Fast microwave-assisted preparation of aryl and vinyl nitriles and the corresponding tetrazoles from organo-halides

Article abstract of DOI:10.1021/jo0009954

Aryl and vinyl nitriles have been prepared in very high yields from the corresponding bromides using palladium-catalyzed reactions with microwave irradiation employed as the energy source. Furthermore, flash heating was used successfully for the conversion of these nitriles into aryl and vinyl tetrazoles by cycloaddition reactions. One-pot transformation of aryl halides directly to the aryl tetrazoles could be accomplished both in solution and on solid support. All reactions were completed in minutes rather than in hours or days as previously reported with the standard thermal heating technique. A very potent HIV-1 protease inhibitor (K(i) = 0.56 nM), comprising two tetrazole heterocycles as carboxyl group bioisosteres, was prepared in one pot by microwave-promoted cyanation of a bromo precursor and a subsequent cycloaddition reaction. The temperature-time profiles at 13, 20, and 60 W magnetron input power in DMF are presented.

Full text of DOI:10.1021/jo0009954

7984
J . Org. Chem. 2000, 65, 7984-7989
F a st Micr ow a ve-Assisted P r ep a r a tion of Ar yl a n d Vin yl Nitr iles
a n d th e Cor r esp on d in g Tetr a zoles fr om Or ga n o-h a lid es
Mathias Alterman and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University,
Box 574, SE-751 23 Uppsala, Sweden
Anders.Hallberg@farmkemi.uu.se
Received J une 30, 2000
Aryl and vinyl nitriles have been prepared in very high yields from the corresponding bromides
using palladium-catalyzed reactions with microwave irradiation employed as the energy source.
Furthermore, flash heating was used successfully for the conversion of these nitriles into aryl and
vinyl tetrazoles by cycloaddition reactions. One-pot transformation of aryl halides directly to the
aryl tetrazoles could be accomplished both in solution and on solid support. All reactions were
completed in minutes rather than in hours or days as previously reported with the standard thermal
heating technique. A very potent HIV-1 protease inhibitor (Ki ) 0.56 nM), comprising two tetrazole
heterocycles as carboxyl group bioisosteres, was prepared in one pot by microwave-promoted
cyanation of a bromo precursor and a subsequent cycloaddition reaction. The temperature-time
profiles at 13, 20, and 60 W magnetron input power in DMF are presented.
In tr od u ction
tetrazoles need long reaction times for completion, often
days when electron-rich aryl nitriles were employed.2a,4
Nitriles are valuable intermediates in organic synthe-
sis and can be transformed to yield a broad spectrum of
functionalities, e.g., thiazoles, oxazolidones, triazoles, and
tetrazoles.1 Tetrazoles are of particular interest to the
medicinal chemist since they probably constitute the
most commonly used bioisostere of the carboxyl group.2
Thus, a retained pharmacological effect and a more
favorable pharmacokinetic profile are often achieved by
the replacement of a carboxyl group with a metabolically
stable tetrazole.
There are several methods available for the prepara-
tion of nitriles,1a,3 and among these, considerable research
efforts have been devoted to the direct transition metal-
catalyzed conversion of aryl halides to aryl nitriles.3e-n
Aryl halides are attractive as starting materials in lead
optimization processes since they can serve as precursors
for a plethora of diverse reactions. In 1994, Tschaen et
al. reported an improvement of the palladium-catalyzed
cyanation of aryl bromides where zinc cyanide was
exploited as the cyanide source.3h Reaction times of 5-7
h were reported. Also the subsequent transformation to
The rapid development of combinatorial and robotized
parallel synthesis has led to a growing demand for fast
reactions and efficient purification procedures. We herein
report that flash heating by microwave irradiation5
allows for the formation of aryl and vinyl nitriles6 from
the corresponding halides and the further conversion of
(3) (a) March, J . Advanced Organic Chemistry; J ohn Wiley & Sons:
New York, 1992. (b) Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev.
1987, 87, 779-794. (c) Friedrich, K., Wallenfels, K., Rappoport, Z., Ed.;
Interscience: New York, 1970; pp 92-93. (d) Patai, S., Zabicky, J .,
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Toyooka, Y. Chem. Lett. 1998, 435-426. (f) Anderson, B. A.; Bell, E.
C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.; Wepsiec, J . P. J . Org. Chem.
1998, 63, 8224-8228. (g) Andersson, Y.; Långstro¨m, B. J . Chem. Soc.,
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King, A. O.; Fortin, M. C.; Pipik, B.; King, S.; Verhoeven, T. R. Synth.
Commun. 1994, 24, 887-890. (i) Sosnovsky, G.; Krogh, J . A. Synthesis
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S.; Hayama, N. Bull. Chem. Soc. J pn. 1975, 48, 3298-3301. (m) Fizet,
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J .; S., H. L. J . Am. Chem. Soc. 1969, 91, 1233-1234.
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35, 405-408. (c) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis
1998, 910-914. (d) LeBlanc, B. W.; J ursic, B. S. Synth. Commun. 1998,
28, 3591-3599.
(5) (a) The dissipation factor (tan δ) expresses the ability of a
material to transform electromagnetic energy into thermal energy at
a given temperature and frequency. A higher value for the tan δ
indicates a higher susceptibility to microwave energy. Gabriel, C.;
Gabriel, S.; Grant, E. H.; Halstead, B. S. J .; Mingos, M. P. Chem. Soc.
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D´ıaz-Ortiz, A.; D´ıez-Barra, E. Contemp. Org. Synth. 1997, 373-386.
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M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20, 1-47.
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Collins, P. W.; Koboldt, C. M.; Veenhuizen, A. W.; Perkins, W. E.;
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Tetrahedron Lett. 1998, 39, 6533-6534. (2) From amides, see (e) Bose,
D. S.; J ayalakshimi, B. J . Org. Chem. 1999, 64, 1713-1714. (3) From
aldoximes, see (f) Sabitha, G.; Syamala, M. Synth. Commun. 1998, 28,
4577-4580.
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D.; Malhotra, R. K. Prog. Med. Chem. 1980, 17, 151-183.
10.1021/jo0009954 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Preparation of Aryl and Vinyl Nitriles
J . Org. Chem., Vol. 65, No. 23, 2000 7985
Ta ble 1. Micr ow a ve-P r om oted Cya n a tion Rea ction s w ith Or ga n o-br om id es
these nitriles to tetrazoles,7 either in solution or on solid
phase, in minutes rather than hours or days. Further-
more, the microwave-assisted synthesis of a potent HIV-1
protease inhibitor, comprising tetrazole rings, which is
a target in an ongoing medicinal chemistry program,8 is
reported.
heating, and in some cases by alternative methods are
presented in the table for comparison.
The nitriles 2a -h were converted to tetrazoles by
treatment with sodium azide and ammonium chloride in
DMF, rather than by employing alkyltin or alkylsilicon
azide reagents, which would require a subsequent depro-
tection step. The sodium azide procedure allowed for a
facile purification but is known to be accompanied by the
sublimation of explosive ammonium azide.9 The results
are presented in Table 2. A microwave power of 20 W
was applied to avoid formation of the side products that
tended to be produced with greater irradiation. Despite
the relatively low power, a temperature of 220 C° was
reached already after 10 min, most likely attributed to
the high salt concentration.10 The reaction times varied
from 10 to 25 min. The yields were generally good and
comparable to those previously reported, although the
sterically hindered ortho-substituted biphenyl 3e, com-
prising the common fragment in many angiotensin II
antagonists,2b was isolated in only moderate yield. The
yield with 3e was considerably lower than that achieved
by other methods, i.e., using trimethylsilyl azide/trimeth-
yaluminum, and standard thermal heating.11 Starting
material (2e) remained after 25 min of microwave heat-
Resu lts
The reactions were performed in a commercially avail-
able single-mode microwave cavity in sealed heavy-
walled Pyrex tubes. The organo-bromides 1a -h were
reacted with 1 equiv of Zn(CN)2 in DMF with Pd(PPh3)4
as catalyst. All bromides were consumed after 2 min at
a magnetron input power of 60 W, with the exception of
the electron-rich thiophene 1g that required a somewhat
longer reaction time, 2.5 min, for full conversion. A
reaction temperature of 175 °C was reached after 2.5 min
at 60 W, as deduced by temperature measurement using
a fluoroptic probe. The preparative results are sum-
marized in Table 1. After chromatography the nitriles
2a -h were isolated in good yields. Corresponding reac-
tion times and yields from reports on the preparation of
the nitriles from the corresponding bromides by thermal
(7) For a microwave-promoted preparation of a tetrazole from a
2-azido-4-methylquinoline, see Kidwai, M.; Goel, Y.; Kumar, R. Indian
J . Chem. 1998, 37B, 174-179.
(8) (a) Alterman, M.; Andersson, H. O.; Garg, N.; Ahlse´n, G.;
Lo¨vgren, S.; Classon, B.; Danielson, U. H.; Kvarnstro¨m, I.; Vrang, L.;
Unge, T.; Samuelsson, B.; Hallberg, A. J . Med. Chem. 1999, 42, 3835-
3844. (b) Alterman, M.; Bjo¨rsne, M.; Mu¨hlman, A.; Classon, B.;
Kvarnstro¨m, I.; Danielson, H.; Markgren, P. O.; Nillroth, U.; Unge,
T.; Hallberg, A.; Samuelsson, B. J . Med. Chem. 1998, 41, 3782-3792.
(9) Although no explosion occurred in any of the described examples
only microwave cavities enclosed in a safety metal case and a reaction
vessel with a pressure releasing septa should be used. In fact, even
experiments with no inert atmosphere were safely performed.
(10) Strauss, C. R.; Trainor, R. W. Aust. J . Chem. 1995, 48, 1665-
1692.
(11) Huff, B. E.; Staszak, M. A. Tetrahedron Lett. 1993, 34, 8011-
8014.

7986 J . Org. Chem., Vol. 65, No. 23, 2000
Alterman and Hallberg
Ta ble 2. Micr ow a ve-P r om oted Cycloa d d ition Rea ction s w ith Or ga n o-n itr iles
Sch em e 1
Sch em e 2
ing. A longer reaction time or alternatively higher power
input led to the formation of side products, and no
improvement of the isolated yield was observed. On the
other hand the microwave irradiation provided the
electron rich tetrazole 3a from 2a in a better yield than
previously reported.12
Bromobenzene can be converted to 5-phenyltetrazole
4 by a convenient one-pot procedure, which delivers a
very high total yield (Scheme 1). The microwave-
promoted heating technique is apparently also suitable
for conversions of iodides to tetrazoles on solid support
as demonstrated in Scheme 2 where a Rink linker on
Tentagel was used as solid support. A high yield of the
aryl tetrazole 5 was isolated after cleavage from the resin,
and only a negligible decomposition of the solid support
had occurred.
A potent C2-symmetric HIV-1 protease inhibitor (7,
Ki ) 0.56 nM) with two carboxyl group bioisosteres,
designed to interact with Arg 8/Arg 108 of the enzyme,8a
was prepared in one pot from the corresponding aryl
bromo precursor 6 (Scheme 3). It is notable that the
bisfunctionalization could be accomplished smoothly in
good yield and that no side products derived by, for
example, elimination of water were detected. Cycloaddi-
tion with ammonium azide in DMF is recognized to
(12) Pusinov, G. L.; Ishmetova, R. I.; Kitaeva, V. G.; Beresnev, D.
G. Chem. Heterocycl. Compd. 1994, 30, 1192-1194.

Preparation of Aryl and Vinyl Nitriles
J . Org. Chem., Vol. 65, No. 23, 2000 7987
Sch em e 3
F igu r e 1. Curve A: 60 W, 2.5 min, DMF, 4-bromoanisole,
Zn(CN)2, Pd(PPh3)4; Curve B: 20 W, 25 min, DMF, 4-meth-
oxybenzonitrile, NaN3, NH4Cl; Curve C: 13 W, 40 min, DMF,
6, NaN3, NH4Cl.
produce side products and to provide a less suitable
combination for the preparation of larger polyfunctional
molecules.4b
< 0.3 kcal/mol at a output frequency of 2450 MHz, to be
responsible for any noteworthy direct molecular activa-
tion.15
Discu ssion
Microwave irradiation has been much exploited as a
heating source for organic reactions. Recently, the Heck,
Stille, and Suzuki reactions, that often need hours or
days for completion with the standard thermal heating
technique, as deduced from literature data, were executed
in a few minutes and delivered high yields by employing
flash heating with microwave irradiation.13 These reac-
tions involve labile organopalladium complexes as key
intermediates. The related cyanation, proceeding by an
oxidative addition of palladium(0) and a subsequent
reductive elimination, could be accomplished in DMF (tan
δ ) 0.16)5a at the same relatively high magnetron input
power (60 W) as the other palladium-catalyzed reactions.
On the other hand, cycloaddition reactions performed
with the same power input (60 W) led to complex
mixtures of products, with low power and somewhat
longer reaction times providing a more satisfying out-
come. Thus, the best balance between microwave power
and irradiation time must be carefully determined for
each individual reaction type. Even though a power of
only 20 W was employed for cycloaddition reactions, a
high reaction temperature (220 °C after 10 min) and a
considerable superheating (bp of DMF ) 153 °C) were
noted. In Figure 1 the temperature profiles in the
septum-sealed reaction mixtures at 60, 20, and 13 W in
DMF are presented.
Con clu sion
In conclusion, aryl and vinyl nitriles have been pre-
pared very efficiently from the corresponding bromides
in palladium-catalyzed reactions where microwave ir-
radiation was employed as the energy source. Flash
heating was also used successfully for the fast conversion
of these nitriles into aryl and vinyl tetrazoles by cycload-
dition reactions. The transformation of aryl halides
directly to the aryl tetrazoles in one pot could be ac-
complished both in solution and on solid support. The
reactions were completed in a few minutes and consider-
ably faster than previously reported with standard heat-
ing technique. Although only a limited number of ex-
amples are given herein, we believe that the flash heating
methodology should provide a very attractive alternative
to standard thermal heating procedures when organo-
nitriles or tetrazoles are required using aryl and vinyl
halides as starting materials.
Exp er im en ta l Section
Gen er a l In for m a tion . 1H and 13C NMR spectra were
recorded at 270.2 and 67.8 MHz, respectively. Chemical shifts
are given as δ values (ppm) downfield from tetramethylsilane.
Infrared spectra were recorded on a FTIR instrument equipped
with a Microfocus Beam Condenser and compression cell.
Elemental analyses were performed by Mikro Kemi AB,
Uppsala, Sweden, and were within (0.4% of calculated values.
Circular chromatography was performed with 1 mm thick
silica gel 60 (0.04-0.063 mm) plates and gradient elution.
FPLC reversed phase chromatography was performed with a
PepRPC 15 µm 30 × 100 mm column. Thin-layer chromatog-
raphy was performed on precoated silica gel F-254 plates (0.25
mm) and visualized with UV light or H2SO4 in ethanol, or
ninhydrin. The palladium tetrakis triphenylphosphine was
freshly made according to procedure described by Heck.16 All
microwave reactions were carried out in heavy-walled Pyrex
tubes, inner diameter 9 mm and height 147 mm, sealed with
screw cap fitted Teflon septa. Microwave heating was carried
out with a MicroWell 10 single-mode cavity (Labwell AB,
Uppsala, Sweden), producing continuous irradiation at 2450
MHz. It is not recommended to repeat these reactions in a
By the in situ mode of energy conversion, microwaves
enable the heating of a reaction mixture very rapidly,
directly and uniformly if single-mode microwave cavities
are used.14 No problems related to heat transfer through
the walls of the reaction vessels are to be expected.15 The
overall advantage of microwave heating is attributable
to the direct rapid in situ heating and the bulk super-
heating that easily can be achieved.10 These factors alone
are thought to account for the accelerated reaction rates.
The energy transmitted by the microwave is too small,
(13) Larhed, M.; Hallberg, A. J . Org. Chem. 1996, 61, 9582-9584.
(14) Stone-Elander, S. A.; Elander, N.; Thorell, J .; Solås, G.; Sven-
nebrink, J . J . Label. Compd. Radiopharm. 1994, XXXIV, 949-959.
(15) Cundy, C. S. Collect. Czech. Chem. Commun. 1998, 63, 1699-
1723.
(16) Heck, R. F. Academic Press INC. (London) Ltd. 1985, 2-3.

7988 J . Org. Chem., Vol. 65, No. 23, 2000
Alterman and Hallberg
multimode domestic microwave oven producing nonuniform
irradiation. Ca u tion ! It is im p or ta n t to n ote th a t w h en
ca r r yin g ou t m icr ow a ve-h ea ted r ea ction s in closed
vessels, qu ite la r ge p r essu r es m a y bu ild u p , a n d th er e-
for e it is im p er a tive th a t a n a p p r op r ia te sep tu m is
u tilized a s a p r essu r e r elief d evice. Temperature profiles
were recorded using a NoEMI-TS Reflex (NortechFibronic,
Inc.) utilizing temperature-sensitive fluoroptic probes (TPP-
01-M2.5-A; Nortech Fibronic). The probe was positioned at the
bottom of the reaction tube. Standard workup: organic layers
were dried with MgSO4 and concentrated in vacuo. The
isolated compounds 2a ,21 b,22 c,23 d ,24 e,25 f,26 g,27 h ,28 3a ,29
b,29a,30 c,29a,30 d ,31 e,32 and 433 have previously been character-
ized and corresponded satisfactory with NMR literature data.
The isolated compounds 3f,34g,35h ,36 have previously been
characterized and corresponded satisfactory with literature
melting point data, NMR data are provided in Supporting
Information. Ca u tion ! Am m on iu m a zid e, w h ich m igh t
su blim a te in r ea ction s w ith sod iu m a zid e a n d a m -
m on iu m ch lor id e, is in d r y for m exp losive a t tem p er a -
tu r es a bove 136 °C.
Gen er a l P r oced u r es for Nitr ile-Cou p lin g Rea ction
(Ta ble 1). A dried heavy-walled Pyrex tube was charged with
organo-bromide (0.2 mmol), Zn(CN)2 (23.5 mg, 0.2 mmol), and
Pd(PPh3)4 (6.9 mg, 6.0 µmol) in DMF (1 mL). The reaction
mixture was flushed with nitrogen and the screw cap tightened
thoroughly before mixing with a Whirlimixer. The reaction
mixture was exposed to microwave irradiation (60 W) for 2
min (for 2g 2.5 min). The reaction tube was allowed to reach
room temperature before the reaction mixture was diluted in
EtOAc (60 mL) and washed with water. The organic phase
was dried, and the solvent was removed under reduced
pressure. The crude product was purified on circular chroma-
tography to give the pure nitrile 2a ,21 b,22 c,23d ,24 e,25 f,26 g,27
h .28
nitrile (0.1 mmol), NaN3 (78 mg, 1.2 mmol), and NH4Cl (64
mg, 1.2 mmol) in DMF (1 mL). The reaction mixture was
flushed with nitrogen and the screw cap tightened thoroughly
before mixing with a Whirlimixer. The reaction mixture was
exposed to microwave irradiation (20 W) for 10-25 min. The
reaction tube was allowed to reach room temperature before
the reaction mixture was diluted in saturated NaHCO3 (60
mL) and washed with EtOAc. The water phase was acidified
to pH < 1 with concentrated HCl and extracted with CHCl3.
The combined organic phases were dried, and the solvent was
removed under reduced pressure to give the pure compounds
3a ,29b,29a,30 c,29a,30 d ,31 e,32 f,34 g,35 h .36
5-P h en yltetr a zole (4), A dried heavy-walled Pyrex tube
was charged with bromobenzene (10.5 µL, 0.1 mmol), Zn(CN)2
(11.7 mg, 0.1 mmol), and Pd(PPh3)4 (11.6 mg, 10 µmol) in DMF
(1 mL). The reaction mixture was flushed with nitrogen and
the screw cap tightened thoroughly before mixing with a
Whirlimixer. The reaction mixture was exposed to microwave
irradiation (60 W) for 2 min. The reaction tube was allowed
to reach room temperature. Thereafter the tube was charged
with NaN3 (78 mg, 1.2 mmol) and NH4Cl (64 mg, 1.2 mmol).
The reaction mixture was flushed with nitrogen and the screw
cap tightened thoroughly before mixing with a Whirlimixer.
The reaction mixture was once again exposed to microwave
irradiation (20 W) for 15 min. The reaction tube was allowed
to reach room temperature before the reaction mixture was
diluted in sat. NaHCO3 (60 mL) and washed with EtOAc. The
water phase was acidified to pH < 1 with concentrated HCl
and extracted with CHCl3. The combined organic phase was
dried, and the solvent was removed under reduced pressure
to give the pure compound 4.33
4-(5-Tetr a zolyl)ben zen eca r boxa m id e (5), 4-Iodobenzoic
acid coupled to TentaGel S Ram (100 mg, 0.25 mmol/g
capacity) was added to a dried heavy-walled Pyrex tube.17 The
resin was swollen in DMF (1 mL) for 15 min. Then Zn(CN)2
(2.9 mg, 0.025 mmol) and Pd(PPh3)4 (2.9 mg, 2.5 µmol) were
added. The reaction mixture was flushed with nitrogen and
the screw cap tightened thoroughly before mixing with a
Whirlimixer. The reaction mixture was exposed to microwave
irradiation (60 W) for 2 min. The reaction tube was allowed
to reach room temperature. Thereafter the tube was charged
with NaN3 (19.5 mg, 0.3 mmol) and NH4Cl (16.0 mg, 0.3
mmol). The reaction mixture was flushed with nitrogen and
the screw cap tightened thoroughly before mixing with a
Whirlimixer. The reaction mixture was once again exposed to
microwave irradiation (20 W) for 15 min. The reaction tube
was allowed to reach room temperature. The resin was
collected on a polypropylene filter and washed with DMF,
water, DMF, MeOH, and CH2Cl2. The resin was transferred
to a polypropylene tube, and a TFA:water mixture (25:1, 1 mL)
was added. The reaction mixture was turned for 5 min and
then filtered through a polypropylene filter. The resin was
washed with CH2Cl2 and MeOH. The combined filtrate was
evaporated and coevaporated with acetonitrile. The residue
was dissolved in saturated NH4OH and was purified using
Waters Oasis Extraction Cartridges (HLB6cc) with water
(20 mL) as eluent, to give pure 5 in 72% yield: IR (compression
Gen er a l P r oced u r es for Tetr a zole F or m a tion (Ta ble
2). A dried heavy-walled Pyrex tube was charged with organo-
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suji, K.; Kato, M.; Yano, S. J . Org. Chem. 1996, 61, 6829-6834.
(27) (a) Mlochowiski, J .; Kloc, K.; Kubicz, E. J . Prakt. Chem. 1994,
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1
cell) ν 3355, 3170, 1658, 1625 cm-1; H NMR (CD3OD) δ 8.14
(m, 2H), 7.99 (m, 2H); 13C NMR (DMSO-d6) δ 167.0, 155.5,
136.2, 128.4, 127.2, 126.7. Anal. Calcd for C8H7N5O + 0.3
TFA: C, 46.1; H, 3.3; N, 31.2. Found: C, 46.1; H, 3.6; N, 30.8.
N1,N6-Bis[(1S)-2-m eth yl-1-(m eth ylca r ba m oyl)p r op yl]-
(2R,3R,4R,5R)-2,5-bis[4-(5-tetr a zolyl)ben zyloxy]-3,4-d ih y-
d r oxyh exa n ed ia m id e (7), A dried heavy-walled Pyrex tube
was charged with 68a (30 mg, 0.04 mmol), Zn(CN)2 (13.7 mg,
0.12 mmol), and Pd(PPh3)4 (5.4 mg, 4.7 µmol) in DMF (1 mL).
The reaction mixture was flushed with nitrogen and the screw
cap tightened thoroughly before mixing with a Whirlimixer.
The reaction mixture was exposed to microwave irradiation
(60 W) for 2.5 min. The reaction tube was allowed to reach
room temperature. Thereafter the tube was charged with NaN3
(61 mg, 0.9 mmol) and NH4Cl (50 mg, 0.9 mmol). The reaction
mixture was flushed with nitrogen and the screw cap tightened
thoroughly before mixing with a Whirlimixer. The reaction
mixture was once again exposed to microwave irradiation (13
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11742.
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1464.
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94, 340-355.

Preparation of Aryl and Vinyl Nitriles
J . Org. Chem., Vol. 65, No. 23, 2000 7989
W) for 40 min. The reaction tube was allowed to reach room
temperature before the reaction mixture was diluted in CH3-
Cl (60 mL) and washed with 1 M HCl. The organic phase was
dried, and the solvent was removed under reduced pressure.
The crude product was purified on FPLC, with water:2-
propanol 0.1% TFA (1:9 to 3:7), to give 24 mg (82%) of the titled
compound as a white solid: IR (KBr) ν 3302, 2927, 2874, 1625,
1539 cm-1; [R]22D ) -8.3 (c ) 2.15, DMSO); 1H NMR (CD3OD)
δ 7.7 (d, J ) 8.3 Hz, 4H), 7.57 (d, J ) 8.3 Hz, 4H), 4.65 (s,
2H), 4.19 (d, J ) 6.9, 2H), 4.11 (m, 4H), 2.75 (s, 6H), 2.09 (m,
2H), 0.94 (d, J ) 6.8 Hz, 6H), 0.92 (d, J ) 6.8 Hz, 6H); 13C
NMR (DMSO-d6) δ 171.1, 170.4, 155.2, 141.4, 128.2, 126.9,
123.2, 79.4, 70.5, 69.6, 57.7, 30.5, 25.4, 19.3, 18.1. Anal. Calcd
for C34H46N12O8 + H2O: C, 53.1; H, 6.3; N, 21.9. Found: C,
53.3; H, 6.1; N, 21.5.
Ack n ow led gm en t. We gratefully acknowledge sup-
port from the Swedish Foundation for Strategic Re-
search (SSF), the Swedish Research Council for Engi-
neering Sciences (TFR), and Medivir AB for the enzyme
activity test of the HIV-1 protease inhibitor.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra for
the compounds 3e; 1H and 13C NMR spectra for the compounds
3f-h . This material is available free of charge on the Internet
at http://pubs.acs.org.
J O0009954