Hydroxylamine as an ammonia equivalent in microwave-enhanced aminocarbonylations

Article abstract of DOI:10.1016/j.tet.2005.11.093

A novel palladium-catalyzed and Mo(CO)₆ promoted aminocarbonylation protocol was developed for rapid generation of primary aromatic amides from aryl bromides and iodides. Employing controlled microwave heating, hydroxylamine was first reduced in situ to ammonia, which thereafter reacted with carbon monoxide and the aryl halide substrate, delivering the benzamide product in less than 20 min. Based on this in situ carbonylation, a facile preparation of a novel HIV-1 protease inhibitor was achieved.

Full text of DOI:10.1016/j.tet.2005.11.093

Tetrahedron 62 (2006) 4665–4670
Hydroxylamine as an ammonia equivalent in
microwave-enhanced aminocarbonylations
*
Xiongyu Wu, Johan Wannberg and Mats Larhed
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry,
Uppsala University, PO Box 574, SE-75123 Uppsala, Sweden
Received 21 October 2005; revised 29 November 2005; accepted 30 November 2005
Available online 31 March 2006
Abstract—A novel palladium-catalyzed and Mo(CO)6 promoted aminocarbonylation protocol was developed for rapid generation of primary
aromatic amides from aryl bromides and iodides. Employing controlled microwave heating, hydroxylamine was first reduced in situ to am-
monia, which thereafter reacted with carbon monoxide and the aryl halide substrate, delivering the benzamide product in less than 20 min.
Based on this in situ carbonylation, a facile preparation of a novel HIV-1 protease inhibitor was achieved.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
amides, and subsequent work has allowed for the extension
of this chemistry into intramolecular examples.12 However,
the preparation of primary benzamides by aminocarbon-
ylation of aryl halides with ammonia as the nucleophile is
recognized as considerably more troublesome, since the
reaction requires two toxic gaseous reactants, ammonia
and carbon monoxide. In addition, the nucleophilicity of
ammonia is limited and the Pd(II) coordination strength
is high.13 Thus, Indolese’s recently reported synthesis of
primary benzamides under pressurized carbon monoxide
(5 bar) using a nucleophilic Lewis base (imidazole or 4-
(dimethylamino)pyridine) as promoter, represented a major
improvement.14 In order to avoid using free carbon monoxide
and to speed up the reaction rate, we further developed the
protocol from Indolese by applying high-density microwave
radiation. Under these high temperature conditions and in the
presence of KOt-Bu, formamide served not only as the sol-
vent, but also as a combined ammonia and carbon monoxide
source.15 Unfortunately, the strong basic reaction medium
prevented utilization of the methodology for preparation of
easily racemized and sensitive target structures. Therefore,
a mild and rapid method for carbonylative preparation of pri-
mary benzamides appeared attractive and of high value for
demanding medicinal chemistry applications. Stimulated
by reports on Mo(CO)6 mediated reductive cleavage of
N–O bonds,16 we decided to investigate hydroxylamine
hydrochloride (1) as a convenient solid ammonia equivalent.
Herein, we report the development of a rapid palladium-cat-
alyzed procedure for benzamide (3) synthesis from hydroxyl-
amine and aryl bromides (2) or iodides (4) by the reductive
and carbon monoxide releasing actions of Mo(CO)6. The
methodology was further applied to the synthesis of a com-
plex HIV-1 protease inhibitor.
Microwave heating has now been used in organic chemistry
for 20 years with a steadily increasing number of reported
examples every year.1 In particular, applications in early
stages of drug discovery have increased dramatically during
the last 5-year period. It is the highly controlled, facile, and
rapid in situ heating that makes controlled high-density mi-
crowave heating ideal, not only for promoting traditional
laboratory-scale reactions, but also for automated organic
and medicinal syntheses.2,3 Despite the impressive advan-
tages, additional robust and selective microwave protocols
must be identified to accelerate lead identification and opti-
mization work in the pharmaceutical industry.4
The greatest advantage of carbonylative reactions mediated
by solid or liquid carbon monoxide sources is that they can
be performed without equipment for introduction of gaseous
carbon monoxide.5 Handling in small-scale experiments is
also more straightforward and much safer compared to pro-
tocols using free carbon monoxide gas. We have previously
reported the exploitation of formamides or Mo(CO)6 as
robust carbon monoxide releasing reagents in palladium-
catalyzedamino-,6–8 alkoxy-,9 sulfonamido-10 andhydrazido-
carbonylations.11 Other research groups have presented
alternative methods for carbon monoxide-free carbonylative
chemistry.5 One of our initial forays into Mo(CO)6 promoted
aminocarbonylations included the investigation of inter-
molecular reactions to form secondary and tertiary aromatic
Keywords: Carbonylation; Microwave; Palladium catalysis; Inhibitors.
* Corresponding author. Tel.: +46 18 4714667; fax: +46 18 4714474;
e-mail: mats@orfarm.uu.se
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.093

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X. Wu et al. / Tetrahedron 62 (2006) 4665–4670
Table 1. Preparation of benzamides from aryl bromides by in situ
carbonylation
2. Results and discussion
O
a
2.1. Aryl bromides as coupling partners
Ar
Ar Br
NH2
To establish the viability of the carbonylation, we first under-
took a small screening of a variety of palladium sources,
ligands, solvents, and reaction variables (temperature and ir-
radiation time) employing bromobenzene (2d) as substrate
and 1 as pronucleophile (Eq. 1). The reactions were per-
formed with 0.5 equiv of Mo(CO)6 in sealed microwave
transparent vessels under air. An excess of DBU was used
in all attempts both to release free hydroxylamine and to
serve as an efficient base in the reaction along with diisopro-
pylethylamine (DIEA). We quickly found that using 5%
Herrmann’s palladacycle (5), 10% [(t-Bu)3PH]BF4 (6) as
an additional ligand source, and with 1,4-dioxane as solvent,
Entry
Ar-Br
Benzamide
Isolated
yield (%)
O
Br
NH2
1
71
O
O
2a
3a
O
Br
NH2
2
3
81
78
ꢀ
2b
microwave heating at 150 C for 20 min furnished a gener-
3b
ally successful reaction protocol (Eq. 1). Product 3d was
obtained in 75% isolated yield and importantly, no phenyl-
hydroxamic acid product from a direct carbonylation with
1 was observed. Based on this result, the method was tested
on seven additional model aryl bromides.
O
O
Br
NH2
2c
3c
NH2OH HCl (1)
Br
Mo(CO)6
Palladacycle 5
O
NH2
75
4
5
69b
Br
[(t-Bu)3PH]BF4 (6)
NH2
(1)
2d
DIEA, DBU, Dioxane
MW, 20 min
3d
2d
3d, 75%
O
Br
NH2
The results are summarized in Table 1. It was quickly proven
that both electron-rich and electron-poor aryl bromides
worked for this transformation, providing 71–81% yield of
3a–g without traces of potentially competing hydroxamic
acid. In addition, the heterocyclic 3-thiophene amide 3h
was isolated in 70% yield (entry 8). To compare 1 with the
perhaps more obvious ammonia source ammonium chloride,
two additional carbonylations were performed. Interestingly,
ammonium chloride delivered lower yields compared with
1 in both reactions due to the formation of nitriles as side
products, indicating a true advantage of hydroxylamine
hydrochloride (Table 1, entries 4 and 7).
81
80
F
F
2e
3e
O
Br
NH2
6
F3C
F3C
2f
3f
Br
O
NH2
71
55b
7
8
2.2. Aryl iodides as coupling partners
2g
3g
We chose the aminocarbonylation of o-tolyl iodide (4c) with
hydroxylamine hydrochloride as the standard reaction to in-
vestigate suitable reaction conditions for both the amidation
of electronically diverse model aryl iodides 4a,b,d–h and for
subsequent decoration of the HIV-1 inhibitor ortho-bromo
precursors 7 and 9. Although the original ligand-free amino-
carbonylative conditions developed by our laboratory for
generation of secondary and tertiary benzamides from aryl
iodides8 delivered significant amounts of product, the reac-
tions failed to reach full conversion of 4c. It was however
found that addition of phosphine ligands, especially [(t-
Bu)3PH]BF4 and the bidentate ligand dppf, dramatically
improved both conversion and yield (Table 2).
O
Br
NH2
70
S
S
2h
3h
a Aryl bromide (0.8 mmol), Mo(CO)6 (0.4 mmol), NH2OH HCl (1.6 mmol),
Herrmann’s palladacycle 5 (5 mol %), [(t-Bu)3PH]BF4 (10 mol %), DBU
(0.8 mmol), DIEA (1.6 mmol), dioxane (2.0 mL), microwave irradiation
at 150 ꢀC for 20 min in a sealed vial.
b NH4Cl as ammonia source.
palladium(0) catalysts. Thus, by employing lower reaction
temperatures (110–130 C) but with an otherwise identical
ꢀ
reaction system as the corresponding aryl bromides, we
could isolate the primary amide 3c in 69–84% yield (Table 2,
This finding was unexpected since aryl iodides normally do
not need sophisticated phosphines to undergo activation by

X. Wu et al. / Tetrahedron 62 (2006) 4665–4670
4667
Table 2. Preparation of benzamides from aryl iodides by in situ
carbonylation
a reaction time of 20 min was sufficient for complete con-
sumption of the aryl iodide and that an increase of the reac-
tion temperature to 130 C afforded reduced yields (Table 2).
ꢀ
O
a
Ar
Ar
I
NH2
2.3. Synthesis of HIV-1 protease inhibitors
Entry
Ar-I
Benzamide
Temp (ꢀC) Isolated
yield (%)
The 1,2-dihydroxyethylene structure derived from L-manni-
tol and depicted in Figure 1 has been shown to be an effective
transition-state mimic in inhibitors of aspartic proteases. By
using this C2-symmetric core scaffold, compounds inhibit-
ing the HIV-1 protease enzyme at low nanomolar or even
sub-nanomolar concentrations have been reported.17,18
O
I
NH2
130
110
67
78
1
O
O
4a
3a
O
P1'
Ar
I
NH2
130
110
74
80
2
O
OH O
P2
R
H
N
4b
R
N
3b
H
P2'
O
OH O
O
O
Ar
P1
I
I
NH2
130
110
69
84
3
4
Figure 1.
4c
3c
The benzylic P1/P10 side chains of these inhibitors have also
been previously decorated in the 2-, 3-, and 4-positions by
palladium(0)-catalyzed couplings and aminocarbonylation
reactions.17,19 Up to this point, however, synthesis of inhib-
itors including a primary benzamide functionality in the P1/
P10 positions has not been accomplished.
NH2
130
110
74
77
4d
3d
O
After preparing 7 according to the literature procedure,18 we
attempted the first carbonylation using 1 as the ammonia sur-
rogate (Scheme 1). The conditions for aryl iodides identified
I
NH2
5
6
110
76
F
F
ꢀ
4e
above furnished complete conversion at 120 C but in a com-
3e
plex product mixture. The purification of the product was fur-
ther hampered by the poor solubility and high retention of 8
on silica. We then decided to protect the hydroxyl groups of
compound 7 in an attempt to block the possibility of intramo-
lecular alkoxycarbonylation and to improve the solubility of
the product.20 Standard conditions for TBDMS protection of
alcohols produced the bis-protected compound 9 as the main
product.21 Carbonylation of 9 proceeded smoothly using
slightly modified conditions and product 10 could be isolated
in a satisfying 66% yield. Compound 10 was subsequently
deprotected with TBAF to deliver inhibitor 8 (Scheme 1).
Even though biological testing of compounds 8 and 10
showed that only 10 was a full inhibitor at 5 mM, the synthe-
sis of 8 and 10 exemplifies the usefulness of the developed
method also when dealing with more complex substrates.
O
I
NH2
130
110
73
76
F3C
F3C
4f
3f
I
O
NH2
110
83
7
8
4g
3g
O
I
NH2
110
80
S
S
2.4. Discussion
4h
3h
a Aryl iodide (0.8 mmol), Mo(CO)6 (0.4 mmol), NH2OH HCl (1.6 mmol),
Herrmann’s palladacycle 5 (5 mol %), [(t-Bu)3PH]BF4 (10 mol %), DBU
(0.8 mmol), DIEA (1.6 mmol), dioxane (2.0 mL), microwave irradiation
for 20 min in a sealed vial.
We propose that the investigated palladium(0)-catalyzed
carbonylation follows the same general pathway as the anal-
ogous reaction with gaseous carbon monoxide and ammo-
nia.22 To examine the hypothesis that ammonia, and not
hydroxylamine, acts as the principal nucleophile in the
aminocarbonylation, we decided to conduct a series of con-
trol reactions. First, benzohydroxamic acid was cleanly re-
duced to benzamide 3d under aryl bromide carbonylation
conditions without the palladium catalyst and 1. At room
temperature, no benzamide formation was detected. These
entry 3). Furthermore, from Table 2 it is clear that this is
a general microwave method that tolerates electronically
diverse coupling partners 4. This trend also held true with
electron-rich thiophene 4h. It is noteworthy that in all cases

4668
X. Wu et al. / Tetrahedron 62 (2006) 4665–4670
NH2
OH
I
O
NH2OH HCl (1), Mo(CO)6
[(t-Bu)3PH]BF4, Palladacycle
OH
OH
O
OH O
O
O
H
N
H
N
N
N
DIEA, DBU, Dioxane
H
H
MW, 120 oC, 20 min
O
OH
O
O
OH O
OH
HO
O
14%
8
I
7
H2N
Ki = >5 µM
TBDMS-Cl
Imidazole
TBAF, THF
rt, 5 h
77%
94%
DMF
rt, 18 h
NH2
I
Si
Si
O
O
O
NH2OH HCl (1), Mo(CO)6
[(t-Bu)3PH]BF4, Palladacycle
O
N
OH
O
O
N
OH O
H
N
H
N
DIEA, DBU, Dioxane
MW, 120 oC, 20 min
H
O
H
O
OH
O
OH O
O
O
O
Si
Si
H2N
I
9
10
Ki = 1.1 µM
66%
Scheme 1.
two experiments established that hydroxylamine might oper-
ate as the nucleophile attacking the intermediate palladium
acyl complex, affording 3d after reduction at 150 C. The
age AB, Uppsala, Sweden) producing controlled irradiation
at 2450 MHz. Reaction temperatures were determined and
controlled via the built-in, on-line IR-sensor. Thin-layer
chromatography was performed using aluminum or glass
supported Merck Silica gel 60 F254 TLC plates and visual-
ized with UV light. Flash column chromatography was per-
formed using Merck Silica gel 60 (0.040–0.063 mm). Mass
spectra (EI, 70 eV) of compounds 3a–h were recorded with
a mass-selective detector interfaced with a gas chromato-
graph equipped with a 30 mꢁ0.25 mm CP-Sil 8 CB capil-
lary column. RPLC–MS analysis of compounds 7–10 were
performed using a Gilson HPLC system with a Chromolith
SpeedROD RP-18e column (50ꢁ4.6 mm) and a Finnigan
AQA quadropole mass spectrometer using a 4 mL/min
CH3CN/H2O gradient (0.05% HCOOH) and detection by
ꢀ
next step was to study the reduction of hydroxylamine hydro-
chloride (1) to ammonia. A complete aminocarbonylation
cocktail (entry 4, Table 1) was stirred for 20 min at room tem-
perature with subsequent addition of benzoyl chloride to trap
all free amines and revealed that only benzamide 3d was
formed without any trace of benzohydroxamic acid. Increase
of the reaction temperature afforded an identical outcome,
strongly supporting the suggestion that hydroxylamine is
directly reduced to ammonia in the presence of Mo(CO)6.
Thus, in summary we believe benzamide products 3a–h are
formed as a result of a carbonylation process with free ammo-
nia, and not hydroxylamine, as the reactive nucleophile.
1
both UV (DAD, 190–350 nm) and MS (ESI+). H and 13C
NMR spectra were recorded on a Varian Mercury-400 spec-
trometer at 400 and 100.5 MHz, respectively. Chemical
shifts were referenced to internal tetramethylsilane when
using CDCl3/CD3OD mixtures and indirectly to tetramethyl-
silanevia the residual solvent signal when using pure solvents.
3. Conclusion
A new Mo(CO)6 promoted and microwave-accelerated route
to primary benzamides from aryl bromides or iodides has
been developed utilizing hydroxylamine hydrochloride as
the solid source of ammonia. Consequently, no cumbersome
handling of gases is needed following this in situ carbonyl-
ation protocol. The synthetic method is rapid, efficient,
and quite practical and we envision that the procedure
may find applications as a valuable amidation reaction.
Employing this in situ ammoniacarbonylation approach,
we successfully prepared a novel HIV-1 protease inhibitor
in a straightforward manner.
All starting materials and reagents were commercially avail-
able and used as received. Herrmann’s palladacycle, trans-
di(m-acetato)bis[o-tolylphosphino)benzyl]dipalladium (II)
5 was purchased from Strem. Mo(CO)6 was obtained from
Acros. Products 3a,15 3b,15 3c,15 3d,15 3f,15 3g,15 3e,23 and
3h24 are known compounds and analytical data were consis-
tent with literature values.
4.2. General procedure for aminocarbonylation with
hydroxylamine hydrochloride salt (1)
4. Experimental
4.1. General
A 2–5 mL process vial was charged with 1 (112 mg,
1.60 mmol) or NH4Cl (86 mg, 1.60 mmol), Mo(CO)6
(106 mg, 0.40 mmol), palladacycle 5 (38 mg, 0.040 mmol),
[(t-Bu)3PH]BF4 (22 mg, 0.080 mmol), DBU (0.120 mL,
0.80 mmol), DIEA (0.277 mL, 1.6 mmol), aryl bromides 2
All microwave-assisted reactions were carried out using
a single-mode microwave cavity (Smith Synthesizer, Biot-

X. Wu et al. / Tetrahedron 62 (2006) 4665–4670
4669
(0.80 mmol) or iodides 4 (0.80 mmol), and dioxane 2.0 mL.
The vessel was sealed under air and exposed to microwave
DBU (0.120 mL, 0.80 mmol) was added and the vial was
cappedꢀwith a Teflon septum and irradiated with microwaves
to 120 C for 20 min. After cooling to room temperature the
reaction mixture was filtered through a short Celite pad and
the solvent was evaporated. The residuewas purified by silica
column flash chromatography (EtOAc/MeOH gradient) to
give 10 (98.6 mg, 66%) as a light yellow solid. MS (ESI+)
ꢀ
ꢀ
heating for 20 min at 150 C (for bromides) or 110–130 C
(for iodides). The reaction tube was thereafter cooled to
room temperature and the mixture was diluted with 5.0 mL
CH2Cl2 and purified on silica gel (30:70 to 100:0 EtOAc/
hexane) to give the corresponding benzamides 3a–h.
1
m/z¼967.7 [M+H+]. H NMR (400 MHz, CDCl3): d 7.54
4.3. Synthesis of HIV-1 protease inhibitors
(dd, J¼5.6, 3.4 Hz, 2H), 7.43 (d, J¼8.6 Hz, 2H), 7.38–7.19
(m, 14H), 6.65 (s, 2H), 6.52 (s, 2H), 5.42 (dd, J¼8.6,
5.3 Hz, 2H), 5.00–4.73 (m, 2H), 4.68 (d, J¼10.2 Hz, 2H),
4.60 (app. dt, J¼5.2, 2.2 Hz, 2H), 4.16 (app. s, 4H), 3.10
(dd, J¼16.2, 5.2 Hz, 2H), 2.90 (dd, J¼16.2, 2.3 Hz, 2H),
0.76 (s, 18H), 0.05 (s, 6H), 0.00 (s, 6H). 13C NMR
(100.5 MHz, CDCl3): d 172.04, 172.02, 141.3, 140.0,
135.7, 134.6, 131.3, 130.8, 128.9, 128.4, 128.1, 127.2,
125.0, 124.9, 80.6, 74.2, 71.9, 70.9, 56.8, 40.7, 25.8, 18.2,
ꢂ4.7. Anal. Calcd (%) for C52H70N4O10Si2: C, 64.57; H,
7.29; N, 5.79. Found: C, 64.30; H, 7.39; N, 5.65.
4.3.1. N1,N6-Bis[(1S,2R)-2-hydroxy-1-indanyl]-
(2R,3R,4R,5R)-2,5-bis(2-iodobenzyloxy)-3,4-dihydroxy-
hexane-1,6-diamide (7). Synthesized according to the
1
procedure in Ref. 18. MS (ESI+) m/z¼905.3 [M+H+]. H
NMR (400 MHz, CDCl3): d 7.79 (dd, J¼7.9, 1.2 Hz, 2H),
7.44–7.37 (m, 4H), 7.31 (ddd, J¼7.9, 7.6, 1.2 Hz, 2H),
7.26–7.18 (m, 8H), 6.99 (ddd, J¼7.9, 7.4, 1.7 Hz, 2H),
5.31 (dd, J¼8.8, 5.2 Hz, 2H), 4.74 (d, J¼11.8 Hz, 2H),
4.70 (d, J¼11.8 Hz, 2H), 4.63 (app. dt, J¼5.4, 2.5 Hz, 2H),
4.34 (AA0 part of AA0BB0, 2H), 4.26 (BB0 part of AA0BB0,
2H), 3.08 (dd, J¼16.6, 5.6 Hz, 2H), 2.88 (dd, J¼16.6,
2.5 Hz, 2H). 13C NMR (100.5 MHz, CDCl3): d 171.4,
141.0, 139.8, 139.7, 139.2, 130.2, 128.7, 128.5, 127.2,
125.5, 124.5, 99.0, 82.3, 72.7, 71.5, 58.0, 39.4. Anal. Calcd
(%) for C38H38I2N2O8+H2O: C, 49.47; H, 4.37; N, 3.04.
Found: C, 49.3; H, 4.6; N, 3.1.
4.3.4. N1,N6-Bis[(1S,2R)-2-hydroxy-1-indanyl]-
(2R,3R,4R,5R)-2,5-bis(2-carbamoyl-benzyloxy)-3,4-
dihydroxyhexane-1,6-diamide (8).
4.3.4.1. Carbonylation of 7. A 0.5–2 mL microwave
vial was charged with 7 (136 mg, 0.150 mmol), Mo(CO)6
(106 mg, 0.40 mmol), palladacycle 5 (19 mg, 0.020 mmol),
[(t-Bu)3PH]BF4 (11 mg, 0.040 mmol), hydroxylamine hy-
drochloride (112 mg, 1.60 mmol), dioxane (2 mL), and
DIEA (0.247 mL, 1.40 mmol). Finally DBU (0.120 mL,
0.80 mmol) was added and the vial was capped with a Teflon
4.3.2. N1,N6-Bis[(1S,2R)-2-(tert-butyl-dimethyl-silanyl-
oxy)-indan-1-yl]-(2R,3R,4R,5R)-2,5-bis(2-iodobenzyl-
oxy)-3,4-dihydroxyhexane-1,6-diamide (9). Imidazole
(272 mg, 4.00 mmol), TBDMSCl (301 mg, 2.00 mmol),
and DMAP (10 mg, catalyst) were added sequentially to a
solution of 7 (181 mg, 0.200 mmol) in 2 mL of DMF. After
stirring at room temperature for 18 h, the reaction mixture
was quenched with MeOH, diluted with ethyl acetate
(40 mL), washed with water (3ꢁ30 mL), dried (MgSO4),
and concentrated under reduced pressure. The residue was
purified by silica gel flash column chromatography (Hex-
anes/EtOAc gradient). A side product consistent with tris-
protected 7 was isolated (43.6 mg, 18%) but the main
product was identified as 9 (176 mg, 77%). MS (ESI+)
ꢀ
septum and irradiated with microwavesto 120 C for 20 min.
After cooling to room temperature the reaction mixture was
filtered through a short Celite pad and the solvent was evap-
orated. The residue was purified by silica column flash chro-
matography (10% MeOH in CHCl3) to give8 (15.5 mg, 14%)
as a white solid.
4.3.4.2. Deprotection of 10. To a solution of 10 (61.1 mg,
0.063 mmol) in THF (2 mL) was added tetrabutylammo-
niumfluoride (TBAF, 1 M in THF, 0.14 mL, 0.14 mmol)
and the mixture was stirred at room temperature. After 5 h
the solvent was evaporated and the solid residue suspended
in 10 mL of water and stirred for 15 min. The water was dec-
anted off and the water wash was repeated once. The suspen-
sion was then filtered and the solid was washed with 10 mL
of ether and thereafter dried to give 8 (43.8 mg, 94%) as
1
m/z¼1133.6 [M+H+]. H NMR (400 MHz, CDCl3): d 7.74
(dd, J¼7.9, 1.3 Hz, 2H), 7.65 (d, J¼9.1 Hz, 2H), 7.39 (dd,
J¼7.6, 1.8 Hz, 2H), 7.28–7.12 (m, 10H), 6.97 (dt, J¼7.6,
1.8 Hz, 2H), 5.44 (dd, J¼9.1, 5.4 Hz, 2H), 4.82 (d,
J¼11.7 Hz, 2H), 4.76 (d, J¼11.7 Hz, 2H), 4.68–4.66 (m,
2H), 4.63 (app. dt, J¼5.3, 2.4 Hz, 2H), 4.29 (d, J¼7.9 Hz,
2H), 4.16–4.09 (m, 2H), 3.11 (dd, J¼16.2, 5.3 Hz, 2H),
2.91 (dd, J¼16.2, 2.5 Hz, 2H), 0.76 (s, 18H), 0.04 (s, 6H),
0.01 (s, 6H). 13C NMR (100.5 MHz, CDCl3): d 173.0,
140.9, 140.1, 139.6, 139.4, 130.5, 130.0, 128.5, 128.1,
127.0, 125.04, 124.99, 99.4, 77.92, 77.87, 74.1, 71.3, 56.4,
40.8, 26.0, 18.2, ꢂ4.6. Anal. Calcd (%) for C50H66I2N2O8Si2:
C, 53.00; H, 5.87; N, 2.47. Found: C, 53.29; H, 6.04; N, 2.33.
1
a white solid. MS (ESI+) m/z¼739.5 [M+H+]. H NMR
(400 MHz, CDCl3/CD3OD, 1:1): d 7.53–7.48 (m, 2H),
7.44–7.35 (m, 6H), 7.31–7.19 (m, 8H), 5.41 (d, J¼5.3 Hz,
2H), 4.85 (d, J¼11.1 Hz, 2H), 4.81 (d, J¼11.1 Hz, 2H),
4.66–4.61 (m, 2H), 4.19–4.12 (m, 4H), 3.19 (dd, J¼16.6,
5.3 Hz, 2H), 2.98 (dd, J¼16.6, 2.3 Hz, 2H). 13C NMR
(100.5 MHz, DMSO-d6): d 171.1, 170.5, 142.0, 140.6,
136.3, 135.0, 129.7, 128.1, 127.3, 127.2, 127.1, 126.3,
124.7, 124.3, 79.7, 72.3, 70.0, 69.1, 56.8, 39.9. Anal. Calcd
(%) for C40H42N4O10+H2O: C, 63.48; H, 5.86; N, 7.40.
Found: C, 63.38; H, 5.94; N, 7.27.
4.3.3. N1,N6-Bis[(1S,2R)-2-(tert-butyl-dimethyl-silanyl-
oxy)-indan-1-yl]-(2R,3R,4R,5R)-2,5-bis(2-carbamoyl-
benzyloxy)-3,4-dihydroxyhexane-1,6-diamide (10).
A
0.5–2 mL microwave vial was charged with 9 (170 mg,
0.150 mmol), Mo(CO)6 (106 mg, 0.40 mmol), palladacycle 5
(19 mg, 0.020 mmol), [(t-Bu)3PH]BF4 (11 mg, 0.040 mmol),
hydroxylamine hydrochloride (112 mg, 1.60 mmol), diox-
ane (2 mL), and DIEA (0.247 mL, 1.40 mmol). Finally
Acknowledgements
We acknowledge the financial support from the Swedish
Research Council and the Knut and Alice Wallenbergs

4670
X. Wu et al. / Tetrahedron 62 (2006) 4665–4670
13. Seligson, A. L.; Trogler, W. C. J. Am. Chem. Soc. 1991, 113,
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Foundation. We also thank Biotage AB for providing us with
the Smith Microwave synthesizer. Finally, we would like to
thank Mr. Shane Peterson and Prof. Anders Hallberg for
intellectual contributions to this project.
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