Catalytic carbonylation of functionalized diamines: Application to the core structure of DMP 323 and DMP 450

Article abstract of DOI:10.1021/jo026816v

W(CO)₆-catalyzed carbonylation provides an alternative to phosgene or phosgene derivatives such as 1,1-carbonyldiimidazole (CDI) for the conversion of amines to ureas. As an illustration, the core structure of the HIV protease inhibitors DMP 32

Full text of DOI:10.1021/jo026816v

aspects of these reactions (e.g., generation of hydrogen
selenide and the need for stoichiometric or excess sele-
nium for certain substrates13,14) are problematic.
We recently reported the catalytic carbonylation of
aliphatic amines to ureas using W(CO)6 as the catalyst
and I2 as the oxidant.15-18 Diamine substrates with
simple hydrocarbon linkers were converted to cyclic ureas
with five- to eight-membered rings.19,20 Because the
reaction conditions are relatively mild and the functional
group tolerance is surprisingly broad, this procedure was
a reasonable candidate for use in synthesis of complex
targets. As an illustration of its utility, we now report
installation of the urea moiety into the core structure of
the HIV protease inhibitors DMP 323 and DMP 45021-23
by catalytic carbonylation of the corresponding diamine.
The availability of a substantial body of literature on the
synthesis of DMP 323 and DMP 450 derivatives allows
direct comparison of the catalytic carbonylation reaction
with stoichiometric reaction of the same substrates with
phosgene derivatives.
Ca ta lytic Ca r bon yla tion of F u n ction a lized
Dia m in es: Ap p lica tion to th e Cor e
Str u ctu r e of DMP 323 a n d DMP 450
Keisha-Gay Hylton, A. Denise Main, and
Lisa McElwee-White*
Department of Chemistry and Center for Catalysis,
University of Florida, Gainesville, Florida 32611-7200
lmwhite@chem.ufl.edu
Received December 6, 2002
Abstr a ct: W(CO)6-catalyzed carbonylation provides an
alternative to phosgene or phosgene derivatives such as 1,1-
carbonyldiimidazole (CDI) for the conversion of amines to
ureas. As an illustration, the core structure of the HIV
protease inhibitors DMP 323 and DMP 450 has been
prepared by catalytic carbonylation of diamine intermediates
from the original syntheses.
Methods for conversion of amines to ureas are gener-
ally based on the nucleophilic attack of amines on phos-
gene or a phosgene derivative.1 A variant of this strategy
involves reaction of amines with isocyanates, which also
ultimately derive from phosgene. For a variety of reasons
including concerns about phosgene2 and the benefits of
having alternative procedures available for synthetic
transformations, we have been developing metal-cata-
lyzed methods for the formation of ureas from amines
and CO.
There are several reasons why prior work on metal-
catalyzed oxidative carbonylation of amines has not been
extended to applications in organic synthesis. Although
transition-metal catalysts involving Ni,3 Co,4 Mn,5,6 Ru,7
Au,8 and Pd9-11 have been demonstrated to yield at least
some urea from amines and CO, it is often a minor
product. These transition-metal-catalyzed processes gen-
erally require high temperatures and pressures and
frequently produce complex mixtures of ureas, forma-
mides, and oxamides. In addition, yields of ureas from
aliphatic amines are generally lower than those obtained
from aromatic substrates, limiting their potential utility
in organic synthesis. Main group elements such as
selenium12-14 can also serve as catalysts; however, certain
In previously reported routes to DMP 323, DMP 450,
and related compounds, the urea moiety was installed
by reaction of phosgene or a phosgene equivalent with
an O-protected diaminediol. In the initial small-scale
preparations, a primary diamine was reacted with the
phosgene derivative 1,1′-carbonyldiimidazole (CDI),22,24-26
followed by N-alkylation as appropriate. The practical
route to DMP 450 utilizes phosgene to form the cyclic
(14) Yoshida, T.; Kambe, N.; Murai, S.; Sonoda, N. Tetrahedron Lett.
1986, 27, 3037-3040.
(15) McCusker, J . E.; Main, A. D.; J ohnson, K. S.; Grasso, C. A.;
McElwee-White, L. J . Org. Chem. 2000, 65, 5216-5222.
(16) McCusker, J . E.; Qian, F.; McElwee-White, L. J . Mol. Catal. A:
Chem. 2000, 159, 11-17.
* To whom correspondence should be addressed. Fax: 352-846-0296.
(1) Hegarty, A. F.; Drennan, L. J . In Comprehensive Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O.,
Rees, C. W., Eds.; Pergamon: Oxford, 1995; Vol. 6, pp 499-526.
(2) Bigi, F.; Maggi, R.; Sartori, G. Green Chem. 2000, 2, 140-148.
(3) Giannoccaro, P.; Nobile, C. F.; Mastrorilli, P.; Ravasio, N. J .
Organomet. Chem. 1991, 419, 251-258.
(4) Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. J . Mol. Catal.
1990, 60, 41-48.
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203-217.
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1998, 17, 4037-4041.
(19) McCusker, J . E.; Grasso, C. A.; Main, A. D.; McElwee-White,
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T.; Rayner, M. M.; Klabe, R. M.; Shum, L. Y.; Winslow, D. L.;
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10.1021/jo026816v CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/24/2003
J . Org. Chem. 2003, 68, 1615-1617
1615

TABLE 1. Ca r bon yla tion of Dia m in es 1-3 to Ur ea s 4-6a
Cl2/H2O solvent system afforded 4 in 38% yield. As we
had observed for the carbonylation of functionalized
benzylamines,15 yields obtained by using the biphasic
solvent system were higher than those in CH2Cl2. Efforts
to optimize the reaction conditions by varying CO pres-
sure, temperature, concentration, and solvent did not
result in higher yields of 4. Although the yields of 4 from
1 are modest, results from the catalytic carbonylation
compare favorably to those obtained with CDI under
typical conditions.
urea
diame
reagent
CDI
solvent
CH3CN
T (°C) yield (%)
NRb 15
ref
1
1
1
1
2
2
3
3
25
25
c
CDI
TCE
147
67
W(CO)6/CO CH2Cl2/H2O 80
W(CO)6/CO CH2Cl2
CDI CH2Cl2
W(CO)6/CO CH2Cl2/H2O 80
CDI CH2Cl2 rt
W(CO)6/CO CH2Cl2/H2O 80
38
80
rt
23
c
62, 76d
49
22, 26, 29
c
52, 93d
75
22, 26
c
a
Typical reaction conditions: diamine 2 (0.200 mmol), W(CO)6
Acyclic protecting groups such as MEM and SEM had
been previously explored as alternatives that would les-
sen the strain problems that had plagued preparation of
bicyclic acetonide 4 from diamine 1.22,29 Accordingly,
MEM ether 2 and SEM ether 3 were chosen as additional
test substrates for conversion to the corresponding cyclic
ureas via catalytic carbonylation. Carbonylation of 2 and
3 was carried out under the conditions used for 1, with
the exception of substrate concentration, which was opti-
mized for 2 and the same used for 3. In comparison to
the literature yields of 62 and 76% for formation of urea
5 from Cbz-protected MEM ether 2 and CDI under slight-
ly different conditions, the catalytic carbonylation reac-
tion provided 5 in 49% yield from 2. Promising results
were also obtained for SEM ether 3, for which catalytic
carbonylation afforded urea 6 in 75% yield, a value
intermediate between the reported yields for reaction of
3 with CDI. Although the yields from both the stoichio-
metric CDI and catalytic carbonylation methods for urea
formation varied with the nature of the protecting group
on the diol, the overall results from the two methods were
roughly comparable. These experiments establish that
the catalytic reaction is compatible with acid-sensitive
substrates and fluoride-sensitive protecting groups.
Intermolecular urea formation in related acyclic sys-
tems was probed by catalytic carbonylation of the O-
protected amines 730 and 8. Both substrates afforded the
corresponding ureas in moderate to good yields (eq 2),
demonstrating that this catalytic methodology can also
be used for formation of symmetrical ureas from the cor-
responding amines. The reaction conditions were identi-
cal to those used for diamines 1-3, with the exception
of concentration. As expected for intermolecular reac-
tions, the maximum yields of urea were obtained at
higher substrate concentrations than those used with the
diamines, for which oligomerization competes with ring
closure.
(0.0219 mmol), K2CO3 (0.635 mmol), and I2 (0.213 mmol), solvent
b
(32 mL of CH2Cl2/8 mL of water), 80 atm of CO, 80 °C, 18 h. Not
d
reported. c This work. Yields are from
a two-step sequence
involving deprotection of the Cbz-protected diamine. Deprotection
is assumed to be quantitative for the purpose of the table.
urea from a secondary diamine.25 Since all of these routes
require protection of the diol, extensive protecting group
studies have been carried out.25,27 We have chosen three
of the previously described O-protected diamine diols,
acetonide 1,28 MEM ether 2,22,29 and SEM ether 3,22 as
representative examples bearing cyclic and acyclic pro-
tecting groups, respectively. Carbonylation of 1-3 (eq 1)
allows comparison of the W(CO)6-catalyzed process to the
stoichiometric reactions of the phosgene derivative CDI.
The difficulties associated with converting acetonide
1 to urea 4 have been discussed in the literature.
Reaction of 1 with CDI in acetonitrile under standard
conditions results in a 15% yield of 4 (Table 1) with the
low conversion attributed to strain in the bicyclic prod-
uct.25 Although higher yields of 4 could be obtained by
monoacylation of 1 with CDI followed by reflux at high
dilution in tetrachloroethane (TCE), there were practical
difficulties with this two-step procedure.25 In comparison,
catalytic oxidative carbonylation of 1 in the biphasic CH2-
(24) Nugiel, D. A.; J acobs, K.; Worley, T.; Patel, M.; Kaltenbach, R.
F.; Meyer, D. T.; J adhav, P. K.; DeLucca, G. V.; Smyser, T. E.; Klabe,
R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J . Med. Chem. 1996,
39, 2156-2169.
(25) Confalone, P. N.; Waltermire, R. E. In Process Chemistry in
the Pharmaceutical Industry; Gadamasetti, K. G., Ed.; Marcel Dek-
ker: New York, 1999; pp 201-219.
(26) Lam, P. Y.; J adhav, P. K.; Eyermann, C. J .; Hodge, C. N.; De
Lucca, G. V.; Rodgers, J . D. US Patent 5,610,294, 1997
(27) Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.; Storace,
L.; Waltermire, R. E.; Wat, E.; J adhav, P. K.; Emmett, G. C. J . Org.
Chem. 1996, 61, 444-450.
(28) Rossano, L. T.; Lo, Y. S.; Anzalone, L.; Lee, Y. C.; Meloni, D.
J .; Moore, J . R.; Gale, T. M.; Arnett, J . F. Tetrahedron Lett. 1995, 36,
4967-4970.
(29) Hodge, C. N.; Aldrich, P. E.; Bacheler, L. T.; Chang, C. H.;
Eyermann, C. J .; Garber, S.; Grubb, M.; J ackson, D. A.; J adhav, P. K.;
Korant, B.; Lam, P. Y. S.; Maurin, M. B.; Meek, J . L.; Otto, M. J .;
Rayner, M. M.; Reid, C.; Sharpe, T. R.; Shum, L.; Winslow, D. L.;
EricksonViitanen, S. Chem. Biol. 1996, 3, 301-314.
In summary, we have established that catalytic car-
bonylation of amines can be used in the preparation of
functionalized ureas. Use of this chemistry in preparation
(30) Herbert, J . M.; Knight, J . G.; Sexton, B. Tetrahedron 1996, 52,
15257-15266.
1616 J . Org. Chem., Vol. 68, No. 4, 2003

1-Be n zyl-2-[2-(t r im e t h ylsilyl)e t h oxym e t h oxy]e t h yl-
a m in e (8). A solution of (R)-N-Cbz-phenylalaninol (999.5 mg,
3.54 mmol), [2-(trimethylsilyl)]ethoxymethoxy chloride (SEMCl)
(2.40 mL, 13.5 mmol), and 2.5 mL of diisopropylethylamine in
10 mL of dry methylene chloride was stirred at room tempera-
ture overnight until TLC indicated that no starting material was
present. The reaction mixture was washed once with water. The
water layer in turn was washed with 4 × 10 mL of methylene
chloride, and the combined organics were washed with water (2
× 10 mL). The combined water layers were washed once with
10 mL of methylene chloride. The combined organics were dried
over magnesium sulfate, and the solvent was removed by evap-
oration to yield 1.456 g of the crude SEM ether as a brown oil.
To a solution of 496.0 mg (1.19 mmol) of the crude SEM ether
in 10 mL of EtOH was added 44.2 mg of 5% Pd/C. The reaction
mixture was degassed and subsequently filled with hydrogen
at 1 atm. The reaction mixture was then stirred for 2.5 h until
TLC showed no starting material. The mixture was then filtered
and evaporated to dryness to yield 320.5 mg of crude 8. The
crude amine was purified by column chromatography eluting
with 2/1 hexanes/ethyl acetate with 1% triethylamine followed
by 1:1 hexanes/ethyl acetate with 1% triethylamine to afford 8
as an oil in 68% yield: 1H NMR (CDCl3) δ 0.05 (s, 9H), 0.97 (t,
2H, J ) 8.1 Hz), 2.56-2.63 (m, 1H), 2.81-2.87 (m, 1H), 3.27-
3.28 (m, 1H), 3.39-3.44 (m, 1H), 3.57-3.69 (m, 3H), 4.73 (s, 2H),
7.22-7.35 (m, 5H); 13C NMR (CDCl3) δ -1.2, 18.3, 41.0, 52.7,
65.4, 72.8, 95.4, 126.5, 128.7, 129.4, 139.0; HRMS (M + H)+ calcd
282.1889, found 282.1886.
of the core structure of DMP 323 and DMP 450 provides
the first demonstration of catalytic amine carbonylation
as synthetic methodology. Due to the extensive literature
on these compounds, the results can be compared with
those previously reported for the stoichiometric reactions
of the phosgene derivative CDI. Yields of the ureas from
the catalytic reaction vary with the protecting group on
the diol, as do those reported for ring closure with
stoichiometric CDI. Studies of the carbonylation reaction
and its application in approaches to complex targets are
continuing.
Exp er im en ta l Section
Gen er a l Meth od s. All experimental procedures were carried
out under nitrogen and in oven dried glassware unless otherwise
indicated. Solvents and reagents were obtained from commercial
vendors in the appropriate grade and used without purification
except for solvents used in carbonylation reactions that were
dried, degassed, and distilled. Syntheses of diamines 1,28 2,22,29
and 322 and amine 722 were carried out according to literature
procedures. W(CO)6 was purified by chromatography on alumina
using hexanes as eluent.
(4R,5S,6S,7R)-Hexa h yd r o-5,6-O-isop r op ylid en e-4,7-bis-
(p h en ylm eth yl)-2H-1,3-d ia za p in -2-on e (4). To a glass-lined
300 mL Parr high-pressure vessel containing 18 mL of CH2Cl2
and 3 mL of water were added diamine 1 (126.7 mg, 0.37 mmol),
W(CO)6 (8.8 mg, 0.025 mmol), K2CO3 (164.9 mg, 1.19 mmol),
and I2 (100.5 mg, 0.39 mmol). The vessel was then charged with
85 atm of CO and heated at 81 °C 48 h. (CAUTION: CO is a
toxic gas.) The pressure was released, and 15 mL of water was
added. The organics were then separated and washed with a
saturated solution of Na2SO3 followed by brine. The resulting
solution was dried over magnesium sulfate and filtered. The
solvent was removed by evaporation, and the resulting residue
was purified via column chromatography on silica using ether
as eluent. Removal of the solvent afforded 4 as a white solid in
38% yield. The product was identified by comparison with
literature data.27 IR (neat) vCO 1671 cm-1; HRMS (M + H)+ calcd
367.2021, found 367.2012.
(4R,5S,6S,7R)-Hexah ydr o-5,6-bis(2-m eth oxyeth oxym eth -
oxy)-4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-on e (5). To a
glass-lined 300 mL Parr high-pressure vessel containing 32 mL
of CH2Cl2 and 8 mL of water were added diamine 2 (101.1 mg,
0.200 mmol), W(CO)6 (7.7 mg, 0.0219 mmol), K2CO3 (87.8 mg,
0.635 mmol), and I2 (54.2 mg, 0.213 mmol). The vessel was then
charged with 80 atm of CO and heated at 82 °C overnight. The
pressure was released, and 15 mL of water was added. The
organics were then separated and washed with a saturated
solution of Na2SO3 followed by brine. The resulting solution was
dried over magnesium sulfate and filtered. The solvent was
removed by evaporation, and the resulting residue was purified
to obtain 5 as a white solid in 49% yield after purification using
literature procedures.29 The product was identified by compari-
son with literature data.29 IR (neat) vCO 1674 cm-1; HRMS (M
+ H)+ calcd 503.2752, found 503.2797.
1,3-Bis[1-(2-m et h oxyet h oxym et h oxym et h yl)-2-p h en yl-
eth yl]u r ea (9). To a glass-lined 300 mL Parr high-pressure
vessel containing 34 mL of CH2Cl2 and 9 mL of water were added
amine 7 (106.8 mg, 0.379 mmol), W(CO)6 (6.8 mg, 0.019 mmol),
K2CO3 (78.8 mg, 0.570 mmol), and I2 (48.2 mg, 0.189 mmol). The
vessel was then charged with 80 atm of CO and heated at 82 °C
overnight. The pressure was released, 15 mL water was added,
and the organics were separated and washed with a saturated
solution of Na2SO3, water, and brine. The resulting solution was
dried over magnesium sulfate and filtered. The solvent was
removed by evaporation, and the resulting residue was purified
by washing with 2:1 hexanes/ethyl acetate and hexanes to afford
9 as a white solid in 82% yield. The product was identified by
1
comparison with literature data.24 IR (neat) vCO 1673 cm-1; H
NMR (CDCl3) δ 2.75-2.94 (m, 4H), 3.36 (s, 6H), 3.45-3.54 (m,
8H), 3.67-3.68 (m, 4H), 4.09-4.11 (m, 2H), 4.63-4.71 (q, 4H (J
) 6.3 Hz), 5.03-5.06 (d, 2H, J ) 8.1 Hz), 7.21-7.29 (m, 10H);
13C NMR (CDCl3) δ 38.4, 51.2, 59.1, 67.1, 69.8, 72.0, 96.1, 126.4,
128.5, 129.6, 138.6, 157.5; HRMS (M + H)+ calcd 505.2914, found
505.2902.
1,3-Bis[2-ph en yl-1-[2-(tr im eth ylsilyl)eth oxym eth oxym eth -
yl]eth yl]u r ea (10). Following the same procedure used to
prepare 9, urea 10 was obtained as an oil in 53% yield after
chromatography on silica using 2/1 hexanes/ethyl acetate as
eluent. Urea 10 was comprised of isomers in a 3:1 ratio. The
spectral data of the major isomer follow: IR (neat) vCO 1673 cm-
1; 1H NMR (CDCl3) δ 0.02 (s, 18H), 0.93 (t, 4H, J ) 8.1 Hz), 2.84
(m, 4H), 3.46 (m, 4H), 3.62 (m, 4H), 4.08 (m, 2H), 4.65 (s, 4H),
7.22-7.29 (m, 10H); 13C NMR (CDCl3) δ -1.4, 18.0, 38.1, 51.3,
64.4, 68.8, 95.3, 126.3, 128.4, 129.3, 138.2, 157.2; HRMS (M +
H)+ calcd 589.3493, found 589.3475.
(4R ,5S ,6S ,7R )-H e xa h yd r o-5,6-b is[2-(t r im e t h ylsilyl)-
eth oxym eth oxy]-4,7-bis(p h en ylm eth yl)-2H-1,3-d ia zep in -2-
on e (6). To a glass-lined 300 mL Parr high-pressure vessel
containing 32 mL of CH2Cl2 and 8 mL of water were added
diamine 3 (92.9 mg, 0.164 mmol), W(CO)6 (2.4 mg, 0.0068 mmol),
K2CO3 (68.8 mg, 0.497 mmol), and I2 (42.2 mg, 0.166 mmol). The
vessel was then charged with 77 atm of CO and heated at 82 °C
overnight. The pressure was released, and 15 mL of water was
added. The organics were then separated and washed with a
saturated solution of Na2SO3 followed by brine. The resulting
solution was dried over magnesium sulfate and filtered. The
solvent was removed by evaporation, and the resulting residue
was purified via column chromatography on silica using 2:1
hexanes/ethyl acetate as eluent. Removal of the solvent afforded
6 as a white solid in 75% yield. The product was identified by
Ack n ow led gm en t. Funding was provided by the
donors of the Petroleum Research Fund. We thank Dr.
William A. Nugent, Process Research and Development
Department, Bristol-Myers Squibb Co., for helpful dis-
cussions and for providing authentic samples of com-
pounds. We also thank I. Shugarman for assistance in
the preparation of starting materials.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 8 and 10. This material is available free
of charge via the Internet at http://pubs.acs.org.
comparison with literature data.22 IR (neat) vCO 1679 cm-1
HRMS (M + H)+ calcd 587.3336, found 587.3355.
;
J O026816V
J . Org. Chem, Vol. 68, No. 4, 2003 1617