Lossen rearrangements under heck reaction conditions

Article abstract of DOI:10.1002/adsc.201400170

The classical Lossen rearrangement converts activated hydroxamic acids to isocyanates that form numerous products upon their reaction with nucleophiles. We report a simple and highly efficient method of using Heck reaction conditions to initiate Lossen rearrangements of hydroxamic acids. In addition, Lossen rearrangements occur in the presence of palladium(II) acetate or triethylamine, components of the Heck reaction, alone. A potential mechanism is provided to explain this reactivity and these results show that Heck reactions and Lossen rearrangements occur under the same conditions and may provide new methods for facile initiation of Lossen rearrangements.

Full text of DOI:10.1002/adsc.201400170

UPDATES
DOI: 10.1002/adsc.201400170
Lossen Rearrangements under Heck Reaction Conditions
El-Shimaa M. N. AbdelHafez,a Omar M. Aly,b
Gamal El-Din A. A. Abuo-Rahma,b and S. Bruce Kinga,*
a
Department of Chemistry, Wake Forest University, Winston-Salem, NC 27106, USA
Fax : (+01)-336-758-4656; phone: (+01)-336-758-5774; e-mail: kingsb@wfu.edu
Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, Egypt
b
Received: February 16, 2014; Revised: June 9, 2014; Published online: September 10, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400170.
Abstract: The classical Lossen rearrangement con-
verts activated hydroxamic acids to isocyanates that
form numerous products upon their reaction with
nucleophiles. We report a simple and highly effi-
cient method of using Heck reaction conditions to
initiate Lossen rearrangements of hydroxamic acids.
In addition, Lossen rearrangements occur in the
presence of palladium(II) acetate or triethylamine,
components of the Heck reaction, alone. A poten-
tial mechanism is provided to explain this reactivity
and these results show that Heck reactions and
Lossen rearrangements occur under the same con-
ditions and may provide new methods for facile ini-
tiation of Lossen rearrangements.
(CDI).[13] Despite these methods of promoting the
Lossen rearrangement, controlling the reactivity of
the nascent isocyanate remains an inherent problem
associated with the reaction.[7] The newly formed iso-
cyanate can react in situ with the generated amine to
give a symmetrical urea or the free parent hydroxa-
mic acid to yield the corresponding O-carbamoylhy-
droxamate, which also yields a symmetrical urea upon
heating.[14] Isocyanates also react with other amines or
alcohols to give unsymmetrical ureas and carbamates,
respectively. Methods that limit the potentially unde-
sirable self-condensations but allow trapping with
other nucleophiles remain an important synthetic goal
for this classic reaction and recent work shows that
the nucleophilic catalyst, N-methylimidazole, facili-
tates carbamate formation from isocyanates.[8] We
report results that demonstrate productive Lossen re-
arrangements occurring along with carbon-carbon
bond formation under typical Heck reaction condi-
tions.[15] During our work on the anti-cancer effects of
derivatives of the alkaloid, rescinnamine, we observed
a one-pot Lossen rearrangement and Heck coupling.
Specifically, treatment of the hydroxamic acid-con-
Keywords: anilines; Heck reaction; hydroxamic
acids; Lossen rearrangement; metal catalysis; ureas
Introduction
The Lossen rearrangement converts hydroxamic acids taining aryl iodides (1 and 2) with acryloylreserpate
to isocyanates through transient acyl nitrene inter- (3) under standard Heck reaction conditions [triethyl-
mediates. The isocyanates can be trapped by nucleo- amine, catalytic PdACHTNUTRGNEUNG(OAc)2, sealed tube at 908C for
philes to form carbamic acid derivatives or hydro- 48 h] produces the amino-containing products (4 and
lyzed to the respective amine.[1] Activation of the hy- 5) in 35% and 41% yields, respectively (Scheme 1).[16]
droxamic acid oxygen atom is essential for the rear- These results show the formation of complex natural
rangement to occur as hydroxide is a poor leaving product derivatives through the combination of
group.[2–4] Lossen rearrangements usually occur with a Heck coupling and Lossen rearrangement with the
O-activated hydroxamic acid derivatives or via in situ amine final product likely forming from isocyanate
activation of free hydroxamic acids with an activating hydrolysis.These results bear some similarity to
agent such as polyphosphoric acid,[4–6] azodicarboxy- a recent report of the tertiary amine-catalyzed conver-
late and triphenylphosphine (Mitsunobu conditions),[7] sion of hydroxamic acids to amines and carbamates.[17]
sulfonyl chloride[8,9] or a sulfur trioxide triethylamine
complex.[10] Recent simple approaches to Lossen rear-
rangements include the conversion of aromatic hy- Results and Discussion
[11]
droxamic acids to amines by heating with K2CO3 or
activation with dehydrating agents such as dicyclohex- To better understand these transformations, similar
ylcarbodiimide (DCC)[5,12] or carbonyldiimidazole treatment of methyl acrylate with 1 and 2 gave the
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Lossen Rearrangements under Heck Reaction Conditions
Scheme 1. Synthesis of amino-substituted rescinnamine derivatives (4 and 5).
Scheme 2. Preparation of amino-substituted cinnamates (6 and7).
amine-substituted cinnamates (6 and 7) in 98% and dimethylformamide (DMF) with stirring in a sealed
97% yields, respectively (Scheme 2). Scheme 1 and glass tube at 908C for 24 h affords either the corre-
Scheme 2 indicate that straightforward Heck reaction sponding amines (9a–f) or symmetrical ureas (10a–f,
conditions mediate Lossen rearrangements and Scheme 3, Table 1). The rearrangement proceeds in
permit carbon-carbon bond coupling and motivated excellent yield for the aromatic hydroxamic acids (8a
further study of the Lossen rearrangement of various and b) generating the aromatic amines 9a and b in
hydroxamic acids (aromatic, aliphatic and heterocy- more than 90% yield in both CH3CN and DMF
clic) under Heck reaction conditions in the presence (Scheme 3, Table 1). In contrast, similar treatment of
and absence of different nucleophiles.
aliphatic and heterocyclic hydroxamic acids (8c–f)
To determine whether Heck reaction conditions does not yield the corresponding amines (9c–f) but
would result in Lossen rearrangements, different
easily prepared hydroxamic acids[18] (8a–f) were ex-
Table 1. Yields of Lossen products in the presence of
Pd(OAc)2 and TEA.
posed to these conditions (Scheme 3, Table 1). Heat-
ing these hydroxamic acids with catalytic Pd(OAc)2
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
and triethylamine (TEA) in acetonitrile (CH3CN) or
Starting material
R
Product [%]
CH3CN
DMF
8a
8b
8c
8d
8e
8f
phenyl
9a (94)
9a (93)
p-toluyl
cyclohexyl
pentyl
9b (98)
10c (57)
10d (50)
10e (49)
10f (33)
9b (96)
10c (16)
10d (39)
10e (61)
10f (39)
CH
3ACHTUGNTERN(NUNG CH2)9CH2
Scheme 3. Lossen rearrangement of hydroxamic acids under
Heck reaction conditions [PdACTHNUTRGNEUNG(OAc)2 and TEA].
4-pyridyl
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El-Shimaa M. N. AbdelHafez et al.
Table 3. Yields of Lossen products under Heck reaction con-
ditions in the absence of TEA.
only forms the symmetrical ureas (10c–f) in modest
yields in both CH3CN and DMF (Table 1). These re-
sults show that hydroxamic acids undergo Lossen re-
arrangements under Heck reaction conditions. The
amines (9) may form through hydrolysis of an isocya-
nate intermediate and the ureas (10) from condensa-
tion of the newly formed amines with the isocyanate
or the decomposition of O-carbamoylhydroxamate in-
termediates. The lack of urea products from the aro-
matic hydroxamic acids (8a and b) may be related to
the relatively lower nucleophilicity of the aromatic
amines (9a and b). In contrast, the urea products
(10c–f) form with substrates that generate more nu-
cleophilic aliphatic amines. The behaviour of the het-
erocyclic hydroxamic acid (8f) remains difficult to ex-
Starting material
R
Product (Yield [%])
CH3CN
DMF
8a
8b
phenyl
9a (35)
10a (44)
9b (23)
10b (36) 10b (23)
10c (67) 10c (16)
9a (28)
p-toluyl
9b (73)
8c
8d
8e
8f
cyclohexyl
pentyl
10d (61) 10d (22)
3ACHTUNGTRNEG(UN CH2)9CH2 10e (67) 10e (44)
CH
4-pyridyl
10f (64)
10f (87)
plain. Overall, the rearrangement of aromatic hy- moderate yield with no clear dependence on the pres-
droxamic acids gives the corresponding aromatic ence or absence of the Pd(OAc)2 catalyst.
AHCTUNGTRENNUNG
amines but the aliphatic hydroxamic acids form the
corresponding symmetrical ureas.
A recent combined experimental and theoretical
study demonstrates that metals (zinc and potassium)
Treatment of hydroxamic acids 8a–f with TEA efficiently catalyze Lossen rearrangements.[19] Follow-
under the same conditions in the absence of ing this mechanism, hydroxamic acid deprotonation
PdACHTUNGTRENNUNG(OAc)2 also results in the formation of Lossen rear- followed by metal complexation gives a metal hydrox-
rangement products (Table 2). Under these condi- amate complex (11, Scheme 4). This activated hy-
tions, the aromatic hydroxamic acids (8a and b) yield droxamic acid complex rearranges from the N-depro-
mixtures of anilines (9a and b) and ureas (10a and b). tonated form to yield a metal carbamate that pro-
The aliphatic and heterocyclic hydroxamic acids (8c– ceeds to products (Scheme 4).[19] Presumably, addition
f) only give the symmetrical ureas (10c–f) in both of PdACTHNUTRGNEUNG(OAc)2 would also form a metal hydroxamic
CH3CN and DMF (Table 2).
acid complex (11, Scheme 4) that could progress in
Finally, the influence of catalyst PdACTHNURTGNENG(U OAc)2 alone in
the absence of TEA was examined (Table 3). Treat-
ment of 8a–f with Pd(OAc)2 in the absence of base
AHCTUNGTRENNUNG
also yields mixtures of amines (9a–f) and ureas (10a–
f). Aromatic hydroxamic acids (8a and b) give both 9
and 10a and b while only the symmetrical ureas (10c–
f) form from the aliphatic and heterocyclic hydroxa-
mic acids (8c–f, Table 3). In general, the combination
of PdACHTUNGTRENNUNG(OAc)2 and TEA gives the best yields for the
conversion of aromatic hydroxamic acids (8a and b)
to the corresponding aromatic amines (9a and b). In-
terestingly, the aliphatic and heterocyclic hydroxamic
acids (8c–f) only yield the symmetric ureas (10c–f) in
Table 2. Yields of Lossen products under Heck reaction con-
ditions in the absence of PdACTHNUTRGENUG(N OAc)2.
Starting material
R
Product (Yield [%])
CH3CN
DMF
8a
8b
phenyl
9a (56)
10a (9)
9b (37)
10b (44)
10c (54)
10d (68)
9a (88)
10a (3)
p-toluyl
9b (56)
10b (52)
10c (23)
10d (59)
10e (59)
10f (60)
8c
8d
8e
8f
cyclohexyl
pentyl
CH
4-pyridyl
(CH2)9CH2 10e (28)
10f (20)
Scheme 4. A possible reaction pathway for Lossen rear-
rangements under Heck conditions.
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Lossen Rearrangements under Heck Reaction Conditions
a similar fashion or the direct reaction of 11 with
TEA may facilitate proton migration and Lossen rear-
rangement to give the isocyanate (13, Scheme 4).[19]
A
separate previously proposed mechanism provides an
explanation for base-catalyzed Lossen rearrangement
(Scheme 4).[11,20] The base-assisted dehydration of the
hydroxamic acid upon heating may directly yield an
isocyanate (13, Scheme 4) or two molecules of hy-
droxamic acid may condense to form an O-acylhy-
droxamate (12), which can rearrange with heat to 13
with release of the carboxylate salt.[11,20] Both metal
and base-mediated mechanisms may operate under
these conditions and Scheme 4 suggests that the
PdACHTUNGTRENNUNG(OAc)2 may initially activate the hydroxamic acid
as 11 with the base accelerating its decomposition and
Lossen rearrangement to the isocyanate (13), which
may explain the improved yields under these condi-
tions. Once formed, 13 can be trapped by various nu-
cleophiles (Scheme 4) to yield derivatives or react
with water to give the corresponding amine (9) along
Scheme 5. Preparation and Lossen rearrangement of 16.
with CO2. Addition of 9 to 13 would yield the sym- bamoylhydroxamate (17) in 65% yield (Scheme 6).[21]
metrical urea (10, Scheme 4). The ratio of amine During a Lossen rearrangement, 17 forms as an unde-
(9):symmetrical urea (10) formed (Table 1, Table 2, sired side product that arises from the consumption of
Table 3) appears directly related to the nucleophilicity two equivalents of hydroxamic acid as one equivalent
of the nascent amine with more nucleophilic aliphatic condenses with the isocyanate (3, Scheme 4). Expo-
and heterocyclic amines yielding the symmetrical sure of 17 to both PdACTHUNRGTNEUNG(OAc)2 and TEA preferentially
ureas presumably through amine (9) addition to the forms 9a in 89% yield and small amounts (5%) of 10a
to the isocyanate (13, Scheme 4). Scheme 4 predicts (Scheme 6).Treatment of 17 with TEA alone only
that addition of other nucleophiles (amines or alco- gives 10a in 82% (Scheme 6) indicating that PdACHTUNGTRENNUNG(OAc)2
hols) will generate unsymmetrical ureas (14) and car- limits formation of 10a from 17.These results confirm
bamates (15) under these reaction conditions. TEA the ability of 17 to rearrange and demonstrate
may also participate as a nucleophilic catalyst for the a metal-dependent product distribution suggesting
addition of other nucleophiles to the addition to 13.[8] that the metal influences intermediate reactivity.
Further experiments were performed to verify the
The generation of highly reactive isocyanate inter-
ability of an O-acylhydroxamic acid, a proposed inter- mediates (13, Scheme 4) should allow trapping with
mediate (12) in Scheme 4, to be converted to prod- other nucleophiles to form various products. Expo-
ucts. Reaction of 8a with benzoyl chloride in diethyl sure of 8a to Heck reaction conditions [Pd
ether under basic conditions affords 16 in 86% yield TEA] in the presence of excess n-butylamine gives
(Scheme 5).[22] Treatment of 16 with both Pd
(OAc)2 the unsymmetrical urea (18a, Scheme 7) in 91% yield.
ACHTUNGERTN(NUNG OAc)2/
AHCTUNGTRENNUNG
and TEA generates 9a in 89% yield (Scheme 5). Treatment of hydroxamic acids 8a–dwith TEA in the
However, treatment with only TEA yields both the
symmetrical urea (10a) in 54% yield and aniline (9a)
in 38% (Scheme 5). These results confirm the ability
of 16 to generate products under Lossen rearrange-
ment conditions and suggest that it may be a viable
reaction intermediate. The presence of PdACTHUNRGTNEUNG(OAc)2
greatly influences the product outcome (only 9a
forms), a result similar to that observed for aromatic
hydroxamic acids (8a and b) treated with Pd
TEA (Table 1). In addition to facilitating isocyanate
formation, the Pd(OAc)2 may also influence isocya-
ACHTUNGRTENNU(G OAc2)/
AHCTUNGTRENNUNG
nate reactivity (13, Scheme 4) by further coordination
to either the isocyanate or other nucleophiles. Clearly,
more work will be needed to illuminate the role of
the metal in these reactions.
Similarly, heating a mixture of phenyl isocyanate
and 8a in THF/CH2Cl2 (1:1) for 1 h affords the O-car- Scheme 6. Preparation and Lossen rearrangement of 17.
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Scheme 7. Lossen rearrangements in the presence of n-butylamine.
Table 4. Yields of unsymmetrical ureas (18) in the presence
of n-butylamine.
rangements and show the future synthetic utility of
these transformations.
Unlike n-butylamine, treatment of 8c and 8d under
the same conditions [TEA, absence of PdACTHNURGTNEUNG(OAc)2] in
Starting material
R
Product (Yield [%])
8a
8b
8c
8d
phenyl
18a (85)
18b (49)
18c (94)
18d (52)
the presence of excess aniline (5 equiv.) only gave the
corresponding symmetrical ureas10c and 10d in 47%
and 52% yield (Scheme 8, Table 5). Unsymmetrical
ureas of aniline did not form during these reactions
suggesting that the weak nucleophilicity of aniline
compared to n-butylamine does not efficiently react
p-toluyl
cyclohexyl
pentyl
absence of Pd
fords the corresponding unsymmetrical ureas 18a–d in
good yields (Scheme 7, Table 4). These results provide under different Lossen rearrangement conditions pro-
examples of one-pot amine trapping of isocyanates duces methyl phenyl carbamate(19a) along with 9a
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
generated by base or metal-mediated Lossen rear- and 10a in various yields depending on conditions
(Scheme 9, Table 6) further showing the ability to
trap reactive intermediates in this process with nucle-
ophiles.
Using a mixture of CH3OH:CH3CN (1:9) in the
presence of both PdACTHNUTRGNE(NUG OAc)2 and TEA gives both 9a
and 10a in reasonable yields (31% and 24%, respec-
tively, in the presence of water and 20% and 28%, re-
spectively in the absence of water, Table 6). The for-
Scheme 8. Lossen rearrangement reaction in presence of
aniline.
Table 5. Yields of symmetrical ureas (10) in the presence of
aniline.
Starting materi- R
al
R
Product (Yield
[%])
8c
8d
cyclohexyl cyclohexyl 10c (47)
n-pentyl n-pentyl 10d (52)
Scheme 9. Lossen rearrangements in the presence of metha-
nol.
Table 6. Lossen rearrangement results in the presence of methanol.
Conditions
Product (Yield [%])
9a
10a
19a
TEA+Pd
(anhydrous) TEA+Pd
TEA+Pd(OAc)2 CH3OH/CH3CN (1:9)+H2O (10 equiv.)
(anhydrous) TEA+Pd(OAc)2 +CH3OH
(anhydrous) TEA+CH3OH
C
31
20
77
–
24
28
9
–
–
detected by LC-MS
detected by LC-MS
–
40
56
U
R
–
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Lossen Rearrangements under Heck Reaction Conditions
Probe temperature was regulated at 258C. All data were
collected and processed with Topspin 1.3 using standard
Bruker processing parameters. Chemical shifts (d) are given
in ppm; multiplicities are indicated by s (singlet), d (dou-
blet), t (triplet), q (quartet), sept (septet) m (multiplet), dd
(doublet of doublet) and bs (broad singlet). Flash chroma-
tography was carried out using a Biotage SP1-B2A0/HPFC
system (single column, single path and variable wave
length). LC-MS measurements were performed on an Agi-
lent Technologies 1100 LC/MSD trap instrument and on
GC-MS spectrometer 7890 A GC 5975C MS. High resolu-
tion mass spectra were obtained using a Thermo Scientific
LTC Orbitrap mass spectrometer equipped with a heated
electrospray ionization source operated in positive ion
mode. IR spectra were processed on a JASCO FT/IR 460.
Reagents were obtained from commercial sources and used
without additional purification. Extraction and flash chro-
matography solvents were technical grade. LC-MS, ESI-MS
and HPLC solvents were HPLC grade.
mation of small amounts of 19a was detected by LC-
MS under both conditions (Table 6). Replacing
CH3CN with anhydrous methanol as the solvent en-
hanced the yield of 19a to 40% [in the presence of
both PdACHTUNGTRENNUNG(OAc)2 and TEA] and 56% (in the presence
of TEA only, Table 6). The structure and purity of
19a was confirmed by TLC, mp and spectroscopic
analysis compared to an authentic standard sample.[23]
These results clearly show that alcohols can also trap
any reactive isocyanates (13, Scheme 4) or reactive in-
termediates to form substituted products
Conclusions
In conclusion, Heck reaction conditions trigger
Lossen rearrangements of hydroxamic acid substrates
in one-pot reactions (Scheme 1 and Scheme 2). These
Lossen rearrangements do not interfere with the
Synthesis of Aromatic Hydroxamic acids 8a and b;[11]
Representative Procedure
À
normal C C bond formation of the classic Heck reac-
tions allowing for tandem Heck reaction/Lossen rear-
rangement sequences. Further experiments show that
Two separate solutions of hydroxylamine hydrochloride
(4.17 g, 0.060 mol) and potassium hydroxide (6.72 g, 0.12
mol) in methanol (30 mL) were prepared. Both were cooled
in ice bath and the one containing alkali was added with
shaking to the hydroxylamine solution. After all the alkali
had been added, the mixture was allowed to stand in an ice
bath for 5 min to ensure complete precipitation of potassium
chloride. The mixture was filtered with suction and the fil-
trate was added to the appropriate ester substrate (0.030
mol) in a 100-mL flask. Additional potassium hydroxide was
added to form a basic solution (pH 10). After 12 h with stir-
ring at room temperature, the methanol was evaporated
under vacuum and water (20 mL) was added to the residue
to become a clear solution, which was acidified with 2M
HCl to pH<4. The solid was collected by filtration and the
filtrate was extracted with ethyl acetate and the organic
phase was evaporated and purified by recrystallization from
ethyl acetate/n-hexane.
N-Hydroxybenzamide (8a) (R=H): Colourless crystals;
yield: 2.5 g (36%); Rf =0.01 (ethyl acetate/n-hexane, 50%);
mp 125–1278C (reported: mp 1268C);[24] 1H NMR
(300 MHz, DMSO): d=11.22 (s, 1H), 9.06 (s, 1H), 7.78–7.72
(m, 2H), 7.47 (ddd, J=14.4, 7.9, 6.1 Hz, 3H); 13C NMR
(75 MHz, DMSO): d=164.21, 132.71, 131.11, 128.35, 126.81.
N-Hydroxy-4-methylbenzamide (8b) (R=CH3): White
needles; yield: 4 g (86%); Rf =0.02 (ethyl acetate/n-hexane,
50%); mp 143–1458C (reported: mp 143–1448C);[25]
1H NMR (300 MHz, DMSO): d=11.43 (bs, 1H), 9.42 (bs,
1H), 7.87 (d, 2H, J=7.85 Hz), 7.43 (d, J=7.87 Hz, 2H),
2.50 (s, 3H); 13C NMR (75 MHz, DMSO): d=164.58,
141.21, 129.57, 128.90, 126.81, 20.82.
TEA or PdACHTUNGTRENNUNG(OAc)2 alone both elicit Lossen rearrange-
ments in these molecules. In general, aromatic hy-
droxamic acids give the corresponding amine product
while aliphatic substrates yield the symmetric urea.
Mechanisms to account to these reactions remain
complex as both base- and metal-mediated pathways
have been proposed. A metal-hydroxamic acid com-
plex likely forms that facilitates the Lossen rearrange-
ment and further reactions. The basic component of
these reactions may aid in isocyanate formation or act
as a nucleophilic catalyst for the further isocyanate re-
actions. More mechanistic work should be done to
clearly define the parameters and limitations of these
reactions. Overall, this work reveals a new method for
initiating Lossen rearrangements that is compatible
À
with powerful C C bond forming methodology that
allows the formulation of single-pot multiple bond
forming reactions leading to complex product.
Experimental Section
General
Analytical thin layer chromatography (TLC) was performed
on silica gel plates with C-4 spectroline 254 indicator.
Mobile phase is the same as used in the chromatography for
purification of the compounds. Visualization was accom-
plished with UV light and 20% phosphomolybdic acid solu-
tion in EtOH or 0.3% ninhydrin in EtOH. Solvents for ex-
traction and purification were technical grade and used as
received. Melting points were determined on a Mel-Temp
apparatus. 1H NMR and 13C NMR spectra were taken in
commercial deuterated solvents and recorded on Bruker
Advance 300 MHz and Bruker DRX-500 spectrometers
using a 5 mm TBI probe equipped with z axis gradients.
General Procedures for the Preparation of Aliphatic
and Heterocyclic Hydroxamic Acids 8c–f
Hydroxylamine hydrochloride (69.49 g, 28.52 mmol) was
mixed with potassium hydroxide (32 g, 57.04 mmol) in de-
ionized water (30 mL). The solution was added to the ap-
propriate methyl ester substrate (9.33 mmol) in methanol
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El-Shimaa M. N. AbdelHafez et al.
(40 mL). The resulting solution was stirred for 72 h at 408C
and acidified to pH 5.5 using 5M HCl. The solvent was re-
moved under vacuum yielding a yellow solid. Methanol
(60 mL) was added and the precipitate was filtered, the sol-
vent was removed under vacuum, diethyl ether (30 mL) was
added and any formed precipitate was filtered. The filtrate
was evaporated under vacuum yielding a white solid, which
was recrystallized from water to give the product.[18]
(N-Hydroxycyclohexanecarboxamide) (8c) (R=cyclohex-
yl): Light yellow needles; yield: 1.8 g (36%); Rf =0.3 (n-
hexane/ethyl acetate, 60%); mp 121–1228C (reported: mp
1208C);[26] 1H NMR (300 MHz, MeOD): d=4.87 (bs, 1H),
2.17–1.33 (m, 11H); 13C NMR (75 MHz, MeOD): d=176.05,
43.46, 30.49, 26.84, 26.79; ESI-MS: m/z=144.3 (M+ +1).
Lossen Rearrangement for the Aromatic Hydroxamic
Acids 8a and b
The respective hydroxamic acid (5 mmol) was heated in ace-
tonitrile (15 mL) or DMF (1 mL) with stirring in a capped
sealed glass tube at 908C for 24 h with Pd
0.005 mmol) and TEA (303 mg, 6 mmol) together, Pd
alone or TEA in the absence of Pd(OAc)2. After cooling
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
the solvent was removed under vacuum to give a residue
which was dissolved in chloroform (50 mL) and washed with
water (3ꢁ30 mL) and brine (1ꢁ30 mL). The collected or-
ganic extracts were dried with anhydrous sodium sulfate and
filtered. The filtrate was evaporated under vacuum to pro-
duce the corresponding amine or symmetrical urea in the
yields described in the results/discussion section:
(N-Hydroxyhexanamide) (8d) [R=CH3ACHTUNTRGENUNG(CH2)4]: White
crystals; yield: 3.4 g (68%); Rf =0.2 (n-hexane/ethyl acetate,
60%); mp 65–678C (reported: mp 65–668C);[27] 1H NMR
(300 MHz, MeOD): d=2.07 (t, J=7.44 Hz, 2H), 1.59
(pentet, J=7.51 Hz, 2H), 1.40–1.23 (m, 4H), 0.95–0.87 (t,
Physical Properties and Spectroscopic Data of the
Aromatic Amines (9a and b)
Aniline (9a) (R=H): Dark yellow liquid; Rf =0.5 (metha-
nol/chloroform, 2%); 1H NMR (300 MHz, DMSO): d=
7.15–7.09 (m, 2H), 6.77–6.74 (t, J=7.3 Hz, 2H), 6.65 (d, J=
7.4 Hz, 2H), 4.55 (s, 2H); 13C NMR (75 MHz, DMSO): d=
146.45, 129.33, 118.57, 115.15; HR-MS (ESI+): m/z=94.0648
[M+H]+, calcd. for C6H8N: 94.0657.
3
J=6.56, 3H); C NMR (75 MHz, MeOD): d=)173.09, 33.80,
32.41, 26.50, 23.40, 14.33; ESI-MS: m/z=132 (M+ +1).
(N-Hydroxydodecanamide) (8e) [R=CH3
ACHTNUGTERN(NUGN CH2)10]:
White crystalline solid; yield: 1.5 g (70%); Rf =0.2 (metha-
nol/chloroform, 8%); mp 79–808C (reported: mp 82–
868C);[18] 1H NMR (300 MHz, DMSO): d=2.12 (t, J=
7.52 Hz, 2H), 1.46–1.41 (m, 2H), 1.25–1.12 (m, 16H), 0.82–
0.77 (t, J=6.48 Hz, 3H); 13C NMR (75 MHz, DMSO): d=
174.15, 33.57, 31.24, 28.96, 28.87, 28.70, 28.66, 28.51, 25.05,
24.40, 22.01, 13.73.
(N-Hydroxyisonicotinamide) (8f) (R=4-pyridyl]: Light
yellow needles; yield: 4.6 g (93%); recrystallized from ace-
tone; Rf =0.1 (methanol/chloroform, 8%); mp: 162–1638C
(reported: m.p=1618C);[28]1H NMR (300 MHz, DMSO):
d=11.59 (s, 1H, br), 8.70 (d, 2H, J=6.28 Hz), 7.68 (d, 2H,
J=6.38 Hz; 13C NMR (75 MHz, DMSO); d=166.16, 150.10,
139.81, 120.96; ESI-MS: m/z=139 (M+ +1), 121 (M+ÀOH).
para-Tolidine (9b) (R=CH3): Yellow liquid; Rf =0.3
1
(ethyl acetate/n-hexane, 30%); H NMR (300 MHz, CDCl3):
d=6.96 (d, J=8.25 Hz, 2H), 6.60 (d, J=8.27 Hz, 2H), 3.50
(bs, 2H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
143.79, 129.75, 127.80, 115.27, 20.44; ESI-MS: m/z=108.2
(M+ +1).
Physical Properties and Spectroscopic Data of the
Symmetrical Ureas (10a and b)
1,3-Diphenylurea (10a) (R=phenyl): White needles; Rf =
0.6 (methanol/chloroform, 5%); mp: 250–2528C (reported:
mp 251–2538C);[29] IR (KBr): n=3300–3070 (Ar-NH), 3035
(Ar-CH, str), 1645 cmÀ1 (C=O); 1H NMR (300 MHz,
DMSO): d=8.69 (bs, 2H), 7.50 (d, J=8.3 Hz, 4H), 7.35–
7.29 (t, J=7.6 Hz, 4H), 7.04–7.01 (t, J=7.3 Hz, 2H);
13C NMR (75 MHz, DMSO): d=152.51, 139.67, 128.74,
121.78, 118.17; GC-MS: rt =13.4 min, m/z=212.1 [M+]; HR-
MS (ESI): m/z=213.1019 [M+H]+, calcd. for C13H13N2O:
213.1028.
General Procedures for Preparation of the Amino-
Substituted Cinnamate Derivatives (6) and (7)[15]
Using the same Heck procedures with methyl acrylate af-
forded the corresponding cinnamate containing amino prod-
ucts (6) and (7), respectively.After the work-up, the residues
were purified by flash chromatography.
For (6) (R1 =OCH3, R2 =NH2): Brown liquid; yield:
150 mg (97%); Rf =0.3 (methanol/chloroform, 4%);
1H NMR (300 MHz, CDCl3): d=7.60 (d, J=15.86 Hz, 1H),
6.97 (d, J=7.96 Hz, 1H), 6.94 (s, 1H), 6.64 (d, J=7.92 Hz,
1H), 6.20 (d, J=15.86 Hz, 1H), 3.86 (s, 3H), 3.77 (s, 3H);
13C NMR (75 MHz, CDCl3): d=168.14, 146.96, 145.63,
139.14, 124.64, 123.29, 114.06, 113.05, 108.90, 55.47, 51.51;
1,3-Di-para-toluylurea (10b) (R=p-tolyl): White crystals;
Rf =0.6 (methanol/chloroform, 5%); mp 270–2728C (report-
1
ed: mp 2738C); H NMR (300 MHz, DMSO): d=8.47 (bs,
2H), 7.32 (d, J=8.38 Hz, 4H), 7.07 (d, J=8.30 Hz, 4H),
2.23 (s, 6H); 13C NMR (75 MHz, DMSO): d=152.63,
137.12, 130.56, 129.12, 118.25, 20.26; ESI-MS: m/z=241.1
(M+ +1).
ESI-MS:
m/z=208
(M+ +1);
anal.
calcd.
for
Lossen Rearrangement of the Aliphatic and
Heterocyclic Hydroxamic Acids 8c–f
C11H13NO3·0.8H2O: C 59.61, H 6.64, N 6.32; found: C 59.28,
H 6.46, N 6.79.
For (7) (R1 =NH2, R2 =OCH3): Yellow liquid; yield:
151 mg (98%); Rf =0.4 (methanol/chloroform, 4%);
1H NMR (300 MHz, CDCl3): d=7.46 (d, J=15.94 Hz, 1H),
6.79–6.76 (m, 2H), 6.63 (d, J=8.79 Hz, 1H), 6.14 (d, J=
15.92 Hz, 1H), 3.84 (s, 2H), 3.75 (s, 3H), 3.68 (s, 3H);
13C NMR (75 MHz, CDCl3): d=167.87, 149.32, 145.26,
136.63, 127.35, 120.09, 114.82, 112.99, 110.07, 55.49, 51.47;
ESI-MS: m/z=208 (M+ +1).
Applying the same Lossen procedures of the aromatic hy-
droxamic acid 8a and b on the aliphatic hydroxamic acids
8c–e and 8f, the corresponding symmetrical ureas were
formed in yields described in the results/discussion section.
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Adv. Synth. Catal. 2014, 356, 3456 – 3464

UPDATES
Lossen Rearrangements under Heck Reaction Conditions
1-Butyl-3-(para-toluyl)urea (18b) (R=p-toluyl): White
crystals; yield: 330 mg (49%); Rf =0.4 (methanol/chloro-
form, 2%); mp 120–1218C (reported: mp 1198C);[35]
1H NMR (300 MHz, CDCl3): d=7.93 (bs, 1H), 7.16 (d, 2H,
J=8.60 Hz), 6.99 (d, 2H, J=8.0 Hz), 6.01 (bs, 1H), 3.19–
3.08 (m, 2H), 2.24 (s, 3H), 1.55–1.31 (m, 2H), 1.33–1.15 (m,
2H), 0.85 (t, 3H, J=7.2 Hz); 13C NMR (75 MHz, CDCl3):
d=157.10, 136.83, 131.94, 129.34, 120.04, 39.81, 32.33, 20.70,
20.08, 13.80; ESI-MS: m/z=207.14 (M+ +1).
(1-Butyl-3-cyclohexylurea) (18c) (R=cyclohexyl): White
crystals; yield: 394 mg (94%); recrystallized from ethyl ace-
tate/n-hexane; Rf =0.3 (methanol/chloroform, 5%); mp 100–
1028C (reported: mp 105);[36] 1H NMR (300 MHz, CDCl3):
d=5.76 (bs, 1H), 3.35 (bs, 1H), 3.20–2.96 (m, 2H), 1.83–
0.72 (m, 18H); 13C NMR (75 MHz, CDCl3): d=158.82,
48.39, 39.70, 33.82, 32.50, 25.56, 24.91, 19.98, 13.63; ESI-MS:
m/z=199.3 (M+ +1).
(1-Butyl-3-pentylurea (18d) (R=pentyl): Off white solid;
yield: 222 mg (52%); Rf =0.5 (methanol/chloroform, 3%);
mp: 30–328C (reported: 32–318C);[37] 1H NMR (300 MHz,
CDCl3): d=5.83 (bs, 1H), 3.39 (bs, 1H), 3.28–2.96 (m, 1H),
1.86–0.74 (m, 18H); 13C NMR (75 MHz, CDCl3): d=158.84,
48.44, 39.75, 33.84, 32.52, 29.65, 25.59, 24.94, 20.01, 13.66;
ESI-MS: m/z=187.2 (M+ +1), 173 (M+ÀCH3).
Physical Properties and Spectroscopic Data of the
Symmetrical Ureas (10c–f)
1,3-Cyclohexylurea (10c) (R=cyclohexyl): After cooling the
sealed tube, white needles that had settled were filtered and
washed with acetonitrile then n-hexane to afford the prod-
uct; yield: 101 mg (67%); mp 229–2308C (reported: mp
229–2318C);[30] 1H NMR (300 MHz, DMSO, 908C): d=5.42
(br, 2H), 3.38–3.36 (m, 2H), 1.77–1.72 (m, 4H), 1.65–1.61
(m, 4H), 1.53–1.43 (m, 2H), 1.31–1.23 (m, 10H); 13C NMR
(75 MHz, DMSO, 908C,): d=156.66, 47.45, 32.94, 25.04,
24.02. ESI-MS: m/z=225 (M+ +1).
1,3-Dipentylurea (10d) [R=CH3ACTHNUTRGNEUNG(CH2)4]: White needles;
recrystallized from n-hexane; yield: 93 mg (62%), mp 808C
(reported: mp 888C);[31] 1H NMR (300 MHz, CDCl3): d=
5.04 (bs, 2H), 3.16–3.10 (m, 4H), 1.52–1.34 (m, 4H), 1.33–
1.27 (m, 8H), 0.93–0.87 (t, J=6.61 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d=159.22, 40.33, 30.06, 29.11, 22.40,
13.93; ESI-MS: m/z=201 (M+ +1), 187 (M+ÀCH3).
1,3-Diundecylurea (10e) [R=CH3 ACHTNUGTRNE(UNG CH2)10]: White crystal-
line solid; recrystallized from acetone, yield: 74 mg (49%),
mp 130–1328C (reported: mp 131–1328C);[32] 1H NMR
(300 MHz, CDCl3): d=3.58 (s, 2H), 2.26 (t, J=7.47 Hz,
4H), 1.60–1.51 (m, 4H), 1.29–1.19 (m, 32H), 0.83–0.76 (t,
J=6.61 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=180.37,
51.33, 34.09, 31.88, 29.57, 29.41, 29.30, 29.22, 29.04, 24.65,
22.63, 13.99; ESI-MS: m/z=271.3 (M+ÀC7H15), 243.2
(M+ÀC9H19), 200.2 (M+ÀC11H23NH).
Preparation of N-[(Phenylcarbamoyl)oxy]benzamide
(17)
1,3-Di(pyridin-4-yl)urea (10f) (R=4-pyridyl]: Colourless
needles; recrystallized from acetone; yield: 96 mg (64%);
Rf =0.4 (methanol/chloroform, 5%); mp: 202–2038C (re-
ported: mp 2008C);[33] 1H NMR (300 MHz, DMSO): d=8.22
(bs, 2H), 8.09 (d, J=6.94 Hz, 4H), 6.85 (d, J=6.97 Hz, 4H);
13C NMR (75 MHz, DMSO): d=159.51, 149.99, 139.80,
108.59; ESI-MS: m/z=215 (M+ +1).
A solution of 8a (1.4 g, 10 mmol) and phenyl isocyanate
(1.2 g, 10 mmol) in dichloromethane (1 mL) and THF
(1 mL) was heated on a water-bath for 1 h. After cooling
and adding n-hexane, crude product was obtained.[21] Re-
crystallization from ethyl acetate afforded 17 as short white
needles; yield: 1.7 g (65%); Rf =0.7 (methanol/chloroform,
5%); mp 1808C (reported: mp 181–1828C);[39] 1H NMR
(300 MHz, DMSO): d=12.42 (s, 1H), 10.41 (s, 1H), 7.91 (d,
2H, J=7.51 Hz), 7.58–7.53 (m, 5H), 7.34 (t, 2H, J=
7.79 Hz), 7.08 (t, 2H, J=7.49 Hz); 13C NMR (75 MHz,
DMSO): d=165.09, 152.36, 138.23, 132.22, 131.13, 128.97,
128.61, 127.36, 123.19, 118.41.
General Procedures for the Reaction of Aromatic
and Aliphatic Hydroxamic Acids with n-Butylamine
TEA (0.06 g, 0.09 mL, 0.645 mmol) was added to a solution
of the hydroxamic acid (5 mmol), and n-butylamine
(25 mmol) in acetonitrile (15 mL), the mixture was then
heated with stirring in a capped sealed glass tube at 908C
for 24 h. After cooling, the solvent was removed under re-
duced pressure; the residue was dissolved in chloroform
(30 mL) and washed with water (3ꢁ15 mL) and brine. The
organic layer was dried with anhydrous sodium sulfate, fil-
tered and evaporated under reduced pressure to give a resi-
due that was further purified by flash chromatography.
Preparation of N-(Benzoyloxy)benzamide (16):[22]
A solution of 8a (500 mg, 3.65 mmol, 1 equiv.) and potassi-
um tert-butoxide (409 mg, 3.65 mmol, 1 equiv.) was stirred at
room temperature in diethyl ether (30 mL) for 30 min. Ben-
zoyl chloride (513 mg, 3.65 mmol, 1 equiv.) was added drop-
wise and the reaction mixture stirred at room temperature
for 16 h, diluted with ethyl acetate and washed with water
and NaHCO3. The collected organic phases were dried with
anhydrous MgSO4 and evaporated under reduced pressure
to afford the desired product as a white solid; yield: 759 mg
(86%); mp 157–1588C (reported: mp 154–1578C);[40]
1H NMR (300 MHz, DMSO): d=12.67 (bs, 1H), 8.16–8.09
(m, 2H), 7.92–7.89 (m, 2H), 7.79–7.71 (t, J=7.5 Hz, 1H),
7.64–7.53 (m, 5H); 13C NMR (75 MHz, DMSO,): d=164.87,
164.37, 134.35, 132.34, 130.95, 129.48, 129.13, 128.68, 127.40,
126.88; ESI-MS: m/z=242 (M+ +1).
Physical Properties and Spectroscopic Data of the
Unsymmetrical Ureas (18a–d)
1-Butyl-3-phenylurea (18a) (R=phenyl): White crystal;
yield: 830 mg (85%); Rf =0.6 (methanol/chloroform, 5%);
mp 128–1308C (reported: mp 131–1338C);[34] 1H NMR
(300 MHz, DMSO): d=8.41 (bs, 1H), 7.39 (d, J=7.99 Hz,
2H), 7.20 (t, J=7.73 Hz, 2H), 6.87 (t, J=7.34 Hz, 1H), 6.14
(bs, 1H), 3.08 (d, J=6.22 Hz, 2H), 1.41–1.29 (m, 4H), 0.89
(t, J=7.16 Hz, 3H); 13C NMR (75 MHz, DMSO): d=155.28,
140.48, 128.48, 120.87, 117.60, 79.06, 31.86, 19.49, 13.57; ESI-
MS: m/z=193 (M+ +1).
Preparation of Methyl Phenyl Carbamate (19a)[23]
A 100-mL, round-bottomed flask equipped with a magnetic
stir bar was charged with anhydrous methanol (40 mL).
Adv. Synth. Catal. 2014, 356, 3456 – 3464
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3463

UPDATES
El-Shimaa M. N. AbdelHafez et al.
With vigorous stirring, phenyl isocyanate (3 g, 25.18 mmol)
was added in one portion. The mixture was refluxed for
30 min and the solvent was removed under vacuum. The re-
maining colourless liquid spontaneously crystallized after
cooling in an ice bath. The colourless crystals were slurried
with n-hexane (20 mL) and filtered to afford methyl phenyl
carbamate; yield: 3.3 g (92%); mp 37–388C (reported: 37–
398C);[23] 1H NMR (300 MHz, CDCl3): d=7.44 (bs, 1H),
7.35 (d, J=8.03 Hz, 2H), 7.22 (t, J=8.29 Hz, 2H), 6.99 (t,
J=7.36 Hz, 1H), 3.68 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=154.70, 138.23, 128.96, 123.41, 119.10, 52.24.
[15] B. A. Patel, C. B. Ziegler, N. A. Cortese, J. E. Plevyak,
T. C. Zebovitz, M. Terpko, R. F. Heck, J. Org. Chem.
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Negureanu, Y. Lu, J. H. Bean, K. Zielke, B. Crowe, A.
Vasilyeva, J. Clodfelter, O. Aly, G. Abuo-Rahma, F. R.
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Acknowledgements
This project was supported the National Cancer Institute
(grant R01A129373). The Comprehensive Cancer Center of
Wake Forest University (grant P30A012197) provided sup-
port for the Synthetic and Computational Biosciences core fa-
cility through. We acknowledge the financial support of an
Egyptian Government studentships to El-Shimaa M. N. Ab-
delHafez through the Channel system between Minia Univer-
sity, Egypt and Wake Forest University, USA.
[21] K. Nagarajan, S. Rajappa, V. S. Iyer, Tetrahedron 1967,
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Adv. Synth. Catal. 2014, 356, 3456 – 3464