Synthesis of methyl-1-(tert -butoxycarbonylamino)-2- vinylcyclopropanecarboxylate via a hofmann rearrangement utilizing trichloroisocyanuric acid as an oxidant

Article abstract of DOI:10.1021/jo101504e

A trichloroisocyanuric acid (TCCA) mediated Hofmann rearrangement was utilized to synthesize methyl-1-(tert-butoxycarbonylamino)-2- vinylcyclopropanecarboxylate. A variety of functional groups are tolerated in this reaction including vinyl, cyclopropyl, pyridyl, aryl, benzyl, and nitro groups.

Full text of DOI:10.1021/jo101504e

pubs.acs.org/joc
More recently, cyclopropane moieties have found applica-
Synthesis of Methyl-1-(tert-butoxycarbonylamino)-
2-vinylcyclopropanecarboxylate via a Hofmann
Rearrangement Utilizing Trichloroisocyanuric Acid
as an Oxidant
tion in peptomimetics, presumably due to conformational
rigidity.1c The synthesis of this class of unnatural amino
acids has been described in the literature, with preparations
on the kilogram scale.2-4
Zackary D. Crane,* Paul J. Nichols, Tarek Sammakia,‡ and
Peter J. Stengel
Department of Process Chemistry, Array Bio Pharma Inc., 3200
Walnut Street, Boulder, Colorado 80301, United States. ‡Present
address: Department of Chemistry and Biochemistry, University
of Colorado, Boulder, CO 80309, United States
zackary.crane@arraybiopharma.com
Received August 20, 2010
FIGURE 1. Examples of naturally occurring and biologically ac-
tive molecules containing cyclopropane amino acids.
We wished to develop a novel approach to compound 1
(Scheme 1) that would be efficient and amenable to kilogram
scale. The racemic synthesis outlined in Scheme 1 accomplishes
this goal and produces 1 in high yield from stable, crystalline
intermediates and inexpensive starting materials.
Further, the lipase-catalyzed kinetic resolution of 1is known,4
and proceeds with high efficiency, thereby providing convenient
access to nonracemic material.
The synthesis begins with the known3a alkylation of dimethyl
malonate with trans-1,4-dibromobutene to provide vinylcyclo-
propane 3 along with small amounts (∼8%) of cyclopentene 4.
This reaction was not subjected to workup, and was instead
directly treated with a methanolic solution of ammonia5 (9
equiv) and sodium methoxide (0.8 equiv) to provide 5 as a
crystalline solid that was isolated in 68% yield. Under these
conditions, malonamide 6 is formed from cyclopentene 4, as is a
small amount of malonamide 7. Both of these compounds are
water-soluble and are removed during the workup by an
aqueous wash. This procedure provides 5 exclusively with the
stereochemistry depicted in Scheme 1 to the limits of NMR
detection.6 This is likely due to steric effects rendering the less
hindered carbonyl of the malonate more prone to substitution.
Further, it is likely that any of the minor isomer of 5 that is
produced will be consumed by undergoing substitution to
malonamide 7 under the reaction conditions.
A trichloroisocyanuric acid (TCCA) mediated Hofmann re-
arrangement was utilized to synthesize methyl-1-(tert-butoxy-
carbonylamino)-2-vinylcyclopropanecarboxylate. A variety
of functional groups are tolerated in this reaction including
vinyl, cyclopropyl, pyridyl, aryl, benzyl, and nitro groups.
A number of naturally occurring and biologically active
compounds contain cyclopropane amino acids (Figure 1).1
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rearrangement. The stereochemistry of compound 5 was determined by
NOE analysis on compound 8 and is consistent with the relative stereochem-
istry depicted in Schemes 1 and 2. Details are provided in the Supporting
Information.
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DOI: 10.1021/jo101504e
r
Published on Web 12/06/2010
J. Org. Chem. 2011, 76, 277–280 277
2010 American Chemical Society

Crane et al.
SCHEME 2. Hofmann Rearrangement NMR Experiment
JOCNote
SCHEME 1. Synthesis of 1 via the Hofmann Rearrangement
a variety of oxidants including bromite,8 N-bromosuccini-
mide (NBS),9 Pb(OAc)4,10 and hypervalent organoiodine
compounds,11 among others. The rearrangement proceeds
via an isocyanate and is mechanistically related to the
Curtius,12 Lossen,13 and Schmidt14 reactions. It has been
used in the synthesis of natural products15 and demonstrated
in large scale manufacturing processes.16
The challenge in the application of this transformation to
substrate 3 is to effect oxidation and rearrangement of the
amide without disturbing the alkene or the cyclopropane in
the molecule. We studied the traditional reagents and pro-
cedures used in the Hofmann rearrangement with limited
success. The succinimide reagents, NBS and N-chlorosucci-
nimide (NCS), were found to effect the desired transforma-
tion in methanol. Unfortunately, using the typical proce-
dures for NBS (refluxing the amide and NBS in methanol in
the presence of base), only partial conversion was observed.
It is known that NBS undergoes decomposition in the
presence of base at higher temperature,17 and as such, excess
NBS can be used to force the reaction to completion.9a
However, using excess NBS resulted in bromination of the prod-
uct. The use of NCS was deemed inferior due to the decom-
position of the reagent via a nucleophilic ring-opening and
subsequent Hofmann rearrangement of the ring-opened prod-
uct as suggested by the presence of impurities in the NMR
spectrum of the crude reaction mixture. The use of NaOCl in
aqueous solution produced a complex mixture of products. The
hypervalent iodine reagent [I,I-bis(trifluoroacetoxy)iodo]ben-
zene (PIFA) was studied but is known to be sensitive to halogen
and solvent impurities18 and was found to be capricious. TCCA
and sodium methoxide in refluxing methanol19 gave the desired
methylcarbamate with some overoxidation of the product to the
N-chloro species. This reaction was deemed promising and
chosen for further study.
Amide 5 was then converted to methylcarbamate 8 in
high yield by a trichloroisocyanuric acid (TCCA)-mediated
Hofmann rearrangement. The Hofmann rearrangement
converts a primary amide to either an amine or a carbamate,
depending on the conditions, with the loss of a carbon atom.7
The reaction is an oxidation and can be performed with
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Crane et al.
JOCNote
TABLE 1. Scope of the TCCA Hofmann Rearrangement
We first studied reducing the amount of active chlorine to
1 equiv in order to prevent over-oxidation of the product.
TLC evidence suggested that the chlorination of the amide
was rapid with TCCA in the presence of 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU), but the rearrangement was slower.
Therefore, the progress of the reaction was studied by NMR in
CD3OD (Scheme 2). At room temperature and in the presence
of stoichiometric amounts of DBU, TCCA cleanly and quanti-
tatively converts amide 5 to chloroamide 9. Both the oxidant
and chloroamide 9 are stable under these conditions, thereby
allowing for the use of stoichiometric amounts of active chlorine
(i.e., 1/3 equiv of TCCA) for the full conversion of the amide to
the chloroamide. Heating this intermediate to reflux in metha-
nol for 2.5 h then induces the rearrangement and provides the
desired carbamate cleanly with no over-oxidation. This two-
stage procedure wherein chlorination is allowed to proceed
to completion under mild conditions prior to heating and
rearrangement was found to be a significant process improve-
ment as compared to procedures in which the oxidant is added
at high temperature.9a The fact that TCCA is inexpensive and
easily handled on scale20 further adds to the appeal of this
method.
This process utilizes methanol as the solvent and therefore
provides a methylcarbamate product that must then be con-
verted to a Boc-carbamate in a subsequent step. The use of tert-
butanol as solvent in place of methanol would save a synthetic
step by directly producing the Boc-carbamate. Unfortunately,
TCCA and other halogen-based oxidants (NBS and NCS) were
incompatible with tert-butanol forming dark insoluble products
under the reaction conditions. Fortunately, the transformation
(20) Tilstam, U.; Weinmann, H. Org. Process Res. Dev. 2002, 6, 384–393.
J. Org. Chem. Vol. 76, No. 1, 2011 279

Crane et al.
JOCNote
of methyl carbamate 8 to the Boc-carbamate could be accom-
plished in high yield (88%) by modification of the Burk21
method wherein a Boc-group is first installed on the carbamate
by treatment with (Boc)2O and DBU in refluxing THF followed
by selective removal of the methyl carbamate by treatment with
sodium methoxide. The route shown in Scheme 1, featuring the
TCCA-mediated Hofmann rearrangement, provides racemic 1
in 46% overall yield on 270 g scale. An additional benefit to this
approach is the potential for enzymatic resolution on inter-
mediates 5 or 8 as well as ester 1 to provide a single enantiomer.
During the course of this research, Hiegel and Hogenauer
reported the use of TCCA in the Hofmann rearrangement
of amides to methyl carbamates.22 However, their work was
limited to simple aliphatic and aromatic substrates. To further
define the scope of this transformation, a number of substrates
bearing a variety of functional groups were examined (Table 1).
We utilized the procedure developed in the synthesis of 1
wherein TCCA is added portion-wise to a mixture of the amide,
methanol, and base, at room temperature. Following chloro-
amide formation, the mixture is then heated to reflux overnight,
concentrated, and purified by flash chromatography.
In general, the reactions proceeded smoothly with a few
exceptions as shown in Table 1. Both nonsubstituted (entry 1,
Table 1) methyl-substituted (entries 2 and 3) and chloro-sub-
stituted (entries 4 and 5) aromatic amides provide high yields
under these conditions. The reaction proceeds in the presence of
both electron-withdrawing and electron-donating aromatic
substituents (entries 6 and 7). Cinnamamide undergoes rear-
rangement to provide the corresponding enamide as a 60/40
mixture of the methoxy-substituted product 19 and the expected
product 20 (entry 8). Nicotinamide provides the desired product
without oxidation of the pyridyl amine (entry 9). Cyclic (entry 10)
and straight chain (entry 11) aliphatic substrates, as well as
phenylacetamide (entry 12), give good yields. Attempted appli-
cation of this method to 2-bromo benzamide resulted in multi-
ple products (entry 14). Benzoic acid and 2-hydroxybenzamide
substrates (entries 15 and 16) decompose under these condi-
tions. In the case of the 2-hydroxybenzamide, this may be
attributed to TCCA’s ability to chlorinate phenols and anilines
under mild conditions without acid catalyst.23
In conclusion, an efficient, safe, and scalable TCCA-medi-
ated Hofmann rearrangement has been employed in a novel
synthesis of an unnatural amino acid moiety that is becoming a
building block in many novel drug candidates. The scope of the
TCCA-mediated Hofmann rearrangement has also been ex-
panded to include a number of functional groups including
olefins, esters, halogens, ethers, heteroaromatic, cyclopropyl,
and nitro functionality.
Experimental Section
General Procedure for the TCCA-Mediated Hofmann Rear-
rangement (12). To a flask equipped with magnetic stirring,
reflux condenser, and N2 inlet was added benzamide (2.0 g, 16.51
mmol), MeOH (20 mL, 10 vol to amide), and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (5.6 g, 37.15 mmol). To the reaction was added
trichloroisocyanuric acid (TCCA) (0.73 g, 3.14 mmol). The reac-
tion was allowed to stir for 15 min at which time additional TCCA
(0.73 g, 3.14 mmol) was added. The reaction temperature was
increased to 65 °C and was stirred for 16 h. The reaction was judged
complete by disappearance of the starting material using TLC. The
reaction was concentrated on a rotary evaporator at 40 °C. The oil
was dissolved in a minimal amount of EtOAc and the solvent was
concentrated. Compound 12 was purified by chromatography to
give 2.3 g (92%) of a white solid: mp 48-50 °C (lit.1 mp 46-
46.8 °C); 1H NMR2 (400 MHz, CDCl3) δ 3.77 (s, 3H), 6.58 (s, 1H),
7.07 (t, J=7.6 Hz, 1H), 7.31 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ154.3, 138.1, 129.2, 123.6, 118.9, 52.5; IR (cm-1) 3355, 3297, 1702,
1600, 1541. Anal. Calcd for C8H9NO2: C, 63.56; H, 6.00; N, 9.27.
Found: C, 63.61; H, 5.66; N, 9.27.
Acknowledgment. We thank Dr. Lingyang Zhu of Array
BioPharma for her help with NMR characterization and Dr.
John A. DeMattei and other members of the process chem-
istry group at Array BioPharma for their helpful insights and
discussions.
Supporting Information Available: Experimental proce-
dures for compounds 1, 5, and 8, as well as full characterization
of 12-18, 21-24, and compounds 1, 5, and 8, and 1H NMR of
compounds 19 and 20. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054–7057.
(22) Hiegel, G. A.; Hogenauer, T. J. Synth. Commun. 2005, 2091–2098.
(23) Juenge, E. C.; Beal, D. A.; Duncan, W. P. J. Org. Chem. 1970, 35,
719–722.
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