain 8 as a colorless liquid (2.8 g, 33% based on 4-bro-
mobut-1-ene): Rf ) 0.87 (hexane, thin-layer chromatography);
1H NMR (CDCl3) δ 7.36 (d, J ) 8.2 Hz, 2H), 7.02 (d, J ) 8.2
Hz, 2H), 5.78 (m, 1H), 5.01 (m, 2H), 2.54 (t, J ) 7.75 Hz, 2H),
2.05 (m, 2H), 1.66 (m, 2H); 13C NMR (CDCl3) δ 141.26, 138.23,
131.25, 130.16, 119.36, 114.89, 34.60, 33.08, 30.35.
9-(4-Br om op h en yl)-1-n on en e (9). This alkene was pre-
pared using the procedure described to prepare 8. 4-Bromo-
benzyl bromide (28.8 mmol, 7.19 g) in THF (20 mL) was added
to 7-octenylmagnesium bromide (26 mmol, 52 mL of a 0.5 M
solution in THF) in the presence of dilithium tetrachlocuprate
(0.29 mL, 2.9 mL of 0.1 M solution in THF) to obtain compound
9 as a colorless liquid (3.1 g, 42% based on 8-bromocten-1-
ene): Rf ) 0.85 (hexane, thin-layer chromatography); 1H NMR
(CDCl3) δ 7.36 (d, J ) 8.2 Hz, 2H), 7.02 (d, J ) 8.2 Hz, 2H),
5.78 (m, 1H), 4.96 (m, 2H), 2.53 (t, J ) 7.5 Hz, 2H), 2.01 (m,
2H), 1.56 (m, 2H), 1.29 (m, 8H); 13C NMR (CDCl3) δ 141.71,
139.04, 131.19, 130.09, 119.21, 114.14, 35.29, 33.73, 31.24,
29.26, 29.08, 28.99, 28.85; IR (neat) 1641; HRMS calcd for
Exp er im en ta l Section
Gen er a l Met h od s. All solvents were reagent grade and
were distilled from appropriate drying agents under a nitrogen
atmosphere prior to use. Tetrahydrofuran and diethyl ether
were distilled from sodium benzophenone ketyl; benzene was
distilled from calcium hydride and stored under nitrogen. All
other chemicals were (Aldrich Chemical Co., Milwaukee, WI)
used as received.
Column chromatography was performed using silica gel (60
Å, 230-400 mesh, ICN Biomedicals GmbH, Eschwege, Ger-
many.). Reverse-phase column chromatography was performed
by utilizing octadecyl-functionalized silica gel (Aldrich Chemi-
cal Co., Milwaukee, WI). Analytical thin-layer chromatography
was performed on 250 µm silica (Analtech Inc., Newark, DE)
and were visualized by phosphomolybdic acid, palladium
chloride, and silver nitrate solutions.
Melting points are uncorrected. Infrared spectra were
obtained either neat or as Nujol mulls. 1H NMR and 13C NMR
spectra were recorded at 250.13 and 62.89 Mz, respectively.
In cases where more than one isomer formed, we have reported
the 13C NMR of the major isomer. Chemical shifts for 1H and
13C NMR spectra were referenced to Si(CH3)4 and measured
with respect to the residual protons in the deuterated solvents.
Microanalysis were performed by Galbraith Laboratories Inc.,
Knoxville, TN. HR-FAB-MS (M + 1) were obtained on a ZAB-
EQ instrument in a glycerol matrix. Positive ion electrospray
mass spectra (ES+) were obtained in instances where satisfac-
tory elemental analyses were obtained for carbon and hydro-
gen but where boron values exceeded acceptable limits (not
uncommon for boron-containing molecules).37
4-(4-Br om op h en yl)-1-bu ten e (7). A 500 mL three-necked
round-bottomed flask equipped with an addition funnel, reflux
condenser, and an argon-filled balloon was charged with
4-bromobenzyl bromide (80 mmol, 20 g) in 50 mL of anhydrous
ether. Allylmagnesium bromide (96 mmol, 96 mL of a 1 M
solution in ether) was then added via the addition funnel over
a period of 30 min, and the reaction mixture was allowed to
stir at room temperature for 2 h. The mixture was then
refluxed in an oil bath for 3 h. The progress of the reaction
was monitored by TLC. After the starting material (aryl
bromide) disappeared, the flask was cooled to room tempera-
ture and the reaction quenched with water and then trans-
ferred to a separatory funnel. The organic layer was washed
with water and then brine, dried over anhydrous magnesium
sulfate, and concentrated using a rotatory evaporator. After
drying under vacuum (50 °C at 1 mmHg), a colorless liquid
(16 g) was obtained. The crude product was purified by
Kugelrhor distillation to yield 7 as a colorless liquid (14 g, 83%
yield): Rf ) 0.86 (hexane, thin-layer chromatography); 1H
NMR (CDCl3) δ 7.37 (d, J ) 8.2 Hz, 2H), 7.06 (d, J ) 8.2 Hz,
2H), 5.61 (m, 1H), 5.06 (m, 2H), 2.67 (t, J ) 8.2 Hz, 2H), 2.35
(m, 2H); 13C NMR (CDCl3) δ 140.68, 137.52, 131.28, 130.16,
119.49, 115.24, 35.21, 34.69; IR (neat) 1639. Anal. Calcd for
C
15H21Br 280.083, found 280.085. Anal. Calcd for C15H21Br:
C, 64.06; H, 7.53. Found: C, 64.13; H, 7.73.
3-(4-Br om op h en yl)cyclobu ta n on e (14). A 500 mL three-
necked, round-bottomed flask equipped with an addition
funnel, reflux condenser, and argon-filled balloon was charged
with 4-bromostyrene (6) (137 mmol, 25.0 g) and diethyl ether
(200 mL) along with a freshly prepared Zn-Cu couple (273
mmol, 17.9 g). A solution of trichloroacetyl chloride (205 mmol,
22.9 mL) and phosphorus oxychloride (205 mmol, 19.1. mL)
in ether (100 mL) was placed in the addition funnel and added
dropwise over a period of 60 min. After the addition, the
reaction mixture was stirred at room temperature for 1 h and
then refluxed for 3 h under an argon atmosphere. The reaction
mixture was then cooled to room temperature and filtered
through a pad of Celite. Additional ether was used to wash
the Celite. The combined organic extract was neutralized with
saturated sodium bicarbonate, washed with water and then
brine, dried over anhydrous magnesium sulfate, and concen-
trated on a rotatory evaporator to obtain 10 as a light yellow
liquid.
Crude 10 was dissolved in glacial acetic acid (50 mL) along
with zinc dust (20 g, excess). The reaction mixture was stirred
at room temperature for 30 min and then heated at 120 °C
(oil bath) for 2 h. TLC indicated disappearance of the starting
material. The mixture was cooled to room temperature and
passed through a pad of Celite. Additional ethyl acetate was
used to wash the Celite pad and to transfer the material from
the flask. The solvent was removed under reduced pressure
and the residue dissolved in ethyl acetate, washed with water
and then brine, dried over anhydrous magnesium sulfate, and
concentrated to obtain a light yellow thick liquid (28 g). The
crude product was purified by Kugelrhor distillation to obtain
3-(4-bromophenyl)cyclobutanone (14) as a colorless liquid (24
g, 78% yield based on alkene 6): Rf ) 0.19 (5% ethyl acetate
C
10H11Br: C, 56.87; H, 5.21. Found: C, 57.07; H, 5.65.
5-(4-Br om op h en yl)-1-p en ten e (8). A 250 mL three-necked
1
in hexane, thin-layer chromatography); H (CDCl3) δ 7.43 (d,
round-bottomed flask, equipped with an addition funnel and
an argon-filled balloon was charged with 4-bromobenzyl
bromide (44 mmol, 11 g) in 25 mL of anhydrous THF.
3-Butenylmagnesium bromide (37 mmol, 74 mL of 0.5 M
solution in THF) was then added via the addition funnel over
a period of 20 min while the reaction was maintained at -70
°C using a dry ice-acetone bath. Following addition of the
Grignard reagent, a solution of dilithium tetrachlorocuprate(II)
(0.18 mmol, 1.9 mL of a 0.1 M solution in THF) was added
while the reaction was maintained at -50 °C. The resultant
solution was stirred overnight while the reaction was allowed
to reach room temperature. The reaction was quenched with
saturated aqueous ammonium chloride and the solvent re-
moved under reduced pressure. The residue was then taken
into ether and washed sequentially with water and brine, dried
over anhydrous magnesium sulfate, concentrated using a
rotatory evaporator, and then dried under vacuum (50 °C at
J ) 8.4 Hz, 2H), 7.16 (d, J ) 8.4 Hz, 2H), 3.62 (m, 1H), 3.44
(m, 2H), 3.17 (m, 2H); 13C (CDCl3) δ 205.52, 142.32, 131.49,
128.07, 119.97, 54.29, 27.69; IR (neat) 1747; HRMS calcd for
C
10H9BrO 223.984, found 223.982.
3-[2-(4-Br om oph en yl)eth yl]cyclobu tan on e (15). The syn-
thesis of 15 was carried out as described for 14. A solution of
trichloroacetyl chloride (71 mmol, 7.9 mL) and phosphorus
oxychloride (71 mmol, 6.6 mL) in ether (20 mL) was allowed
to react with with 7 (47 mmol, 10 g) in ether (100 mL) in the
presence of Zn-Cu couple (118 mmol, 7.7 g) to obtain 2,2-
dichloro-3-[2-(4-bromophenyl)ethyl]cyclobutanone (11). The
dichloro ketone 11 was subjected to a reductive dechlorination
with zinc (7.7 g, excess) and acetic acid (30 mL) to yield a light
yellow liquid (14 g). The crude product was purified by column
chromatography using silica gel (30 × 4 cm, 10% ethyl acetate
in hexane) to yield 15 as a colorless liquid (10 g, 84% yield
based on olefin 7): Rf ) 0.26 (10% ethyl acetate in hexane,
1
thin-layer chromatography); H NMR (CDCl3) δ 7.33 (d, J )
(37) Gomez, F. A.; Hawthorne, M. F. J . Org. Chem. 1992, 57, 1384.
8.0 Hz, 2H), 6.98 (d, J ) 8.0 Hz, 2H), 3.06 (m, 2H), 2.58 (m,

8498 J . Org. Chem., Vol. 64, No. 23, 1999
Srivastava et al.
4H), 2.28 (m, 1H), 1.79 (m, 2H); 13C NMR (CDCl3) δ 207.59,
140.29, 131.38, 130.02, 119.62, 52.32, 37.64, 33.90, 23.25; IR
(neat) 1785. Anal. Calcd for C12H13BrO: C, 56.92; H, 5.14.
Found: C, 56.92; H, 5.29.
3-[3-(4-Br om op h en yl)p r op yl]cyclobu ta n on e Eth ylen e
Keta l (20). The synthesis was carried out as described for 18.
A solution of 16 (10.5 mmol, 2.80 g) and ethylene glycol (105
mmol, 5.85 mL) in benzene (50 mL) was refluxed in the
presence of p-toluenesulfonic acid (1.05 mmol, 0.199 g). The
product was purified by Kugelrhor distillation to obtain 20 as
a colorless liquid (2.96 g, 91% yield). Rf ) 0.44 (5% ethyl
acetate in hexane, thin-layer chromatography); 1H NMR
(CDCl3) δ 7.34 (d, J ) 8.2 Hz, 2H), 6.99 (d, J ) 8.2 Hz, 2H),
3.83 (s, 4H), 2.53 (t, J ) 6.9 Hz, 2H), 2.36 (m, 2H), 1.98 (m,
1H), 1.87 (m, 2H), 1.45 (br s, 4H); 13C NMR (CDCl3) δ 141.47,
131.28, 130.11, 119.34, 106.66, 63.96, 63.51, 41.05, 35.91,
3-[3-(4-Br om op h en yl)p r op yl]cyclobu ta n on e (16). The
synthesis of 16 was carried out as described for 14. A solution
of trichloroacetyl chloride (18.8 mmol, 2.08 mL) and phospho-
rus oxychloride (18.8 mmol, 1.70 mL) in ether (15 mL) was
allowed to react with 8 (12.5 mmol, 2.82 g) in 25 mL of ether
in the presence of Zn-Cu couple (25 mmol, 2.16 g) to obtain
dichlorocyclobutanone 12. The dichloroketone 12 was subjected
to dechlorination in the presence of Zn (2.16 g, excess) and
acetic acid (20 mL) to obtain a light yellow thick liquid that
was purified by Kugelrhor distillation to obtain 16 as a
colorless liquid (2.89 g, 86.5% yield based on olefin 8): Rf )
0.35 (5% ethyl acetate in hexane thin-layer chromatography);
1H NMR (CDCl3) δ 7.39 (d, J ) 7.75 Hz, 2H), 7.04 (d, J ) 7.75
Hz, 2H), 3.11 (m, 2H), 2.64 (m, 4H), 2.35 (m, 1H), 1.61 (br s,
4H); 13C NMR (CDCl3) δ 208.04, 140.93, 131.29, 130.01, 119.45,
52.39, 35.62, 34.95, 29.76, 23.66; IR (neat) 1788. Anal. Calcd
for C13H15BrO: C, 58.44; H, 5.66. Found: C, 58.65; H, 5.88.
3-[7-(4-Br om op h en yl)h ep tyl]cyclobu ta n on e (17). The
synthesis of 17 was carried out as described for 14. A solution
of trichloroacetyl chloride (16.4 mmol, 1.82 mL) and phospho-
rus oxychloride (16.4 mmol, 1.52 mL) in ether (10 mL) was
allowed to react with alkene 9 (10.9 mmol, 3.09 g) in ether
(25 mL) in the presence of Zn-Cu couple (21.8 mmol, 1.43 g).
The dichloro ketone 13 (4.98 g, crude) thus obtained was
reacted with Zn (1.50 g) in acetic acid (20 mL) to obtain a thick
liquid that was purified via silica gel chromatography using
10% ethyl acetate in hexane to obtain 17 as a colorless liquid
(2.59 g, 73% yield based on starting alkene): Rf ) 0.73 (10%
ethyl acetate in hexane thin-layer chromatography); 1H NMR
(CDCl3) δ 7.36 (d, J ) 8.2 Hz, 2H), 7.03 (d, J ) 8.2 Hz, 2H),
3.11 (m, 2H), 2.59 (m, 4H), 2.31 (m, 1H), 1.56 (br s, 4H), 1.29
(br s, 8H); 13C NMR (CDCl3) δ 208.31, 141.54, 131.07, 130.01,
119.09, 52.34, 36.14, 35.14, 31.09, 29.18, 28.92, 28.07, 23.66;
IR (neat) 1784. Anal. Calcd for C17H23BrO: C, 63.16; H, 7.17.
Found: C, 63.26; H, 7.22.
3-(4-Br om op h en yl)cyclobu ta n on e Eth ylen e Keta l (18).
A 500 mL three-necked round-bottomed flask equipped with
a Dean-Stark apparatus and a reflux condenser was charged
with ketone 14 (78.2 mmol, 17.6 g), ethylene glycol (391 mmol,
21.8 mL), and p-toluenesulfonic acid (3.91 mmol, 0.743 g) in
benzene (250 mL). The reaction mixture was refluxed at 120
°C (oil bath) for 20 h and the reaction was monitored by thin-
layer chromatography. After 20 h, the flask was cooled to room
temperature and NaOH (2 mL of 3 N aqueous solution) was
added to make the reaction mixture basic. The mixture was
transferred to a separatory funnel, washed with water and
then brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to yield a colorless oil.
The product was purified by Kugelrhor distillation to obtain
18 as a colorless liquid (19.3 g, 82.5% yield): Rf ) 0.29 (5%
ethyl acetate in hexane, thin-layer chromatography); 1H NMR
(CDCl3) δ 7.38 (d, J ) 8.3 Hz, 2H), 7.11 (d, J ) 8.3 Hz, 2H),
3.89 (m, 4H), 3.24 (m, 1H), 2.71 (m, 2H), 2.41 (m, 2H); 13C NMR
(CDCl3) δ 143.73, 131.29, 128.37, 119.69, 105.74, 64.23, 63.69,
43.10, 29.44; IR (Nujol) 1297. Anal. Calcd for C12H13BrO2: C,
53.53; H, 4.83; Br, 29.74. Found: C, 53.39; H, 4.99; Br, 29.84.
3-[2-(4-Br om op h en yl)et h yl]cyclob u t a n on e E t h ylen e
Keta l (19). The synthesis was carried out as described for 18.
A solution of 15 (33 mmol, 8.3 g) and ethylene glycol (330
mmol, 18.4 mL) in benzene (180 mL) was refluxed in the
presence of p-toluenesulfonic acid (3.3 mmol, 0.6 g). The
compound was purified by Kugelrohr distillation to obtain 19
as a colorless thick oil that solidified upon standing at room
temperature (8.9 g, 91% yield): Rf ) 0.26 (10% ethyl acetate
in hexane, thin-layer chromatography); 1H NMR (CDCl3) δ 7.30
(d, J ) 8.2 Hz, 2H), 6.95 (d, J ) 8.2 Hz, 2H), 3.77 (s, 4H), 2.43
(t, J ) 7.4 Hz, 2H), 2.33 (m, 1H), 1.90 (m, 4H), 1.69 (m, 2H);
13C NMR (CDCl3) δ 140.99, 131.19, 130.04, 119.30, 106.48,
63.89, 63.45, 40.92, 37.88, 33.42, 24.46; IR (neat) 1293. Anal.
Calcd for C14H17BrO2: C, 56.57; H, 5.72. Found: C, 56.81; H,
5.90.
35.14, 29.37, 24.91; IR (neat) 1292. Anal. Calcd for C15H19
BO2: C, 57.89; H, 6.15. Found: C, 58.02; H, 6.48.
-
3-[7-(4-Br om op h en yl)h ep tyl]cyclobu ta n on e Eth ylen e
Keta l (21). The synthesis was carried out as described for 18.
A solution of 17 (7.23 mmol, 2.34 g) and ethylene glycol (72.3
mmol, 4.00 mL) in benzene (40 mL) was refluxed in the
presence of p-toluenesulfonic acid (0.723 mmol, 0.137 g). The
crude material was purified using a silica gel column to obtain
21 as a thick liquid (2.42 g, 90.9% yield). Rf ) 0.67 (10% ethyl
acetate in hexane, thin-layer chromatography); 1H NMR
(CDCl3) δ 7.36 (d, J ) 8.2 Hz, 2H), 7.02 (d, J ) 8.2 Hz, 2H),
3.86 (s, 4H), 2.53 (t, J ) 7.4 Hz, 2H), 2.39 (m, 2H), 1.94 (m,
3H), 1.56 (m, 2H), 1.42 (br s, 2H), 1.28 (m, 8H); 13C NMR
(CDCl3) δ 141.65, 131.13, 130.04, 119.13, 106.66, 63.84, 63.37,
40.98, 36.37, 35.22, 31.18, 29.30, 29.03, 27.57, 24.97; IR (neat)
1294. Anal. Calcd for C19H27BrO2: C, 61.96; H, 7.66. Found:
C, 62.23; H, 7.44.
3-(4-Bor on oph en yl)cyclobu tan on e Eth ylen e Ketal (22).
A 250 mL three-necked round-bottomed flask equipped with
an argon-filled balloon was charged with 18 (15.0 mmol, 4.00
g) in anhydrous tetrahydrofuran (80 mL). The flask was cooled
to -78 °C using a dry ice-acetone bath. Butyllithium (17.8
mmol, 11.2 mL of a 1.60 M solution in hexane) was added
dropwise via a syringe. The resultant yellow solution was
stirred at -70 °C for 30 min and then triisopropyl borate (17.8
mmol, 4.12 mL) was added dropwise via syringe. The reaction
mixture was allowed to stir overnight (during this time the
bath temperature was allowed to rise to room temperature).
The flask was then cooled to 0 °C and the reaction quenched
with H2SO4 (6 mL of 2 N aqueous sulfuric acid). The mixture
was stirred for an additional 30 min at the 0 °C and then
transferred to a separatory funnel. The product was extracted
into ether and the organic layer was washed sequentially with
water and brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to obtain a faint yellow
solid (4.02 g). The product was purified by column chroma-
tography using silica gel (22 × 1.5 cm, 30% ethyl acetate in
hexane) to obtain 22 as a white solid (2.89 g, 83% yield): Rf )
0.46 (50% ethyl acetate in hexane, thin-layer chromatography);
1
mp 158-160 °C; H NMR (CDCl3) δ 8.17 (d, J ) 7.8 Hz, 2H),
7.40 (d, J ) 7.8 Hz, 2H), 3.96 (m, 4H), 3.41 (m, 1H), 2.78 (m,
2H), 2.59 (m, 2H); 13C NMR (CDCl3) δ 149.63, 135.83, 126.34,
106.01, 64.35, 63.78, 43.12, 30.34; IR (Nujol) 3370. Anal. Calcd
for C12H15BO4: C, 61.58; H, 6.46; B, 4.62. Found C, 63.40; H,
6.56; B, 4.62.
3-[2-(4-Bor on op h en yl)et h yl]cyclob u t a n on e E t h ylen e
Keta l (23). The synthesis of 23 was carried out as described
for 22. A solution of 19 (6.7 mmol, 2.0 g) in anhydrous
tetrahydrofuran (40 mL) was treated with butyllithium (8.0
mmol, 5.0 mL of a 1.6 M solution in hexane) followed by
triisopropyl borate (8.0 mmol, 1.9 mL) to obtain a colorless
thick liquid (1.9 g). The product was purified by column
chromatography using silica gel (25 × 2 cm, 30% ethyl acetate
in hexane) to obtain 23 as a white solid (1.5 g, 87% yield): Rf
) 0.56 (50% ethyl acetate in hexane, thin-layer chromatogra-
1
phy); mp 78-80 °C; H NMR (CDCl3) δ 8.06 (d, J ) 7.5 Hz,
2H), 7.23 (d, J ) 7.5 Hz, 2H), 3.81 (s, 4H), 2.53 (m, 2H), 2.36
(m, 1H), 1.95 (m, 4H), 1.74 (m, 2H); 13C (CDCl3) δ 147.14,
135.74, 128.12, 106.66, 63.96, 63.50, 40.99, 37.96, 34.47, 24.71;
IR (Nujol) 3370. Anal. Calcd for C10H11B: C, 64.15; H, 7.31;
B, 4.12. Found: C, 63.47; H, 7.08; B, 4.26.
3-[3-(4-Bor on op h en yl)p r op yl]cyclobu ta n on e Eth ylen e
Keta l (24). The synthesis of 24 was carried out as described

Boron Neutron Capture Therapy Agents
J . Org. Chem., Vol. 64, No. 23, 1999 8499
for 22. A solution of 20 (8.39 mmol, 2.60 g) in anhydrous
tetrahydrofuran (50 mL) was treated with butyllithium (10.1
mmol, 6.30 mL of a 1.6 M solution in hexane) followed by
triisopropyl borate (10.1 mmol, 2.32 mL) to obtain a white solid
(2.64 g). The product was purified by column chromatography
using silica gel to obtain 24 as a white solid (1.76 g, 76%
yield): Rf ) 0.51 (50% ethyl acetate in hexane, thin-layer
chromatography); mp 128-130 °C; 1H NMR (DMSO-d6) δ 7.99
(s, 2 H, disappears upon addition of D2O), 7.74 (d, J ) 7.8 Hz,
2H), 7.2 (d, J ) 7.8 Hz, 2H), 3.31 (s, 4H), 2.03 (m, 2H), 1.86
(m, 1H), 1.45 (m, 4H), 1.24 (m, 2H); 13C (DMSO-d6) δ 144.22,
134.21, 127.41, 105.88, 63.37, 62.91, 40.71, 35.56, 35.10, 29.01,
24.46; IR (Nujol) 3239; HR-FAB-MS (M + H; glycerol matrix)
calcd for C18H26O4B: 333.188, found: 333.189. Anal. Calcd for
C15H21BO4: C, 66.24; H, 7.67. Found: C, 69.45; H, 7.60.
3-[7-(4-Bor on op h en yl)h ep tyl]cyclobu ta n on e Eth ylen e
Keta l (25). The synthesis of 25 was carried out as described
for 22. A solution of 21 (5.94 mmol, 2.19 g) in anhydrous
tetrahydrofuran (50 mL) was treated with butyllithium (7.12
mmol, 4.46 mL of a 1.60 M solution in hexane) followed by
triisopropyl borate (7.12 mmol, 1.64 mL) to obtain a solid that
was purified by column chromatography using silica gel to
obtain 25 as a white solid (1.58 g, 80% yield): Rf ) 0.61 (50%
ethyl acetate in hexane, thin-layer chromatography); mp 76-
1.72 (m, 4H); 13C (DMSO-d6) δ 208.19, 144.12, 134.23, 127.41,
51.99, 35.13, 35.01, 29.48, 23.15; IR (Nujol) 3364, 1765. Anal.
Calcd for C13H17BO3: C, 67.28; H, 7.38; B, 4.66. Found: C,
66.90; H, 7.90; B, 4.64.
3-[7-(4-Bor on op h en yl)h ep tyl]cyclobu ta n on e (29). The
synthesis was carried out as described for 26. A solution of
ketal 25 (5.80 mmol, 1.94 g) in methanol (30 mL) was stirred
with concentrated hydrochloric acid (0.5 mL) to obtain a solid
which upon purification (silica gel chromatography) yielded
29 as a white solid (1.26 g, 75% yield): Rf ) 0.57 (50% ethyl
acetate in hexane, thin-layer chromatography); mp 70-76 °C;
1H (CDCl3) δ 8.13 (d, J ) 7.4 Hz, 2H), 7.30 (d, J ) 7.4 Hz,
2H), 3.10 (m, 2H), 2.64 (m, 4H), 2.32 (m, 1H), 1.66 (br s, 2H),
1.55 (m, 2H), 1.33 (br s, 8H); 13C (CDCl3) δ 208.71, 147.69,
135.63, 128.07, 52.44, 36.23, 31.16, 29.27, 29.15, 28.16, 23.78;
IR (Nujol) 3304, 1765; FAB-MS (M + H; glycerol matrix) calcd
for C20H30O4B 345.224, found 345.223. Anal. Calcd for C17H25
-
BO3: C, 70.85; H, 8.74; B, 3.75. Found: C, 72.50; H, 7.65; B,
4.03.
Hyd a n toin 30 of 3-(4-Bor on op h en yl)cyclobu ta n on e
(26). A 15 mL Ace pressure tube was charged with 26 (3.70
mmol, 0.700 g), aqueous ethanol (50% ethanol in water, 12.0
mL), potassium cyanide (7.4 mmol, 0.48 g), and ammonium
carbonate (18.5 mmol, 1.78 g). The reaction vessel was sealed
and heated at 60 °C (oil bath) for 4 h. A faint yellow precipitate
formed. The reaction vial was cooled to room temperature and
carefully opened in a fume hood. The reaction mixture was
acidified using dilute aqueous hydrochloric acid. The solvent
was removed under reduced pressure and the solid obtained
was recrystallized from water (containing 5% ethanol) to yield
30 as a faint yellow solid (0.748 g, 77.8% yield): Rf ) 0.65
(10% methanol in methylene chloride, thin-layer chromatog-
1
80 °C; H NMR (DMSO-d6) δ 7.92 (s, 2 H, disappears by the
addition of D2O), 7.68 (d, J ) 7.7 Hz, 2H), 7.12 (d, J ) 7.7 Hz,
2H), 3.75 (s, 4H), 2.53 (t, J ) 7.3 Hz, 2H), 2.28 (m, 2H), 1.81
(m, 3H), 1.53 (m, 2H), 1.34 (m, 2H), 1.23 (m, 8H); 13C (DMSO-
d6) δ 144.33, 134.21, 127.39, 105.91, 63.37, 62.89, 40.74, 35.95,
35.25, 30.86, 28.89, 28.65, 27.22, 24.61; IR (Nujol) 3382; HR-
FAB-MS (M + H; glycerol matrix) calcd for C22H34O5B 389.250,
found 389.253. Anal. Calcd for C19H29BO4: C, 68.69; H, 8.8.
Found: C, 69.00; H, 8.50.
1
raphy); mp 248-250 °C (dec); H NMR (DMSO-d6) δ 7.59 (d,
3-(4-Bor on oph en yl)cyclobu tan on e (26). A 100 mL round-
bottomed flask was charged with ketal 22 (12.8 mmol, 3.00 g)
in methanol (30 mL) along with concentrated hydrochloric acid
(0.5 mL). The contents of the flask were stirred overnight at
room temperature. TLC indicated complete disappearance of
the starting ketal. The solvent was removed under reduced
pressure and the residue dissolved in ether and washed with
water and then brine. The organic layer was dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure to yield a faint yellow viscous material (2.6 g). The
product was purified using a silica gel chromatography (20 ×
2 cm, 30% ethyl acetate in hexane) to obtain 26 as a white
solid (1.92 g, 79% yield): Rf ) 0.46 (50% ethyl acetate in
J ) 7.5 Hz, 2H), 7.10 (d, J ) 7.5 Hz, 2H), 2.62 (m, 2H), 2.22
(m, 2H), benzylic protons (2H) are covered by H2O of DMSO.
13C NMR (DMSO-d6) δ 178.87, 155.98, 146.24, 134.35, 125.65,
57.32, 30.79; IR (Nujol) 3313, 1728, 1718; FAB-MS (M + H;
glycerol matrix) calcd for C15H17O5BN2 317.1, found 317.1.
Anal. Calcd for C12H13BN2O4 C, 55.42; H, 5.04; N, 10.77. Found
C, 53.85; H, 5.06; N, 10.10.
Hyd a n toin 31 of 3-[2-(4-Bor on op h en yl)eth yl]cyclobu -
ta n on e (27). The synthesis was carried out as described for
30. A solution of 27 (1.1 mmol, 0.28 g) in aqueous ethanol (50%,
7.0 mL) was allowed to react with potassium cyanide (3.0
mmol, 0.19 g) and ammonium carbonate (5.0 mmol, 0.48 g) to
obtain a faint yellow solid that was recrystallized by water
(containing 5% ethanol) to yield 31 as a faint yellow solid (0.23
g, 62% yield): Rf ) 0.39 (5% methanol in methylene chloride,
thin-layer chromatography); mp 224-226 °C (dec); 1H (DMSO-
d6) δ 7.68 (d, J ) 7.7 Hz, 2H), 7.12 (d, J ) 7.7 Hz, 2H), 2.45
(m, 4H), 2.19 (m, 1H), 1.86 (m, 2H), 1.65 (m, 2H); 13C (DMSO-
d6) δ 178.78, 155.89, 143.70, 134.18, 127.32, 57.76, 38.11, 32.74,
25.89; IR (Nujol) 3296, 1738, 1713; ES+ (M + H; obtained in
MeOH-H2O solvent mixture containing 1% formic acid) calcd
1
hexane, thin-layer chromatography); mp 94-98 °C; H NMR
(CDCl3) δ 7.63 (d, J ) 7.3 Hz, 2H), 7.20 (d, J ) 7.3 Hz, 2H),
3.56 (m, 1H), 3.30 (m, 2H), 3.08 (m, 2H); 13C NMR (CDCl3) δ
208.81, 147.25, 135.29, 126.76, 55.19, 29.57; IR (Nujol) 3358,
1768. Anal. Calcd for C10H11BO3C: 63.21; H, 5.84; B, 5.69.
Found: C, 63.50; H, 6.05; B, 6.12.
3-[2-(4-Bor on op h en yl)eth yl]cyclobu ta n on e (27). The
synthesis was carried out as described for 26. A solution of
ketal 23 (6.90 mmol, 1.80 g) in methanol (30 mL) was stirred
with concentrated hydrochloric acid (0.5 mL) to obtain a faint
yellow viscous material (1.7 g) which was purified by silica
gel chromatography to yield 27 as a white solid (1.2 g, 78%
yield): Rf ) 0.56 (50% ethyl acetate in hexane, thin-layer
chromatography); mp 93-95 °C; 1H (CDCl3) δ 8.12 (d, J ) 7.8
Hz, 2H), 7.27 (d, J ) 7.8 Hz, 2H), 3.09 (m, 2H), 2.69 (m, 4H),
2.35 (m, 1H), 1.93 (m, 2H); 13C (CDCl3) δ 208.07, 146.37,
135.86, 128.07, 52.43, 37.69, 34.91, 23.45; IR (Nujol) 3340,
1761. Anal. Calcd for C12H15BO3: C, 66.10; H, 6.93; B, 4.96.
Found: C, 65.95; H, 6.94; B, 5.12.
for C16H22O4N2B 317.1, found: 317.0. Anal. Calcd for C14H17
-
BN2O4: C, 58.36; H, 5.96; N, 9.72; B, 3.75. Found: C, 57.54;
H, 6.15; N, 9.17, B, 1.49.
Hyd a n toin 32 of 3-[3-(4-Bor on op h en yl)p r op yl]cyclo-
bu ta n on e (28). The synthesis was carried out as described
for 30. A solution of 28 (3.71 mmol, 0.862 g) in aqueous ethanol
(50% ethanol in water, 12.0 mL) was allowed to react with
potassium cyanide (7.4 mmol, 0.48 g) and ammonium carbon-
ate (18.6 mmol, 1.78 g) to obtain a faint yellow solid that was
purified using silica gel chromatography (10% methanol in
methylene chloride) to obtain 32 as a white solid (0.74 g, 66%
yield): Rf ) 0.46 (5% methanol in methylene chloride, thin-
layer chromatography); mp 220-224 °C; 1H (DMSO-d6) δ 7.89
(s, 2 H, disappears by the addition of D2O), 7.88 (d, J ) 7.7
Hz, 2H), 7.36 (d, J ) 7.7 Hz, 2H), 2.68 (m, 3H), 2.50-2.29 (m,
3H), 2.08 (m, 1H), 1.62 (m, 4H); 13C (DMSO-d6) δ 178.99,
156.04, 144.16, 134.29, 127.48, 57.88, 38.28, 37.07, 35.14,
28.25, 26.32; IR (Nujol) 3168, 1776, 1733; ES+ (M + H;
obtained in MeOH-H2O solvent mixture containing 1% formic
acid) calcd for C17H24O4N2B 331.1, found 330.9. Anal. Calcd
3-[3-(4-Bor on op h en yl)p r op yl]cyclobu ta n on e (28). The
synthesis was carried out as described for 26. A solution of
ketal 24 (3.62 mmol, 1.00 g) in methanol (30 mL) was stirred
with concentrated hydrochloric acid (0.5 mL) to obtain a faint
yellow viscous material (0.86 g) which was purified by silica
gel chromatography to yield 28 as a white solid (0.69 g, 83%
yield): Rf ) 0.52 (50% ethyl acetate in hexane, thin-layer
1
chromatography); mp 105-110 °C; H (DMSO-d6) δ 8.1 (s, 2
H, disappear by adding D2O), 7.87 (d, J ) 7.8 Hz, 2H), 7.33
(d, J ) 7.8 Hz, 2H), 3.25 (m, 2H), 2.75 (m, 4H), 2.49 (m, 1H),

8500 J . Org. Chem., Vol. 64, No. 23, 1999
Srivastava et al.
for C15H19BN2O4: C, 59.63; H, 6.34; B, 3.58; N, 9.27. Found:
C, 59.67; H, 6.30; N, 8.67; B, 3.31.
°C. The crude material was purified to obtain 3 as a white
solid (0.18 g, 69% yield): Rf ) 0.41 (mixture of acetonitrile,
methanol and water, in the ratio of 10:2:1.5); compound turns
brown (without melting) at 224-228 °C; 1H NMR (DCl) δ 6.96
(d, J ) 7.7 Hz, 2H), 6.56 (d, J ) 7.7 Hz, 2H), 1.96 (m, 2H),
1.84 (m, 2H), 1.72 (m, 1H), 1.38 (m, 2H), 1.09 (m, 2H); 13C (DCl)
δ 174.77, 146.35, 134.72, 129.04, 54.65, 38.43, 36.68, 33.22,
28.24; IR (Nujol) 3404, 1608; HR-FAB-MS (M + H; obtained
in glycerol matrix) calcd for C16H23O5BN 320.167, found
320.167.
Hyd a n toin 33 of 3-[7-(4-Bor on op h en yl)h ep tyl]cyclobu -
ta n on e (29). The synthesis was carried out as described for
30. A solution of 29 (3.67 mmol, 1.06 g) in aqueous ethanol
(50%, 12.0 mL) was allowed to react with potassium cyanide
(7.34 mmol, 0.479 g) and ammonium carbonate (18.4 mmol,
1.76 g) to obtain a faint yellow solid that was purified using
silica gel chromatography (10% methanol in methylene chlo-
ride) to obtain 33 as a white solid (0.261 g, 40% yield): Rf )
0.72 (10% methanol in methylene chloride, thin-layer chro-
1-Am in o-3-[3-(4-b or on op h en yl)p r op yl]cyclob u t a n e-
ca r boxylic Acid (4). The synthesis was carried out as
described for 2. A solution of hydantoin 32 (0.662 mmol, 0.200
g) and aqueous sodium hydroxide (2 N, 2 mL) was heated at
160 °C in a pressure tube. The crude material was purified to
obtain 4 as a white solid (0.112 g, 61% yield): Rf ) 0.46
(mixture of acetonitrile, methanol, and water in the ratio of
10:2:1.5); compound turns brown (without melting) at 228-
1
matography); mp 206-208 °C (dec); H (DMSO-d6 with 10%
D2O) δ, 8.13 (d, J ) 7.7 Hz, 2H), 7.59 (d, J ) 7.7 Hz, 2H), 2.99
(t, J ) 6.5 Hz, 2H), 2.88 (m, 2H), 2.73-2.55 (m, 2H), 2.32 (m,
1H), 1.97 (br s, 2H), 1.79 (m, 2H), 1.67 (bs, 8H); 13C (DMSO-
d6) δ 178.84, 155.92, 144.25, 134.16, 127.33, 57.76, 38.25, 37.02,
36.48, 35.22, 28.85, 28.62, 26.43, 26.31; IR (Nujol) 3169, 1779,
1733; HR-FAB-MS (M + H; glycerol matrix) calcd for C22H32
-
BN2O5 415.241, found 415.241. Anal. Calcd for C19H27BN2O4:
C, 63.70; H, 7.60; B, 3.02; N, 7.82. Found: C, 65.88; H, 7.65;
N, 7.46; B, 2.92.
1
232 °C; H NMR (DMSO-d6 with 5% D2O) δ 7.84 (d, J ) 7.5
Hz, 2H), 7.39 (d, J ) 7.5 Hz, 2H), 2.90-2.38 (m, 6H), 2.22 (m,
1H), 1.63 (br s, 4H); 13C (CD3OD) δ 176.31, 145.79, 134.93,
128.67, 57.24, 39.23, 38.02, 36.67, 29.53, 26.47; IR (Nujol) 3352,
1610; HR-FAB-MS (M + H; obtained in glycerol matrix) calcd
for C17H25O5BN 334.183, found 334.182.
1-Am in o-3-(4-bor on oph en yl)cyclobu tan ecar boxylic Acid
(2). The hydantoin of 3-(4-boronophenyl)cyclobutanone, 30
(1.54 mmol, 0.400 g), was placed in a 15 mL Ace pressure tube
along with a solution of aqueous sodium hydroxide (2 N, 4.0
mL). The tube was sealed and then heated at 160 °C (oil bath)
for 40 min. After cooling to room temperature, it was carefully
opened. TLC indicated disappearance of the starting hydan-
toin. The reaction mixture was decolorized with charcoal (0.2
g) and filtered. The filtrate was neutralized with dilute
aqueous hydrochloric acid and concentrated under reduced
pressure. The crude material was purified using a reverse
phase column (2 × 16 cm, using 50% methanol water with 2%
acetic acid) to obtain 2 as a white solid (0.188 g, 52% yield):
Rf ) 0.32 (mixture of acetonitrile, methanol, and water in the
ratio of 10:2:1.5); compound turns brown (without melting) at
1-Am in o-3-[7-(4-b or on op h e n yl)h e p t yl]cyclob u t a n e -
ca r boxylic Acid (5). The synthesis was carried out as
described for 2. A solution of 33 (1.03 mmol, 0.369 g) and
aqueous sodium hydroxide (2 N, 7 mL) was heated at 160 °C.
The crude material was purified to obtain 5 as a white solid
(0.288 g, 84% yield). Rf ) 0.61 (mixture of acetonitrile,
methanol, and water in the ratio of 10:2:1.5); compound soften
1
and turns brown (without clear melting) at 204-208 °C; H
NMR (CD3OD with 5% D2O) δ 7.05 (d, J ) 7.5 Hz, 2H), 6.88
(d, J ) 7.5 Hz, 2H), 2.33 (m, 4H), 2.06 (m, 2H), 1.61 (br s, 1H),
1.33 (br s, 2H), 1.19 (br s, 2H), 1.05 (br s, 8H); 13C (CD3OD) δ
177.36, 144.02, 134.16, 128.21, 55.93, 38.32, 36.93, 36.76,
32.51, 30.52, 30.25, 29.62, 27.87; IR (Nujol) 3504, 3147, 1636,
1611; HR-FAB-MS (M + H; obtained in glycerol matrix) calcd
for C21H33O5BN 390.246, found 390.245
1
262-265 °C; H NMR (DCl) δ 7.54 (d, J ) 6.1 Hz, 2H), 7.16
(d, J ) 6.1 Hz, 2H), 3.69 (m, 1H), 2.85 (m, 2H), 2.42 (m, 2H);
13C NMR (DCl) δ 174.91, 147.05, 134.89, 126.74, 54.46, 37.79,
32.85; IR (Nujol) 3361, 1607; HR-FAB-MS (M + H; obtained
in glycerol matrix) calcd for
292.136.
C14H19O5BN 292.136, found
Ack n ow led gm en t. This research was supported by
the U.S. Department of Energy and the Robert H. Cole
Foundation.
1-Am in o-3-[2-(4-b or on op h e n yl)e t h yl]cyclob u t a n e -
ca r boxylic Acid (3). The synthesis was carried out as
described for 2. A solution of 31 (0.63 mmol, 0.18 g) and
aqueous sodium hydroxide (2 N, 4.0 mL) was heated at 160
J O990878C