Synthesis of α-Chlorolactams by Cyanoborohydride-Mediated Radical Cyclization of Trichloroacetamides

Article abstract of DOI:10.1002/chem.201800210

A cyanoborohydride-promoted radical cyclization methodology has been developed to access α-chlorolactams in a simple and efficient way using NaBH₃CN and trichloroacetamides easily available from allylic and homoallylic secondary amines. This methodology allowed the synthesis of a library of α-chlorolactams (mono- and bicyclic), which were tested for herbicidal activity, trans-3-chloro-4-methyl-1-(3-trifluoromethyl)phenyl-2-pyrrolidinone being the most active.

Full text of DOI:10.1002/chem.201800210

A Journal of
Accepted Article
Title: Synthesis of α-Chlorolactams by Cyanoborohydride-Mediated
Radical Cyclization of Trichloroacetamides
Authors: Guilhem Coussanes, Harald Jakobi, Stephen Lindell, and
Josep Bonjoch
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201800210
Link to VoR: http://dx.doi.org/10.1002/chem.201800210
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10.1002/chem.201800210
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Synthesis of α-Chlorolactams by Cyanoborohydride-Mediated
Radical Cyclization of Trichloroacetamides
Guilhem Coussanes,[a] Harald Jakobi,[b] Stephen Lindell*[b], and Josep Bonjoch*[a]
Abstract:
A
cyanoborohydride-promoted radical cyclization
radicals, which allow nitrogen-containing heterocycles to be
synthesized in intramolecular processes.11
methodology has been developed to access α-chlorolactams in a
simple and efficient way, using NaBH3CN and trichloroacetamides
easily available from allylic and homoallylic secondary amines. This
methodology allowed the synthesis of a library of α-chlorolactams
(mono and bicyclic), which were tested for herbicidal activity, trans-3-
chloro-4-methyl-1-(3-trifluoromethyl)phenyl-2-pyrrolidinone being the
most active.
(a) Ryu´s work from iodoalkanes
reduction
RI
cyclization
radical
initiation
BH3CN
BH2CN
R
Giese reaction
carbonylation
BH2CH2NH2I
Introduction
hydroxy-
methylation
Borohydrides are involved in two interesting applications in
synthetic radical chemistry: a) they enable methodologies to be
developed with a reduced amount of organotin reagent/hydride,
generated in situ by reduction of a catalytic trialkyltin halide; b)
they provide a tin-free procedure in which borohydrides play a
conceptually different role, acting as radical precursors of boryl
radicals and reducing carbon-centered radicals by hydrogen atom
transfer.
(b) This work: from trichloroacetamides to α-chlorolactams
O
O
NaBH3CN, AIBN
R1
R1
Cl
N
CCl3
R2
N
t-BuOH, reflux, 4 h
n
n
R2
As a source of hydride, borohydrides can be employed to
reduce the amount of tin reagents in radical processes involving
catalytic tin hydride reactions. Either sodium borohydride or
cyanoborohydride can be used as the stoichiometric reducing
agent of trialkyltin halides, allowing the tin hydride reagent to be
generated in situ.1 Furthermore, polymer-bound tin hydrides can
also be used in catalytic quantities with a stoichiometric amount of
a corresponding reducing reagent (e.g. a borohydride).2 On the
other hand, ten years ago Ryu envisioned the synthetic potential
of radical methodologies based on cyanoborohydride, harnessing
the latter’s ability to form boryl radicals and react as a hydrogen
donor.3-5 Since then, cyanoborohydride reagents6-8 have been
used as radical mediators and iodoalkanes as proradicals
(Scheme 1) in several studies.9
Scheme 1. Radical processes using sodium cyanoborohydride as a radical
promoter to abstract an halogen atom and as a reducing agent via a hydrogen
atom transfer in the last step of the radical chain process. (a) Ryu´s previous
work (reference 6); (b) The current study.
Results and Discussion
Initial Studies. Our initial interest was in performing radical ring-
closing reactions in a catalytic manner from trichloroacetamides
using a supported tin hydride reagent, generated in situ by a
reducing agent (e.g. NaBH4). The few examples of reductive
radical cyclization using grafted polymers with organotin reagents
feature bromides as proradical carbon-center species.12 In order
to apply this chemistry to the radical cyclization of
In this context, the expansion of borohydride–based protocols
to new, easy to handle functionalities would be highly desirable.
The current paper introduces the use of sodium
cyanoborohydride and AIBN as the initiator to promote radical
cyclizations from trichloroacetamides.10 The synthetic procedure
enables the preparation of valuable α-chlorolactams and also
constitutes a new tool to generate dichloromethylcarbamoyl
trichloroacetamides, we decided to use
a
stannylated
polynorbornene, which was reported13 and recently employed by
Albéniz for radical reductive bromoaryl reduction processes using
polymethylhydrosiloxane (PMHS) as a reductor.14
Trichloroacetamide 1 was chosen as a model substrate for
the initial studies and submitted to the reaction conditions
depicted in Table 1 using a supported tin reagent provided by the
Albéniz group. When the reagent was employed with NaBH4 and
AIBN, it led to the full decomposition of 1 in MeCN (entry 1) and
to the formation of the formylated amine 3 in t-BuOH (entry 2).
Avoiding the use of the tin-supported reagent (entry 3), NaBH4
promotes a clean reduction process (1 → 3) when using t-BuOH
as the solvent, via a hydride attack upon the trichloroacetamide
carbonyl group with a concomitant release of the trichloromethyl
anion as a leaving group. In fact this transformation constitutes a
new procedure to obtain formamides from secondary amines via
trichloroacetylation and treatment with sodium borohydride.15
Studies on the scope of this process are underway.
[a]
[b]
Dr. G. Coussanes, Prof. J. Bonjoch
Laboratori de Química Orgànica, Facultat de Farmàcia, IBUB,
Universitat de Barcelona, Av. Joan XXIII s/n, 08028-Barcelona,
Spain.
E-mail: josep.bonjoch@ub.edu
Dr. H Jakobi, Dr. S. Lindell
Bayer AG, Crop Science Division, Industriepark Höchst G836,
65926 Frankfurt am Main, Germany.
E-mail: stephen.lindell@bayer.com
Supporting information and the ORCID identification numbers for the
authors of this article are given via a link at the end of the document.
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10.1002/chem.201800210
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Table 2. Effects of the number of chlorine atoms.
O
O
O
Table 1. Initial studies to optimize reaction conditions.
X
Bn
Bn
NaBH3CN, AIBN
Bn
N
N
N
CH Cl
m
n
Bn
N
Bn
N
Bn
N
SnBu2Cl
t-BuOH, reflux, 4 h
H
H
P
O
O
O
Me
or without polymer
Borohydride
4
5
4a-0
(X = H or Cl)
CCl3
H
Cl
H
Compd
m
2
n
1
Conversion[a]
32%
5
4a-0
OAc
OR
OH
AIBN (0.2 equiv)
solvent, reflux
3
4a-1
X = H,H; traces
X = Cl,H; 70%
31%
1
2a, R = Ac
2b, R = H
4a-2
4a
1
0
2
3
90%
20%
---
Entry
Polymer [[a]
20%
Borohydride[b]
NaBH4
Solvent
T (h)
12
Compd[c]
--- [d]
X = Cl,Cl; 100%
(73%) [b]
100%
1
2
3
4
MeCN
3 n.d. [e,f]
3 (77%)
[a] Determined by NMR. [b] Isolated yield.
20%
NaBH4
t-BuOH
t-BuOH
t-BuOH
12
none
NaBH4
12
We then decided to explore the effect of the number of
chlorine atoms on the cyclization reaction. Monochloroacetamide
4a-1 was submitted to the previously described reaction
conditions and a low conversion was observed, giving only traces
of γ-lactam 5 together with small amounts of the reduced
compound 4a-0 (Table 2, entry 1). As expected, the cyanoborane
radical anion (BH2CN•−) failed to fully abstract the single chlorine
atom, while the dichloro- (4a-2) and trichloroacetamide 4a
underwent the most efficient conversions, the latter providing the
highest amount of the cyclized product 5, as an epimeric mixture,
showing that the additional chlorine atoms facilitates the
cyclization.17
2a (30%)
2b (32%)
20%
NaBH3CN
12
5
6
none
none
NaBH3CN
NaBH3CN
t-BuOH
t-BuOH
12
4
2a (85%)
2a (83%)
[a] P refers to the aliphatic scaffold VA-PNB (vinylic addition polynorbornene),
see reference 13 and cited therein. [b] A 4:1 molar ratio was used. [c] Isolated
yield. [d] Full decomposition. [e] n.d.: not determined. [f] Traces of 2 were
observed in the NMR of the crude reaction mixture.
Next examined was the effect of the counter cation in the
cyclization of trichloroacetamide 4a. NaBH3CN and Bu4NBH3CN
led to the expected γ-lactam 5 in similarly good yields (Scheme 2).
Sodium cyanoborohydride led preferentially to the formation of
the thermodynamically more stable product trans-5, while in the
case of tetrabutylammonium cyanoborohydride, the steric
hindrance generated by the counter cation Bu4N+ favored the
formation of cis-5. The influence of the counter cation on the
course of the reaction indicated that the reacting radical species
was the cyanoborane radical anion (BH2CN•−). As our research
was then focused on the synthesis of trans b-alkyl-a-
chlorolactams, the impact of the counter cation was not explored
any further.
Most important was the use of less reactive hydride source,
NaBH3CN instead of NaBH4, in refluxing t-BuOH. Thus, a full
conversion of trichloroacetamide 1 to monochloromorphans 2
was gratifyingly observed using NaBH3CN and the tin-supported
reagent (entry 4). Moreover, when the reaction from 1 was
performed without polymer (i.e. without a tin hydride source), it
unexpectedly gave a clean conversion to monochloromorphan 2a
(entry 5). Initially, the reaction was performed over a period of 12
h, but we were pleased to observe that reducing the reaction time
to 4 h did not affect the outcome (entry 6).
Interestingly, the process stopped at the level of α-
chlorolactam and further reduction did not take place, since the
cyanoborane radical anion (BH2CN•−) failed to abstract the final
chlorine atom. It is known that halogen substituents weaken the
bond dissociation energy,6 which allowed the homolytic cleavage
of tri- and dichloroamides in the transformation of 1 to 2, but not
an additional reduction. Moreover, a potential reduction of α-
chlorolactam 2, via hydride transfer seems to be precluded since
secondary alkyl halides are quite unreactive when sodium
cyanoborohydride is used.16
O
O
Bn
Borohydride, AIBN
Bn
Cl
Me
N
N
CCl3
t-BuOH, reflux, 4 h
5
4a
For NaBH3CN: 73% (d.r. cis/trans 33:67)
For Bu4NBH3CN: 75% (d.r. cis/trans 56:44)
Scheme 2. Effects of the counter cations.
Under the same conditions, but using NaBD3CN instead of
NaBH3CN, the dideuterated products 5a-D2 were obtained
(Scheme 3), with the incorporation of 89-90% deuterium
(determined by NMR), thus confirming that the origin of the
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hydrogen atoms was the borohydride species. No major changes
in diastereoselectivity were observed.
Synthesis of α-chlorolactams. In order to further explore
these results, we extended the methodology to the synthesis of a
series of α-chlorolactams in collaboration with the Bayer Crop
Science Division (Frankfurt am Main, Germany), due to their
importance as herbicides in the agrochemical sector.19 For
example, flurochloridone (Figure 1) is a commercial herbicide (a
racemic trans-cis mixture in a 3:1 ratio) that inhibits phytoene
89% deuteration
O
O
desaturase,
an
enzyme
involved
in
carotenoid
D
NaBD3CN, AIBN
t-BuOH, reflux, 4 h
( 66%)
Bn
biosynthesis.20 Commercial chloroacetamide herbicides, as
exemplified by acetochlor (Figure 1), metazachlor, metolachlor
and thenylchlor, are structurally related to chlorolactams but work
by inhibiting the biosynthesis of very long chain fatty acids.20
These acyclic chloroacetamides all contain a 2,6-dialkylphenyl
moiety and it has been proposed that incorporating this structural
element into a chlorolactam might lead to new herbicidal lead
structures that block very long chain fatty acid biosynthesis
instead of phytoene desaturase. Chlorolactams are also useful
intermediates for the pharmaceutical and agrochemical
industries21 and can be found in natural products such as
chloromatrine.22 (Figure 1).
Bn
Cl
90% deuteration
N
N
CCl3
CH2D
5D-2
(cis:trans, 37:63)
4a
Scheme 3. NaBD3CN-mediated radical cyclization.
Based on the above results, as well as the photo-induced
radical cyclizations from aromatic halides with NaBH3CN18 and
Ryu’s research,6 the following radical mechanism is proposed
(Scheme 4): after the initiation phase (using AIBN), BH2CN•−
abstracts a chlorine atom from the trichloroacetamide (e.g. 4a) to
yield dichlorocarbamoylmethyl radical I, which undergoes
cyclization in a 5-exo fashion to give radical II. The primary C-
centered radical is then reduced by cyanoborohydride to afford
dichlorolactam III along with a borane radical anion, which can
sustain the radical chain by abstracting a chlorine atom from
trichloroacetamide 4a, returning the dichloromethyl radical I and
the chlorinated borane (NaBH2ClCN). Finally, a dehalogenation
occurs through radical IV to afford a monochlorinated lactam (e.g.
5).16b
F3C
Et
O
O
Cl
Cl
N
N
Me
OEt
Cl
Cl
Flurochloridone
Acetochlor
H
O
H
H
O
Cl
N
N
H
The efficiency of the cyclization ending with a primary alkyl
radical in these reaction conditions (II → III) is notable, since Ryu
showed by theoretical calculations that the hydrogen transfer
between alkyl radicals and NaBH3CN was slower than that
observed with radicals bearing an electron-withdrawing group,
which are formed in cyanoborohydride-mediated Giese-type
reactions.9a Additionally, it cannot be ruled out that the
mechanism of the chlorine atom transfer may be an electron
transfer process between BH2CN*- (expected to be a strong
reducing agent) and trichloroacetamide.18
N
H
Intermediate in
the synthesis of ACE inhibitors
chloromatrines
Figure 1. α-Chlorolactams/amides of biological interest.
Several methods for α-chlorolactam preparation have been
reported (Scheme 5): (i) lactamization of α-chloro-γ-amino
acids;23 (ii) radical cyclization using atom transfer radical
cyclizations,24 or promoted by Ni,25 Bu3SnH,20c,26 or TTMSS;27 (iii)
α-monochlorination of lactams using NCS28 or by enolate
quenching with tosyl chloride;29 (iv) mono reduction of
dichlorolactams;30 (v) chlorination followed by decarboxylation;20b
(vi) substitution of the diazo moiety using anhydrous HCl;31 and
(vii) hydroxyl substitution using thionyl chloride.32 However, most
of these methods are inconvenient because they require noxious
reagents, strong bases, or explosive diazocompounds and in
many cases are low yielding.
O
O
O
Cl
Bn
Bn
Bn
BH2CN
Cl
BH3CN
N
CCl3
N
CCl2
N
Atom Transfer
Reduction
Cyclization
4a
II
I
O
O
O
Cl
BH2CN
Bn
Bn
Bn
BH3CN
Cl
Cl
Cl
N
N
N
Me
5
IV
III
Scheme 4. Possible mechanism of the NaBH3CN-mediated radical cyclization.
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Most of the examined substrates afforded the corresponding
γ-lactam in moderate to high yield, allowing direct access to the
desired α-chloro-γ-lactams (Table 3). Compounds 5-16 (Table
3.A) were obtained as a mixture of diastereoisomers, with a
majority of trans-γ-lactams. In some cases, non-negligible
amounts of α,α-dichloro γ-lactams (e.g. 6-8) were obtained,
clearly due to an early quenching of the radical chain reaction. In
the case of substrate 4h, no reduction of the chlorine on the
phenyl ring was observed (Table 3, compounds 12).
Unexpectedly, trichloroacetamide 4r did not cyclize and instead
decomposed during the course of the reaction, even though 4r
has been previously reported33 to cyclize under ATRC conditions.
This failure could be due to a non-chemoselective process
caused by a competitive reduction of the styrene moiety.34
Electron-poor alkene 4s cyclized in good yield, without any
reduction of the ester moiety.
Cl
H2N
CO2H
O
O
OH
N
N
CCl2X
lactamization
SOCl2
n
radical
cyclization
O
Cl
N
O
O
HCl
R
n
N
N2
N
R = H, CH2Cl or Me
mono
chlorination
R
n
n
chlorination /
decarboxylation
mono-reduction
O
O
O
Cl
Cl
N
OH
N
The structural elucidation of epimeric lactams 5-16 was based
on their NMR data, considering the steric and electric field effects
in chlorine substituent chemical shifts.35 Taking into account the
coupling constants in the 1H NMR spectra, both cis- and trans-
compounds seem to have the same conformation, with the methyl
n
n
Scheme 5. Known methods for the synthesis of α-chlorolactams.
substituent at
a
pseudo-equatorial disposition. The most
noteworthy diagnostic in the 13C NMR spectra are signals of the
methyl groups upfielded in the cis series (δ ~13.3) with respect to
those of trans compounds (δ ~16.8), as well as the chemical shift
for C-4 (δ 33.4 vs δ 38.2 in cis and trans series, respectively). In
1H NMR data the signal due to the CHCl at C-3 is always more
deshielded in cis compounds compared with the trans epimer by
an average of + 0.35 ppm (e.g. δ 4.39 for cis-5 and δ 4.04 for
trans-5, see Table in SI).
In order to establish the substrate scope of the reaction and
synthesize small library of compounds, series of
trichloroacetamides (Figure 2) was submitted to the standard
conditions (Table 1, entry 6).
a
a
R1
R1
N-homoallyclic trichloroacetamides 4q and 4s cyclized in a 6-
exo fashion to afford α-chloro-δ-lactams 24 and 25 in moderate
yields (Table 3.D). In addition, the over-reduction products, 24b
and 25b, were obtained in non-negligible amounts.36 The
diastereoisomeric ratio in favor of the trans isomer in 25 was the
highest observed, as in the five-membered-ring lactam 23. Thus,
the ester group embedded in both compounds must have
interacted with the cyanoborohydride in the last chlorine atom
reduction that controls the diastereoselectivity of the process.
Under the standard conditions, N-cyclohex-2-enyl
tricloroacetamides 4v-x cyclized in a 5-exo fashion to afford α-
chloro-cis-octahydroindoles 26-28 in moderate to good yield, as
mixtures of diastereoisomers, with a majority of the endo-bicyclic
lactam epimers (Table 3.E).
N
O
O
a = Bn
b = Me
c = C6H13 i = 3-FPh
g = 2-FPh
h = 2-ClPh
R1
CCl3
N
CCl3
Me
d = Cy
e = Allyl
f = Ph
j = 3-CNPh
k = 3-CF3Ph
l = 2,6-diMePh
4
m = Bn
n = 2-ClBn
o = Cy
4
p = Ph
Bn
N
O
Bn
N
O
R1
CCl3
O
N
CCl3
R1
4
CCl3
v = Bn
w = Me
x = Ph
q = Me
r = Ph
s = CO2Et
t = H
R1
u = CO2Et
4
4
Figure 2. Trichloroacetamides used in the NaBH3CN/AIBN-promoted radical
cyclizations.
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Table 3. Substrate scope of NaBH3CN-mediated synthesis of α-chlorolactams
O
n
O
NaBH3CN, AIBN
R1
R1
Cl
R2
N
N
CCl3
t-BuOH, reflux, 4 h
R3
n
R3
R2
A. Scope of the N-substituent R1
O
O
O
X
O
O
O
X
X
X
Bn
Me
C6H13
Cy
Ph
Cl
Cl
Cl
Cl
Cl
Cl
N
N
N
N
N
N
Me
5 (73%)
Me
6 (59%)
Me
Me
8 (46%)
Me
9 (61%)
Me
10 (46%)
7 (46%)
d.r. 33:67 (cis:trans) d.r. 36:64 (cis:trans) d.r. 45:55 (cis:trans) d.r. 36:64 (cis:trans)
d.r. 45:55 (cis:trans)
d.r. 40:60 (cis:trans)
82% gram-scale
6a (5%)
7a (11%)
8a (44%)
10a (5%)
O
O
N
O
N
O
O
O
Cl
N
Cl
Me
Cl
Me
Cl
Cl
Me
Cl
Me
N
N
N
F
NC
F3C
F
Cl
Me
Me
11 (43%)
d.r. 40:60 (cis:trans)
11b (17%)
12 (49%)
13 (49%)
14 (32%)
d.r. 26:74 (cis:trans)
15 (29%)
d.r. 31:69 (cis:trans)
16 (47%)
d.r. 38:62 (cis:trans)
d.r. 42:58 (cis:trans) d.r. 41:59 (cis:trans)
12b (11%) 13b (9%)
14b (11%)
15b (8%)
B. Scope of alkenes substituted in R2
C. Scope of alkenes substituted in R3
O
O
O
O
O
O
O
Cl
Bn
Cl
Bn
Cy
Ph
Bn
Bn
N
Cl
Cl
Cl
Cl
Cl
Cl
Ph
N
N
N
N
N
N
Me
Me
Me
Me
Et
21 (58%)
Me
Me
Me
Me
CO2Et
17 (65%)
18 (66%)
19 (57%)
20 (69%)
22 (---)
23 (61%)
d.r. 29:71 (cis:trans)
d.r. 23:77 (cis:trans)
D. Scope of homoallyclic
E. Scope of cyclic alkenes
trichloroacetamides
O
H
O
O
H
Bn
H
Me
H
Ph
H
O
O
N
N
N
Bn
N
Cl
Bn
Cl
N
Cl
Cl
H
Cl
Me
CO2Et
24 (49%)
25 (31%)
26 (76%)
27 (61%)
28 (59%)
d.r. 45:55 (cis:trans)
d.r. 15:85 (cis:trans)
d.r. 24:76 (exo:endo) d.r. 18:82 (exo:endo) d.r. 24:76 (exo:endo)
24b (8%)
25b (30%)
[a] All yields refer to isolated yields following silica gel chromatography. Epimeric ratio determined by NMR. [b] In the compound numbering, a indicates a
dichloroderivative (X = Cl) and b indicates an over-reduced dechlorinated compound.
Finally, trichloroenamide 4y was submitted to the standard
conditions, affording 5-endo cyclization products in moderate
overall yield, with endo-26 as the major isomer (Scheme 6). The
formation of trans-octahydroindole trans-26 could be explained
by the in situ generation of an acyl iminium species, which was
reduced in a non-selective manner by the excess of NaBH3CN.
The formation of acyliminium ions from a-amino radicals has
been previously reported, either by atom transfer followed by
elimination or an electron transfer mechanism37 or by
oxidation.37b
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Bn
O
N
Acknowledgements
NaBH3CN
AIBN
CCl3
Financial support for this research was provided by the Projects
CTQ2016-41338-P from the Ministry of Economy, Industry, and
Competitiveness of Spain (MINEICO) and the FP7 Marie Curie
Actions of the European Commission via the ITN ECHONET
Network (MCITN-2012–316379). The authors acknowledge Prof.
Ana C. Albéniz (Valladolid) for a sample of used tin-supported
polymer. We thank colleagues in Bayer weed Control Biology for
testing the herbicidal activity of our compounds.
t-BuOH, reflux
4 h
4y
Bn
H
O
H
Bn
Bn
O
H
O
H
N
N
H
N
H
Cl
Cl
Cl
(54% overall,
14:76:20)
exo-26
endo-26
trans-26
Conflict of interest
Scheme 6. Cyclization of trichloroenamide 4y.
The authors declare no competing financial interest.
The α-chlorolactams 5-28 were all tested for herbicidal
activity at the Bayer Crop Science Division research site in
Frankfurt. The most active compound was the m-CF3-substituted
trans-15 derivative, which showed good broad-spectrum pre-
emergence activity at 1.3 kg/ha and reasonable activity at 320
g/ha in the glasshouse. The m-CF3-substituted phenyl ring and
herbicide symptomology (chlorosis, bleaching) observed for
trans-15 are typical of herbicidal inhibitors of phytoene
desaturase, which is very likely the mode of action of this
compound. Interestingly, m-CF3 cis-15 was herbicidally inactive
and unfortunately, the 2,6-dimethyl derivatives 16, which we had
hoped might inhibit very long chain fatty acid biosynthesis, were
also inactive. Although trans-15 is itself a novel compound, the
activity is not significantly better than flurochloridone (Figure 1)
and the structure falls under the general patent claim from ICI.19b
Consequently, it was decided not to follow up on this biological
activity.
Keywords: borohydride • herbicide • lactams • radical
cyclizations • synthetic methods
REFERENCES
[1] a) Using NaBH4, see: E. J. Corey, J. W. Suggs, J. Org. Chem. 1975, 40,
2554-2555; b) using NaBH3CN, see: G. Stork, P. M. Sher, J. Am.
Chem. Soc. 1986, 108, 303-304; c) see also, R. P. Attrill, M. A. Blower,
K. R. Mulholland, J. K. Roberts, J. E. Richardson, M. J. Teasdale, A.
Wanders, Org. Process. Res. Dev. 2000, 4, 98-101.
[2]
For representative examples of radical cyclizations, using tin-supported
reagents, see: a) Y. Ueno, K. Chino, M. Watanabe, O. Moriya, M.
Okawara, J. Am. Chem. Soc. 1982, 104, 5564-5566; b) D. Lapôtre, D.
Deleuze, B. Maillard, K. Mulholland, Synth. Commun. 2001, 31, 3207-
3218.
[3]
[4]
I. Ryu, S. Uehara, H. Hirao, T. Fukuyama, Org. Lett. 2008, 10,
1005−1008.
Conclusions
For a seminal work using NaBH3CN, AIBN to promote the radical
cyclization of 10-iododecylacrylate, see: M. Abe, T. Hayashikoshi, T.
Kurata, Chem. Lett. 1994,1789-1792.
[5]
For photoinduced cyclization of ω-iodoalkenes with electron-
withdrawing groups using cyanoborohydride, see: a) T. Kurata, R.
Kinoshita, J. Oleo Sci. 2001, 50, 759-762; b) Q. Liu, B. Han, W. Zhang,
L. Yang, Z.-L. Lin, W. Yu, Synlett 2005, 2248-2250; c) See also ref 4
For a review of the radical reactions of borohydrides, see: T. Kawamoto,
I. Ryu, Org. Biomol. Chem. 2014, 12, 9733-9742.
In conclusion, we have shown that α-chlorolactams can be
easily prepared in good to high yields, employing cheap
reagents, starting from easily accessible trichloroacetamides
and using a simple procedure, which is easily performed on
gram-scale. The generation of carbamoyldichloromethyl radicals
from trichloroacetamides using NaBH3CN/AIBN is described for
the first time. Under these reaction conditions the
carbocyclization upon alkenes (electronically rich, neutral or
poor) provides an efficient synthetic entry to several classes of
[6]
[7]
N-heterocyclic carbene (NHC)−boryl radicals, generated by hydrogen
atom abstraction of NHC−BH3 complexes, have also shown versatile
reactivities to enable a range of radical reactions: a) S.-H. Ueng, M.
Makhlouf Brahmi, É. Derat, L. Fensterbank, E. Lacôte, M. Malacria, D.
P. Curran, J. Am. Chem. Soc. 2008, 130, 10082-10083; (b) X. Pan, E.
Lacôte, J. Lalevée, D. P. Curran, J. Am. Chem. Soc. 2012, 134, 5669-
5674. (c) S.-C. Ren, F.-L. Zhang, J. Qi, Y.-S. Huang, A.-Q. Xu, H.-Y.
Yan, Y.-F. Wang, J. Am. Chem. Soc. 2017, 139, 6050-6053 and
references therein.
α-chlorolactams
(pyrrolidinones,
piperidones,
octahydroindolones, and morphans). The standard conditions
favored the diastereoselectivity toward the formation of
thermodynamic trans β-substituted α-chlorolactam products.
[8]
[9]
For the use of NaBH4 and transition metals (Ga, In, Zr, Ti, and Fe) in
radical processes, see: S. H. Kyne, M. Clémancey, G. Blondin, E. Derat,
L. Fensterbank, A. Jutand, G. Lefèvre, C. Ollivier, Organometallics
2018, DOI: 10.1021/acs.organomet.7b00603.
Experimental Section
a) T. Kawamoto, S. Uehara, H. Hirao, T. Fukuyama, H. Matsubara, I.
Ryu, J. Org. Chem. 2014, 79, 3999-4007; b) J. Guiard, Y. Rahali, J.-P.
Praly, Eur. J. Org. Chem. 2014, 4461-4466. This paper includes an
All experimental details can be found in the Supporting Information. The
material includes compound characterization data and copies of spectra
of all compounds.
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isolated example of using NaBH3CN/AIBN to promote
a
radical
(23) M. Sato, M. Takemura, S. Atarashi, K. Higashi, T. Nagahara, M.
cyclization from N-tosyl-N-allyl-2-bromo-2-methylpropanamide leading
to a lactam (yield not reported); c) J. Li, C. Zhao, J. Liu, Y. Du,
Tetrahedron 2015, 71, 3885-3889.
Furukawa, J. Antibiot. 1987, 40, 1292-1302.
[24]
For a review about ATRC, see: A. J. Clark, Eur. J. Org. Chem. 2016,
2231-2244 and references therein.
[10] For a review of radical cyclization of trichloroacetamides, see: G.
Coussanes, X. Vila, F. Diaba, J. Bonjoch, Synthesis 2017, 49, 1481-
149.
[25] J. Boivin, M. Yousfi, S. Z. Zard, Tetrahedron Lett. 1994, 35, 5629-5632.
[26] H. Ishibashi, K. Kodama, M. Higuchi, O. Muraoka, G. Tanabe, Y.
Takeda, Tetrahedron 2001, 57, 7629-7637.
[11] For recent results in this field, see: a) G. Coussanes, J. Bonjoch, Org.
Lett. 2017, 19, 878-881; b) A. D. G. Yamagata, D. J. Dixon, Org. Lett.
2017, 19, 1894-1897.
[27] J. Quirante, C. Escolano, F. Diaba, M. Torra, J. Bonjoch, Magn. Reson.
Chem. 2000, 38, 891-893 and references therein.
[28] B. Sreedhar, P. Surendra Reddy, M. Madhavi, Synth. Commun. 2007,
37, 4149-4156.
[12]
For a review about the use of polymeric supported tin reagents, see: E.
Le Grognec, J.-M. Chrétien, F. Zammattio, J.-P. Quintard, Chem. Rev.
2015, 115, 10207-10260.
[29]
M. J. Beard, J. H. Bailey, D. T. Cherry, M. G. Moloney, S. B. Shim, K.
A. Statham, Tetrahedron 1996, 52, 3719-3740.
[13]
a) N. Carrera, E. Gutierrez, R. Benavente, M. M. Villavieja, A. C.
Albéniz, P. Espinet, Chem. Eur. J. 2008,14, 10141-10148; b) I. Meana,
A. C. Albéniz, P. Espinet, Adv. Synth. Catal. 2010, 352, 2887-2891; c)
S. Martínez-Arranz, N. Carrera, A. C. Albéniz, P. Espinet, A. Vidal-
Moya, Adv. Synth. Catal. 2012, 354, 3551-3560.
[30] Ni Raney: a) R. Henning, H. Urbach, Tetrahedron Lett. 1983, 24, 5339-
5342; Sodium hypophosphite: b) S. K. Boyer, J. Bach, J. McKenna, E.
Jagdmann Jr. J. Org. Chem. 1985, 50, 3408-3411; Zn: c) P. Martin, E.
Eginhard Steiner, J. Streith, T. Winkler, D. Bellus, Tetrahedron 1985, 41,
4057-4078; Electroreduction: d) T. Shono, N. Kise, Chem. Lett. 1987,
697-700.
[14]
[15]
R. García-Loma, A. C. Albéniz, Eur. J. Org. Chem. 2017, 4247-4254.
For
a
related N-formylation process of amines using the more
[31] H. S. Hutchinson, S. A. Matlin, A. Mete, Tetrahedron 2002, 58, 3137-
3143.
expensive carbonyldiimidazole followed by reduction with NaBH4, see:
Z. Chen, Y. Cao, Z. Tian, X. Zhou, W. Xu, J. Yang, H. Teng,
Tetrahedron Lett. 2017, 58, 2166-2170.
[32] F. M. Cordero, F. Pisaneschi, K. Meschini Batista, S. Valenza, F.
Machetti, A. Brandi, J. Org. Chem. 2005, 70, 856-867.
[33] a) M. Pattarozzi, F. Roncaglia, L. Accorsi, A. F. Parsons, F. Ghelfi,
Tetrahedron 2010, 66, 1357-1364; b) R. Casaroli, F. Felluga, V. Frenna,
F. Ghelfi, U. M. Pagnoni, A. F. Parsons, D. Spinelli, Tetrahedron 2011,
67, 408-416.
[16]
[17]
a) R. O. Hutchins, D. Kandasamy, C. A. Maryanoff, D. Masilamani, B.
E. Maryanoff, J. Org. Chem. 1977, 42, 82-91; b) For the stability of a
dichlorolactam
against
an
ionic
reduction
with
sodium
cyanoborohydride, see: C. V. Stevens, E. Van Meenen, Y. Eeckhout, B.
Vanderhoydonck, W. Hooghe, Chem. Commun. 2005, 4827-4829.
A. J. Clark, D. P. Curran, J. V. Geden, N. James, P. Wilson, J. Org.
Chem. 2011, 76, 4546-4551 and references therein.
[34]
a) Ono, A; Suzuki, N.; Kamimura, J. Synthesis 1987, 736-738; b) A. T.
Tran, V. A. M. Huynh, E. M. Friz, S. K. Whitney, D. B. Cordes,
Tetrahedron Lett. 2009, 50, 1817-1819.
[18] Q. Liu, B. Han, W. Zhang, L. Yang, Z.-L. Liu, W. Yu, Synlett 2005,
2248-2250.
[35] R. J. Abraham, M. A. Warne, L. Griffiths, J. Chem. Soc. Perkin Trans 2
1997, 881-886.
[19] For a selection of patented α-chlorolactams, see: a) E. G. Teach, US
4110105, August 29, 1978; b) F. X. Woolard, US 4956006, September
11, 1990; c) K. Oda, K. Moriyasu, K. Arai, M. Nishida, M. Oyamada, A.
Fujiwara, EP 0495981 A1, July 29, 1992.
[20] The Pesticide Manual, 16th Edition, C. MacBean Ed., British Crop
Protection Council, 2012 (ISBN 978 1 901396 86 7)
[36]
Perhaps an ionic reduction of the C-Cl bond in α-chlorolactams is
possible in a less sterically demanding six-membered ring as opposed
to the five-membered compounds reported.
[37] a) G. K. Friestad, Y. Wu, Org. Lett. 2009, 11, 819-822; b) F. Diaba, J. A.
Montiel, J. Bonjoch, Chem. Commun., 2016, 52, 14031-14034.
(21) a) J. W. H.; Watthey, J. L. Stanton, M. Desai, J. E. Babiarz, M. B. Finn, J.
Med. Chem. 1985, 28, 1511-1516; b) J. W. H. Whattey, US 4575503,
March 11, 1986.
(22) a) S. Okuda, M. Yoshimoto, K. Tsuda, N. Utzugi, Chem. Pharm. Bull.
1966, 14, 314-318; b) S. Iskandarov, D. D. Kamalitdinov, M. R.
Yagudaev, S. Y. Yunusov, Chem. Nat. Compd. 1971, 7, 165-170.
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Entry for the Table of Contents
FULL PAPER
Guilhem Coussanes, Harald Jakobi,
Stephen Lindell*, and Josep Bonjoch*
Page No. – Page No.
Synthesis of α-chlorolactams by
cyanoborohydride-mediated radical
cyclization of trichloroacetamides
The
generation
of
carbamoyldichloromethyl
radicals
from
trichloroacetamides using NaBH3CN/AIBN is described for the first time. Under
these reaction conditions the carbocyclization upon alkenes (electronically rich,
neutral or poor) provides an efficient synthetic entry to several classes of α-
chlorolactams (pyrrolidinones, piperidones, octahydroindolones, and morphans).
This article is protected by copyright. All rights reserved.