Synthesis of nitrogen-substituted methylenecyclopropanes by strain-driven Overman rearrangement of cyclopropenylmethyl trichloroacetimidates

Article abstract of DOI:10.1021/jo501423u

Nitrogen-substituted methylenecyclopropanes have been prepared by a strain-driven Overman rearrangement of cyclopropenylmethyl trichloroacetimidates. The reaction proceeds at room temperature and without the need of a transition-metal catalyst. Furthermor

Full text of DOI:10.1021/jo501423u

Note
pubs.acs.org/joc
Synthesis of Nitrogen-Substituted Methylenecyclopropanes by
Strain-Driven Overman Rearrangement of Cyclopropenylmethyl
Trichloroacetimidates
James K. Howard,‡ Chintan Amin,§ Brendan Lainhart,§ Jason A. Smith,‡ Jack Rimington,†
and Christopher J. T. Hyland*,†
†School of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia
‡School of Physical Sciences (Chemistry), University of Tasmania, Private Bag 75, Hobart, TAS 7001, Australia
§Department of Chemistry and Biochemistry, California State University, Fullerton, California 92831, United States
S
* Supporting Information
ABSTRACT: Nitrogen-substituted methylenecyclopropanes
have been prepared by a strain-driven Overman rearrangement
of cyclopropenylmethyl trichloroacetimidates. The reaction
proceeds at room temperature and without the need of a
transition-metal catalyst. Furthermore, it has been shown that
C-3-substituted cyclopropenylmethyl trichloroacetimidates
undergo a hydrolytic ring-opening reaction to form allenylcarbinols.
Scheme 1. Previous Syntheses of Heteroatom-Substituted
Methylenecylopropanes and Proposed Overman
Rearrangement of Cyclopropenylmethyl
Trichloroacetimidates
ethylenecyclopropanes are strained, but remarkably
Mstable, unsaturated carbocycles that have attracted
significant interest for their strain-driven reactivity.1−4
Typically, these highly strained systems are susceptible to
ring-opening reactions,5−17 cycloaddition reactions,18−23 and
ring-expansion reactions.23−28 They have also proved to be
precursors for densely functionalized cyclopropanes via ring-
retaining C−C29−37 and C−heteroatom bond-forming reac-
tions to their exocyclic double bond.38−40
A range of methods for the synthesis of methylenecyclopro-
panes exist;4,41 however, relatively few of these consider the
synthesis of heteroatom-substituted structures. Cyclopropenes,
bearing an allylic leaving group, can be transformed into
methylenecyclopropanes upon nucleophilic attack to the
cyclopropene double bond. Such a process is thermodynami-
cally favored due to the relief of strain energy associated with
movement of the double bond to the exocyclic position. This
approach has been developed for the synthesis of carbon/
hydrogen-substituted methylenecyclopropanes42−47 but is also
one of the limited ways to prepare heteroatom-substituted
systems. One notable example is the strain-driven [3,3]-
sigmatropic rearrangement of cyclopropenylmethyl esters to
acetoxy-substituted methylenecyclopropanes by Marek and co-
workers (eq 1, Scheme 1).43 The groups of Marek43 and
Rubin47 also reported a [2,3]-sigmatropic rearrangement of
cyclopropenes to provide methylenecyclopropylphosphine
oxides (eq 2 and 3, Scheme 1). Such heteroatom-substituted
systems are of interest as phosphorus, oxygen, and nitrogen
substituents are ubiquitous in bioactive small molecules. In
particular, N-substituted methylenecyclopropanes may act as
precursors to cyclopropylamines and cyclopropylureas, which
are found in a range of bioactive molecules. For example,
cyclopropylurea I is a kinase inhibitor,48 II displays anti-HIV
activity,49 and phenylcyclopropylamine III is a monoamine
oxidase (MAO) inhibitor (Figure 1).50 As there are no general
methods for the synthesis of nitrogen-substituted methylene-
cyclopropanes there is a need for methodology to allow their
preparation. To address this gap, we hypothesized that an allylic
trichloroacetimidate rearrangement (Overman rearrangement)
of cyclopropenylmethyl trichloroacetimidates (eq 4, Scheme 1)
Received: June 26, 2014
© XXXX American Chemical Society
A
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Note
yield a single isomer of 3a. This two-step yield was significantly
increased by the addition of K2CO3 as a base. However,
changing the solvent to DMF resulted in a faster but lower
yielding reaction (entry 4, full conversion in 22 h). It also
quickly became apparent that catalysis of the rearrangement by
PdCl2(MeCN)2 was inefficient in comparison to the mild
thermal conditions (entry 3, Table 1). The Pd catalyst gave
only trace product accompanied by significant decomposition.
Evidence for methylenecyclopropane formation was indicated
by 1H NMR resonance of the proton adjacent to the oxygen of
the imidate shifting from a singlet at 6.76 ppm to a triplet at
7.13 ppm corresponding to the alkene.
A range of different aryl-substituted cyclopropenylmethyl
trichloroacetimidates was subjected to rearrangement (Table
2). It can be observed that derivatives with electron-rich (3d,e)
and heterocyclic (3b) aryl groups underwent efficient
rearrangement. Halogen-substituted phenyl groups were well
tolerated (3a and 3g), as was ortho-substitution (3g). Highly
electron-deficient aryl nitro-substituted systems, however, did
not undergo rearrangement at all and only provided recovered
starting material. This lack of reactivity is likely due to the
electron-deficient aryl groups disfavoring the development of
positive charge in the transition state at the oxygen-bearing
carbon. This observation, coupled with the higher reactivity of
electron-rich aryl groups, suggests the possibility of a transition
state with ionic character. Curiously, the dodecyl aldehyde-
derived cyclopropenylcarbinol 1j could not be converted to the
corresponding imidate despite extended reaction times and
excesses of reagents.53
All of the methylenecyclopropanamides were obtained as a
single E-isomer, suggesting that the reaction likely proceeds
through a [3,3] sigmatropic rearrangement mechanism as is
normally observed for the Overman rearrangement.52 The
stereochemistry of the rearrangement is assigned on the basis of
NOE correlations and is explained by a pseudochair
conformation 4 similar to that proposed by Marek and co-
workers.43
Attempts to reduce or hydrolyze the trichloroacetamides to
reveal the free amines were not successful. Conditions
investigation included acid hydrolysis (1 M HCl, 0 °C), basic
hydrolysis (KOH/EtOH), and reductive cleavage (DIBAL-H or
NaBH4); in each case, recovery of starting material along with
decomposition was observed. This was attributed to an unstable
isocyanate intermediate resulting in the loss of chloroform, as
shown by Nishikawa et al.54 A different course of action was
taken, which was to generate the isocyanate intermediate from
3a/3f at −78 °C with Cs2CO3 in DMF before capturing it with
Figure 1. Representative bioactive N-substituted cyclopropanes.
should afford 2,2,2-trichloro-N-(2-methylenecyclopropyl)-
acetamides.
The Overman rearrangement is a powerful method for
converting allylic alcohols to allylic amines. Typically, allylic
trichloroacetimidates undergo either thermal or Pd(II)-
catalyzed rearrangement to allylic trichloroacetamides that
may be subsequently transformed into allylic amines by
hydrolysis.51,52 The thermal conditions typically require xylenes
at reflux, however, we hypothesized that the strain relief
associated with a cyclopropenylmethyl trichloroacetimidate
undergoing rearrangement to a 2,2,2-trichloro-N-(2-methylene-
cyclopropyl)acetamide would allow the reaction to occur
without a catalyst and without the need for high temperatures.
Herein, we report the successful catalyst-free rearrangement of
these systems at ambient temperature.
Initial optimization of both imidate synthesis and subsequent
Overman rearrangement utilized p-bromobenzaldehyde-derived
cyclopropenylcarbinol 1a (Table 1). The optimum conditions
for trichloroacetimidate synthesis involved treating alcohol 1a
with a catalytic amount of DBU in CH2Cl2 at −78 °C, followed
by addition of trichloroacetonitrile and warming to −15 °C.
The imidate 2a could be identified in the 1H NMR spectrum by
the shift of the singlet corresponding to the proton adjacent to
oxygen from 5.63 ppm in 1a downfield to 6.76 ppm for the
imidate 2a. The use of other bases such as NaH and KH gave
only recovered starting material. It was found to be important
that the imidation reaction with DBU should be left for no
longer than 3 h and allowed to warm to a maximum of −15 °C.
Longer reaction time or higher temperature led to decom-
position and/or lower yield, indicating partial rearrangement to
the amide. The imidate could be obtained after rapid removal
of all volatile components under reduced pressure and was used
directly without further purification.
With conditions for the preparation of the imidate in hand,
attention was turned toward identifying optimum conditions
for the Overman rearrangement. We were delighted to find that
imidate 2a underwent efficient [3,3]-sigmatropic rearrangement
under mild conditions (30 °C, CH2Cl2, Table 1, entry 1) to
Table 1. Optimization of the Overman Rearrangement of 2a To Yield Trichloroacetimidate 3a
a
entry
additive
conditions
time (h)
yield (%)
1
2
3
4
none
30 °C, CH2Cl2
30 °C, CH2Cl2
30 °C, CH2Cl2
30 °C, DMF
40
40
24
22
21
63
<5
53
K2CO3 (1 equiv)
PdCl2(MeCN)2 (5 mol %)
K2CO3 (1 equiv)
a
Isolated yields.
B
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Note
a
Table 2. Scope of the Overman Rearrangement To Yield 2,2,2-Trichloro-N-(2-methylenecyclopropyl)acetamides 3
a
b
c
Isolated yields over two steps, representing a single E-isomer of the product. Imidate was formed, but rearrangement did not proceed. Imidate
could not be formed.
pyrrolidine to successfully yield the desired ureas 5a/5f,
remaining chloride in 7, representing a useful handle for further
respectively (Scheme 2). Cyclopropylureas are valuable targets
functionalization by substitution or coupling chemistry.
Scheme 2. Manipulation of Methylenecyclopropane 3a/f
under Basic Conditions To Yield Ureas 5a/f or
Oxaacetamide 6
Scheme 3. Catalytic Hydrogenation of
Methylenecyclopropane 3f To Yield Saturated
Amidocyclopropane 7
We also briefly investigated the Overman rearrangement of
cyclopropenylmethyl trichloroacetimidate 9 bearing a gem-
dimethyl group at C-3. While the trichloroacetimidates 9 could
be readily prepared, they underwent rapid hydrolytic ring
opening in the presence of silica gel to form allenylcarbinols 10
(Scheme 4). This reaction pathway is highly favored due to the
stabilization of the allenyl cation by the gem-dimethyl group in
conjunction with the relief of ring strain. Indeed, we have
previously demonstrated that related cyclopropenylmethyl
acetates undergo ring opening to allenyl cations 11 in the
presence of TiCl4.57
given their occurrence in a range of bioactive molecules,
including kinase inhibitors,48 epoxide hydrolase inhibitors,55
and HIV-1 reverse transcriptase inhibitors.49 Interestingly,
when bench-grade DMF, which contained traces of water,
was used a 2-oxaacetamide 6 was formed in a moderate yield.56
Given the potential of methylenecyclopropanes 3 as
precursors to nitrogen-substituted cyclopropanes, a catalytic
hydrogenation was also attempted in order to provide the
saturated system. Hydrogenation initially yielded a mixture of
reduction products identified as various dehalogenated cyclo-
propanes. Fortuitously, with extended reaction times, hydro-
genation yielded the monochloro amide 7 as a 2.5:1 mixture of
diastereoisomers in 41% yield (Scheme 3). Of note is the
CONCLUSION
■
In summary, we have developed a method for the preparation
of functionalized nitrogen-substituted methylenecyclopropanes
via an Overman rearrangement. There are currently no general
methods available for these structures, which as we have shown
have some potential as precursors to cyclopropylureas. These
C
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Note
111.7, 114.3, 123.8, 126.9, 130.0, 134.9, 136.2, 145.2. HRMS (+EI-
Orbitrap): m/z for C16H17NO3SNa calcd 326.0826, found 326.0821.
1-(2-Methylcycloprop-1-enyl)dodecan-1-ol (1d). From dodecylal-
dehyde as a colorless oil using 20% ethyl acetate/hexanes; 345 mg,
57%. 1H NMR (400 MHz, CDCl3): δ 0.89 (t, J = 7.0 Hz, 3H), 0.92 (d,
J(ab) = 9.0 Hz, 1H), 0.95 (d, J(ab) = 9.0 Hz, 1H), 1.19−1.47 (m, 18H),
1.70 (dd, J = 7.0, 15.0 Hz, 2H), 1.87 (br s, 1H), 2.10 (d, J = 1.5 Hz,
3H), 4.60 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 8.2, 11.5, 14.1,
22.7, 25.2, 29.3, 29.5, 29.6, 29.6, 29.6, 31.9, 35.8, 68.0, 108.3, 111.2. IR:
3416 cm−1. HRMS (MMI-TOF) (m/z): (M − H)+ calcd for C16H29O
237.2213, found 237.2214.
Scheme 4. Formation of Allenylcarbinols 10 by Silica Gel-
Induced Hydrolytic Ring Opening of Acetimidate 9 via
Allenyl Cation 11
(2-Methylcycloprop-1-enyl)(3-methoxyphenyl)methanol (1f).
From 3-methoxybenzaldehyde as pale yellow oil using 20% ethyl
acetate/hexanes; 45.5 mg, 20% yield. IR (ATR): 3403, 2943, 2869,
1260 cm−1. 1H NMR (300 MHz, CDCl3): δ 1.02 (d, J = 8.4 Hz, 1H),
1.06 (d, J = 8.4 Hz, 1H), 2.09 (d, J = 1.2 Hz, 3H), 3.80 (s, 3H), 5.64
(bs, 1H), 6.82−6.86 (m, 1H), 6.96−6.99 (m, 2H), 7.27 (t, J = 8.1 Hz,
1H). 13C NMR (75 MHz, CDCl3): δ 20.0, 20.9, 55.3, 112.6, 113.5,
119.9, 121.1, 128.3, 129.7, 138.1, 159.8, 162.3. HRMS (+EI-Orbitrap):
m/z for C12H15O2 calcd 191.1072, found 191.1067.
rearrangements occur under very mild conditions by virtue of
strain relief and also occur with complete stereoselectivity to
give the E-methylenecyclopropanes. We have also described
initial studies on the manipulation of these systems and
divergent reactivity toward the formation of allenyl carbinols
when cation-stabilizing groups are present.
(2-Methylcycloprop-1-enyl)(2-chlorophenyl)methanol (1g). From
2-chlorobenzaldehyde as a clear oil using 20% ethyl acetate/hexanes;
1
184.8 mg >99% yield. IR (ATR): 3357, 2964, 2871, 1441 cm−1. H
NMR (300 MHz, CDCl3): δ 1.03 (s, 2H), 2.06 (s, 3H), 2.59 (bs, 1H),
6.03 (bs, 1H), 7.22−7.28 (m, 2H), 7.30−7.37 (m, 1H), 7.50−7.53 (m,
1H). 13C NMR (75 MHz, CDCl3): δ 9.1, 11.4, 67.2, 109.7, 110.6,
127.1, 127.9, 128.9, 129.6, 132.3, 138.7. HRMS (+EI-Orbitrap): m/z
for C11H12ClO calcd 195.0571, found 195.0569.
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise stated, all reactions were
carried out under an argon or nitrogen atmosphere in dry glassware.
Reactions were monitored by TLC using glass-backed silica gel plates
or by GC and GC/MS. Compounds were purified using flash column
chromatography or by radial chromatography with a Chromatotron.
Reaction solvents were obtained from a solvent purification system
having passed through anhydrous alumina columns. n-BuLi was
titrated against diphenylacetic acid prior to use. 1,2,2-Tribromo-1-
methylpropane,58 1,1,2-tribromo-2,3,3-trimethylcyclopropane,59 (2-
methylcycloprop-1-enyl)(4-bromophenyl)methanol (1a),58 phenyl-
(2,3,3-trimethylcycloprop-1-en-1-yl)methanol (1c),60 (2-methylcyclo-
prop-1-enyl)(4-methoxyphenyl)methanol (1d),58 2-methylcycloprop-
1-enyl)(4-methylphenyl)methanol (1e),58 phenyl(2,3,3-trimethylcy-
cloprop-1-enyl)methanol (8a),59 and (4-bromophenyl)(2,3,3-trime-
thylcycloprop-1-enyl)methanol (8b)59 were synthesized and charac-
terized as previously reported. Other reagents were commercially
available and used without further purification.
2-Methylcycloprop-1-enyl)(4-nitrophenyl)methanol (1h). From 4-
nitrobenzaldehyde as a yellow semisolid using 50% Et2O/pentane;
1
335.1 mg, 94% yield. IR (ATR): 3594, 3054, 2986, 1268 cm−1. H
NMR (400 MHz, CDCl3) δ 1.05 (d, J(ab) = 8.3 Hz, 1H), 1.08 (d, J(ab)
=
8.3 Hz, 1H), 2.11 (d, J = 1.4 Hz, 3H), 5.80 (s, 1H), 7.61 (d, J = 8.9 Hz,
2H), 8.24 (d, J = 8.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 9.1,
11.4, 69.2, 110.0, 111.6, 123.8, 127.0, 148.4. HRMS (MMI-TOF): m/z
for (2 M + NH4)+ calcd for C22H26N3O6 428.1822, found 428.1828.
(2-Methylcycloprop-1-enyl)(3-nitrophenyl)methanol (1i). From 3-
nitrobenzaldehyde as an off-white semisolid without need for
purification by column; 309.2 mg, 88% yield. IR (ATR): 3583,
1
2857, 1529, 1350 cm−1. H NMR (300 MHz, CDCl3): δ 1.04 (d, J =
8.3 Hz, 1H), 1.08 (d, J = 8.3 Hz, 1H), 2.11 (d, J = 1.4 Hz, 3H), 5.79 (s,
1H), 7.55 (t, J = 7.9 Hz, 1H), 7.81−7.72 (m, 1H), 8.14−8.18 (m, 1H),
8.29−8.31 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 9.1, 11.4, 69.1,
109.9, 111.5, 121.4, 122.8, 129.5, 132.5, 143.4, 189.9. HRMS (+EI-
Orbitrap): m/z for C11H11NO3Na calcd 228.0636, found 228.0631.
(2-Fluorophenyl)(2,3,3-trimethylcycloprop-1-en-1-yl)methanol
(8c). From 2-fluorobenzaldehyde as a clear oil using 20% ethyl acetate/
hexanes for purification; 610.5 mg, 20% yield. IR (ATR): 3447, 2957,
1610, 1487, 1454, 1032, 1032, 754 cm−1. 1H NMR (300 MHz,
CDCl3): δ 1.03 (s, 3H), 2.10 (3, 3H), 1.63 (bs, 1H), 1.97 (s, 3H), 5.93
(s, 1H), 7.03 (app t, J = 8.7 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.26−
7.28 (m, 1H), 7.47 (t, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): δ 8.6,
22.2, 25.3, 25.6, 65.1 (d, J = 4.6 Hz), 115.3 (d, J = 21.8 Hz), 124.6 (d, J
= 13.8 Hz), 124.9 (d, J = 3.5 Hz), 128.5 (d, J = 4.6 Hz), 129.9 (d, J =
8.1 Hz), 159.9 (d, J = 245.1 Hz). HRMS (ASAP-TOF): m/z for
C13H15FO + H − H2O calcd 189.1080, found 189.1071.
1
The following abbreviations were used to describe H spectra peak
splitting patterns: s = singlet, d = doublet, dd = doublet of doublets,
ddd = doublet of doublet of doublets, dddd = doublet of doublet of
doublet of doublets, t = triplet, dt = doublet of triplets, q = quartets, dq
= doublet of quartets, bs = broad singlet, m = multiplet and ad =
apparent doublet. IR spectra were recorded as films on NaCl plates
(liquids) or in a NaCl solution cells (solids).
General Procedure of the Synthesis of Cyclopropenylcarbi-
nols. In an oven-dried two-neck flask were added 1,2,2-tribromo-1-
methylpropane (1.0 equiv) and anhydrous Et2O (20 mL) before
cooling to −78 °C and addition of n-BuLi (1.45 M, 1.9 equiv). The
resultant solution was warmed to −10 °C for 30 min before cooling to
−50 °C and addition of the selected aldehyde. The solution was taken
to room temperature after 10 min and allowed to stir for 2 h before
quenching with H2O (20 mL). The mixture was then extracted with
Et2O (3 × 20 mL), dried on Na2SO4, and filtered before the solvent
was removed under reduced pressure. The crude oil was the purified
by means of flash chromatography on silica gel treated with Et3N
(typically ethyl acetate/hexanes).
General Procedure for the Synthesis of Nitrogen-Substi-
tuted Alkylidenecyclopropanes. To a stirred solution of cyclo-
propenylcarbinol (1 equiv) in CH2Cl2 (∼0.1 M) was added DBU
(0.15 equiv) followed by trichloroacetonitrile (1.5 equiv) at −78 °C.
The resulting solution was allowed to warm to −10 °C over a period
of 2 h before the reaction mixture was evaporated to dryness under
reduced pressure. The resulting oil was in most cases identified as the
intermediate imidate by NMR of the crude reaction mixture and was
(2-Methylcycloprop-1-enyl)[1-(p-toluenesulfonyl)pyrrol-2-yl]-
methanol (1b). From N-toluenesulfonylpyrrole-2-carboxaldehyde as a
yellow oil using 100% CH2Cl2 for purification; 179.5 mg, 29% yield. IR
1
used directly in the rearrangement step. Where the H NMR of the
1
(ATR): 3534, 2948, 2869, 1596, 1362, 1173 cm−1. H NMR (300
crude imidate was clean a listing of the signals is provided below. A
solution of crude imidate (1 equiv) and K2CO3 (1.5 equiv) in CH2Cl2
(1 mL) was allowed to stir at 30 °C for 40 h. After this time, the
solution was filtered before removal of solvent by evaporation under
reduced pressure. The crude semisolid was purified by means of flash
MHz, CDCl3): δ 0.99 (d, J = 8.4 Hz, 1H), 1.05 (d, J = 8.4 Hz, 1H),
2.09 (d, J = 1.5 Hz, 3H), 2.40 (s, 3H), 2.94 (d, J = 6 Hz, 1H), 5.99 (s,
1H), 6.22−6.25 (m, 2H), 7.26−7.30 (m, 3H), 7.73 (d, J = 8.4 Hz,
2H). 13C NMR (75 MHz, CDCl3): δ 9.9, 11.5, 21.7, 62.8, 109.1, 110.8,
D
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Note
chromatography on a neutral alumina column (ethyl acetate/hexanes)
to yield the alkylidenecyclopropane.
yield over two steps. 3f. IR (cm−1): 3443, 2957, 1600, 1511, 1249,
1170, 1030. 1H NMR (300 MHz, CDCl3): δ 1.60 (s, 3H), 1.79 (dd, J
= 10.9, 2.6 Hz, 1H), 1.86 (dd, J = 10.9, 2.6 Hz, 1H), 3.82 (s, 3H),
6.81−6.86 (m, 1H), 7.06 (s, 1H), 7.09 (t, J = 2.4 Hz, 1H), 7.12 (ap,
1H), 7.15−7.16 (m, 1H), 7.27 (t, J = 7.8 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 20.0, 20.9, 29.9, 55.3, 92.6, 112.6, 113.5, 119.9, 121.1,
128.3, 129.7, 138.1, 159.8, 162.3. MS: m/z 356 (M+Na, 100), 213
(17). HRMS (+EI-Orbitrap): m/z for C14H14Cl3NO2 + Na calcd
355.9987, found 355.9982.
1-[(E)-2-(4-Bromophenyl)methylidene-1-methylcyclopropylami-
no]-2,2,2-trichloro-1-ethanone (3a). From 1a as an off-white
semisolid after purification with 20% ethyl acetate/hexanes; 51 mg,
1
63% yield over two steps. Imidate. H NMR (300 MHz, CDCl3): δ
1.06 (d, J = 8.3 Hz, 1H), 1.14 (d, J = 8.3 Hz, 1H), 2.09 (d, J = 1.5 Hz,
3H), 6.76 (s, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H),
1
8.43 (s, 1H). 3a. IR (ATR): 3289, 2922, 2850, 1694, 1506 cm−1. H
NMR (300 MHz, CDCl3): δ 1.60 (s, 3H), 1.76 (dd, J = 10.9, 2.6 Hz,
1H), 1.83 (dd, J = 10.9, 2.6 Hz, 1H), 7.07 (s, 1H), 7.13 (t, J = 2.6 Hz,
1H), 7.39 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H). 13C NMR (75
MHz, CDCl3): δ 19.9, 20.9, 29.9, 120.3, 121.8, 128.7, 128.8, 131.8,
135.6, 162.3. HRMS (+EI-Orbitrap): m/z for C13H11BrCl3NONa
calcd 403.8987, found 403.8982.
1-[(E)-2-(2-Chlorophenyl)methylidene-1-methylcyclopropylami-
no]-2,2,2-trichloro-1-ethanone (3g). From 1g as an off-white
semisolid after purification with 20% ethyl acetate/hexanes; 88.8 mg,
1
48% yield over two steps. Imidate. H NMR (300 MHz, CDCl3): δ
1.08 (d, J = 8.4 Hz, 1H), 1.26 (d, J = 8.4 Hz, 1H), 2.08 (d, J = 1.5 Hz,
3H), 7.15 (s, 1H), 7.25−7.32 (m, 2H), 7.38−7.41 (m, 1H), 7.53−7.56
(m, 2H), 8.46 (s, 1H). 3g. IR (ATR): 3317, 2968, 1695, 1495 cm−1.
1H NMR (300 MHz, CDCl3): δ 1.62 (s, 3H), 1.81 (dd, J = 11.1, 2.6
Hz, 1H), 1.88 (dd, J = 11.1, 2.6 Hz, 1H), 7.10 (bs, 1H), 7.18−7.25 (m,
2H), 7.38 (dd, J = 7.7, 1.6 Hz, 1H), 7.58 (t, J = 2.6 Hz, 1H), 7.79 (dd,
J = 7.6, 1.8 Hz, 1H). 13C NMR (75 MHz, CHCl3): δ 20.1, 20.9, 30.0,
117.1, 126.8, 127.2, 129.0, 129.9, 130.7, 133.6, 134.2, 162.2. HRMS
(+EI-Orbitrap): m/z for C13H11Cl4NO + Na calcd 359.9492, found
359.9487.
1-[(E)-2-[[1-(p-Tolylsulfonyl)-1H-pyrrol-2-yl]methylidene]-1-meth-
ylcyclopropylamino]-2,2,2-trichloro-1-ethanone (3b). From 1b as a
yellow oil after purification with 100% CH2Cl2; 275 mg, >99% yield
over two steps. IR (ATR): 3364, 2969, 2027, 1713, 1494, 1367, 1174
1
cm−1. H NMR (300 MHz, CDCl3): δ 1.55 (s, 3H), 1.55−1.59 (m,
1H), 1.62 (dd, J = 11.1, 2.7 Hz, 1H), 2.36 (s, 3H), 6.27 (t, J = 3.9 Hz,
1H), 6.52−6.52 (m, 1H), 6.99 (s, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.34
(dd, J = 4.8, 1.5 Hz, 1H), 7.64 (t, J = 2.7 Hz, 1H), 7.72 (d, J = 8.1 Hz,
2H). 13C NMR (75 MHz, CHCl3): δ 19.6, 21.0, 21.7, 31.4, 110.5,
112.5, 112.7, 123.1, 127.1, 128.5, 130.1, 131.9, 135.9, 145.1, 161.98.
HRMS (+EI-Orbitrap): m/z for C18H17Cl3N2O3S + H calcd 447.0103,
found 447.0098.
1-[(E)-2-[(4-Bromophenyl)methylidene]-1-methylcyclopropyl-
amino](1-pyrrolidinyl)formaldehyde (5a). To a solution of 3a (62
mg, 0.16 mmol) in anhydrous DMF (2 mL) under nitrogen was added
Cs2CO3 (140 mg, 0.43 mmol) at −78 °C. The mixture was allowed to
stir for 1 h before the slow addition of pyrrolidine (140 μL, 120 mg,
1.69 mmol), which was subsequently allowed to warm to room
temperature over 18 h. After this time, the mixture was diluted with
50% ethyl acetate in hexanes and washed with water. The crude
mixture was dried on Na2SO4 and filtered, and the solvent was
removed under reduced pressure. The crude oil was purified by means
of flash chromatography with 100% ethyl acetate to afford 5a as a
yellow oil in a 39% yield (21.0 mg, 0.06 mmol). IR (ATR): 3252,
1-[(E)-2-Phenylmethylidene-1-methylcyclopropylamino]-2,2,2-tri-
chloro-1-ethanone (3c). From 1c as an off-white semisolid after
purification with 20% ethyl acetate/hexanes; 80.1 mg, 83% yield over
1
two steps. Imidate. H NMR (300 MHz, CDCl3): δ 1.07 (d, J = 8.4
Hz, 1H), 1.15 (d, J = 8.4 Hz, 1H), 2.09 (d, J = 1.4 Hz, 3H), 6.82 (s,
1H), 7.32−7.40 (m, 3H), 7.45−7.48 (m, 2H), 8.42 (s, 1H). 1c. IR
1
(ATR): 3415, 3054, 2986, 1719, 1492, 1421, 1265, 895 cm−1. H
NMR (300 MHz, CDCl3): δ 1.61 (s, 3H), 1.80 (dd, J = 10.8, 2.6 Hz,
1H), 1.86 (dd, J = 10.8, 2.6 Hz, 1H), 7.06 (bs, 1H), 7.19 (t, J = 2.6 Hz,
1H), 7.27−7.38 (m, 3H), 7.45−7.56 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 20.0, 21.0, 29.9, 121.2, 127.2, 127.9, 128.0, 128.7, 136.6,
162.3. HRMS (MMI-TOF) m/z: (M + H)+ calcd for C13H13NOCl3
304.0063, found 304.0057.
1
2970, 1689, 1489, 1383, 1161 cm−1. H NMR (400 MHz, CDCl3): δ
1.56 (s, 3H), 1.74−1.77 (m, 4H), 2.02 (s, 3H), 2.41−2.47 (m, 2H),
2.68−2.72 (m, 2H), 6.65 (bs, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.53 (d, J
= 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 11.8, 23.9, 24.5, 46.2,
77.9, 122.1, 129.7, 130.3, 131.0, 131.5, 158.5, 171.7. HRMS (+EI-
Orbitrap): m/z for C16H19BrN2O + H calcd 335.0759, found
335.0754.
1-[(E)-2-(4-Methoxyphenyl)methylidene-1-methylcyclopropyla-
mino]-2,2,2-trichloro-1-ethanone (3d). From 1d as an off-white
semisolid after purification with 30% ethyl acetate/hexanes; 145.6 mg,
1-[(E)-2-[(3-Methoxyphenyl)methylidene]-1-methylcyclopropyl-
amino](1-pyrrolidinyl)formaldehyde (5f). To a solution of 3f (88.1
mg, 0.26 mmol) in anhydrous DMF (2 mL) under nitrogen was added
Cs2CO3 (214.5 mg, 0.75 mmol) at −78 °C. The mixture was allowed
to stir for 1 h before the slow addition of pyrrolidine (130 μL, 112 mg,
1.57 mmol), which was subsequently allowed to warm to room
temperature over 18 h. After this time, the mixture was diluted with
50% ethyl acetate in hexanes and washed with water. The crude
mixture was dried on Na2SO4 and filtered, and the solvent was
removed under reduced pressure. The crude oil was purified by means
of flash chromatography with 30% ethyl acetate/hexanes to afford 5f as
a yellow oil in a 24% yield (18.3 mg, 0.06 mmol). IR (ATR): 3222,
1
77% yield over two steps. Imidate. H NMR (300 MHz, CDCl3): δ
1.09 (dd, J = 23.7, 8.4 Hz, 2H), 2.09 (d, J = 1.5 Hz, 3H), 3.79 (s, 3H),
6.75 (s, 1H), 6.85−6.92 (m, 2H), 7.38 (d, J = 8.7, 2H), 8.38 (s, 1H).
3d. IR (ATR): 3423, 3054, 2986, 1717, 1512, 1421, 1265, 705 cm−1.
1H NMR (300 MHz, CDCl3): δ 1.60 (s, 3H), 1.75 (dd, J = 8.6, 2.4 Hz,
1H), 1.81 (dd, J = 10.7, 2.8 Hz, 1H), 3.81 (s, 3H), 6.89 (d, J = 8.8 Hz,
2H), 7.12 (t, J = 2.6 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H). 13C NMR (75
MHz, CHCl3): δ 19.8, 21.0, 29.9, 55.3, 114.1, 120.5, 125.5, 128.4,
129.4, 159.4, 162.3. HRMS (MMI-TOF) m/z: (M + H+) calcd for
C14H15NO2Cl3 334.0170, found 334.0157.
1-[(E)-2-(4-Methylphenyl)methylidene-1-methylcyclopropylami-
no]-2,2,2-trichloro-1-ethanone (3e). From 1e as an off-white
semisolid after purification with 30% ethyl acetate/hexanes; 281 mg,
1
2964, 2834, 1689, 1600, 1578 cm−1. H NMR (400 MHz, CDCl3): δ
1.57 (s, 3H), 1.75−1.78 (m, 4H), 2.03 (s, 3H), 2.42−2.47 (m, 2H),
2.69−2.74 (m, 2H), 3.82 (s, 3H), 6.54 (bs, 1H), 6.86−6.89 (m, 1H),
7.01−7.03 (m, 2H), 7.32 (t, J = 8.4 Hz, 1H). 13CNMR (100 MHz,
CDCl3): δ 11.8, 23.9, 24.5, 46.7, 55.3, 77.7, 113.7, 114.9, 121.8, 129.3,
130.7, 132.7, 158.2, 159.5, 172.1. HRMS (+EI-Orbitrap): m/z for
C17H22N2O2 + H calcd 287.1759, found 287.1754.
1
98% yield over two steps. Imidate. H NMR (300 MHz, CDCl3): δ
1.06 (d, J = 8.4 Hz, 1H), 1.14 (d, J = 8.4 Hz, 1H), 2.10 (d, J = 1.5 Hz,
3H), 2.36 (s, 3H), 6.78 (s, 1H), 7.19 (d, J = 7.9 Hz, 2H), 7.35 (d, J =
7.9 Hz, 2H), 8.39 (s, 1H). 3e. IR (cm−1): 3417, 3050, 3030, 2971,
1
2929, 2864, 1715, 1513, 1489, 1236, 821, 711. H NMR (300 MHz,
CDCl3): δ 1.60 (s, 3H), 1.77 (dd, J = 10.6, 2.6 Hz, 1H), 1.83 (dd, J =
10.7, 2.6 Hz, 1H), 2.35 (s, 3H), 7.01 (bs, 1H), 7.11−7.19 (m, 3H),
7.44 (d, J = 8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 20.1, 23.1,
21.5, 30.0, 121.1, 126.9, 127.2, 129.5, 134.0, 138.0, 162.4. HRMS
(MMI-TOF) m/z: (M + H)+ calcd for C14H15NOCl3 318.0221, found
318.0214.
1-[(E)-2-(3-Methoxyphenyl)methylidene-1-methylcyclopropyla-
mino]-2,2,2-trichloro-1-ethanone (3f). From 1f an off-white semi-
solid after purification with 30% ethyl acetate/hexanes; 38 mg, 47%
1-[(E)-2-[(m-Methoxyphenyl)methylidene]-1-methylcyclopropyla-
mino]-2-(1-pyrrolidinyl)-1,2-ethanedione (6). To a solution of 3f
(19.8 mg, 0.06 mmol) in DMF (1 mL, bench grade) under nitrogen
was added pyrrolidine (50 μL, 43 mg, 0.6 mmol) followed by Cs2CO3
(45.0 mg, 0.14 mmol) at −78 °C. The mixture was subsequently
allowed to warm to room temperature over 18 h. After this time, the
mixture was diluted with 50% ethyl acetate in hexanes (5 mL) and
washed with water (5 × 5 mL). The crude mixture was dried on
Na2SO4 and filtered and had the solvent removed under reduced
E
dx.doi.org/10.1021/jo501423u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
pressure. The crude oil was purified by means of flash chromatography
with 30% ethyl acetate/hexanes to afford 6f as a yellow oil in 58% yield
(10.8 mg, 0.03 mmol). IR (ATR): 3297, 2969, 1687, 1623, 1428 cm−1.
1H NMR (400 MHz, CDCl3): δ 1.56 (s, 3H), 1.76 (dq, J = 10.8, 2.8
Hz, 2H), 1.83 (p, J = 6.6 Hz, 2H), 1.95 (p, J = 6.6 Hz, 2H), 3.52 (t, J =
6.8 Hz, 2H), 4.00 (dt, J = 6.8, 3.6 Hz, 2H), 6.79−6.82 (m, 1H), 7.07−
7.12 (m, 3H), 7.25 (t, J = 8.0 Hz, 1H), 7.9 (bs, 1H). 13C NMR (100
MHz, CDCl3): δ 19.9, 21.5, 23.5, 26.9, 28.5, 48.0, 48.8, 55.3, 112.4,
113.3, 119.9, 120.4, 129.6, 129.7, 138.6, 159.3, 159.9, 161.4. HRMS
(+EI-Orbitrap): m/z for C18H22O3N2 + Na calcd 337.1528, found
337.1523.
134.7, 201.9. HRMS (ASAP-TOF): m/z for C13H15BrO + H calcd
267.0385, found 267.0378.
5-(2-Fluorophenyl)-2,3-dimethylpenta-3,4-dien-2-ol (10c). From
8c as a clear oil after purification with 20% ethyl acetate/hexanes; 38.6
1
mg, 30% yield. IR (ATR): 3313, 2977, 1953, 1492, 1235 cm−1. H
NMR (500 MHz, CDCl3): δ 1.43 (s, 6H), 1.89 (d, J = 2.5 Hz), 6.40 (s,
1H), 7.01 (t, J = 10 Hz, 1H), 7.07 (t, J = 7.0 Hz, 1H), 7.13−7.18 (m,
1H), 7.31 (dt, J = 7.5, 1.5 Hz). 13C NMR (125 MHz, CDCl3): δ 14.4,
28.9, 29.0, 71.5, 88.8, 111.5, 115.6 (d, J = 20.9 Hz), 122.7 (d, J = 11.5
Hz), 124.1, 128.0, 128.1, 159.8 (d, J = 246.0 Hz), 201.5. HRMS
(ASAP-TOF): m/z for C13H15FO + H − H2O calcd 189.1080, found
189.1051.
2-Chloro-1-[2-[(m-methoxyphenyl)methyl]-1-methylcyclopropy-
lamino]-1-ethanone (7). Under an atmosphere of H2, 3f (88.9 mg,
0.26 mmol) was stirred in ethanol (10 mL) for 2 days with Pd/C (8.0
mg) at room temperature. After this time, the mixture was passed
through a short plug of Celite before the solvent was removed under
reduced pressure to reveal a brown oil which was subsequently purified
be means of flash chromatography with 30% ethyl acetate/hexanes to
reveal 7 as a slightly yellow oil in a 41% yield (30.3 mg, 0.11 mmol). IR
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
(ATR): 3292, 3096, 2959, 1663, 1489, 1251 cm−1. H NMR (400
AUTHOR INFORMATION
Corresponding Author
*E-mail: chris_hyland@uow.edu.au.
■
MHz, CDCl3): δ 0.57 (t, J = 6.0 Hz, minor isomer), 0.68 (t, J = 6.0 Hz,
major isomer), 1.01 (dd, J = 9.0, 6.0 Hz, 1H, major isomer), 1.05 (dd, J
= 10.0, 6.0 Hz, 1H, minor isomer), 1.20−1.28 (m, 1H, major isomer),
1.28−1.34 (m, 1H, major isomer), 1.44 (s, 3H, major isomer), 1.49 (s,
3H, minor isomer), 2.51 (dd, J = 15.0, 8.0 Hz, 1H, minor isomer), 2.62
(dd, J = 15.0, 8.0 Hz, 1H, major isomer), 2.83 (dd, J = 15.0, 7.0 Hz,
1H, major isomer), 2.93 (dd, J = 15.0, 6.0 Hz, 1H, minor isomer), 3.83
(s, 3H, major isomer), 3.83 (s, 3H, minor isomer), 3.99 (s, 2H, minor
isomer), 4.03 (s, 2H, major isomer), 6.78−6.90 (m, 3H, minor and
major isomer), 7.25 (t, J = 8.0 Hz, 1H, major isomer), 7.25 (t, J = 8.0
Hz, 1H, major isomer). 13C NMR (100 MHz, CDCl3): δ 18.3, 20.4,
20.6, 23.6, 25.4, 26.2, 33.3, 33.5, 35.0, 35.3, 42.8, 42.9, 55.3, 55.3,
111.4, 111.5, 114.1, 114.3, 120.6, 120.8, 129.5, 129.7, 142.7, 142.9,
159.8, 159.9, 166.0, 166.8. HRMS (+EI-Orbitrap): m/z for
C14H18ClNO2 + Na calcd 290.0923, found 290.0918.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
University of Wollongong and University of Tasmania is
gratefully acknowledged. The acquisition of an NMR
spectrometer at California State University, Fullerton, was
funded by NSF CHE-0521665. This work was partially
supported by the NSF REU (CHE-0649087) program summer
research scholarship to B.L.
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mixture was evaporated to dryness under reduced pressure. The
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dryness, and purified by flash column chromatography (15% ethyl
acetate/hexanes) to yield the pure allenyl carbinol.
■
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