Carbonylation of tertiary carbon radicals: synthesis of lactams

Article abstract of DOI:10.1039/C9CC02112D

Herein, we disclose an interesting iron-catalyzed approach for the carbonylation of a tertiary carbon radical. The tertiary carbon radical generated from a 1,5-hydrogen atom transfer can be captured by CO gas smoothly. Various six-membered lactams were constructed chemo-selectively in high yields.

Full text of DOI:10.1039/C9CC02112D

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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first methanofullerene derivatives of Sc N@D5h-C80
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DOI: 10.1039/C9CC02112D
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Carbonylation of Tertiary Carbon Radical: Synthesis of Lactams
Zhiping Yin,a Zhuan Zhang,b Youcan Zhang,a Pierre H. Dixneuf,b and Xiao-Feng Wu*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Herein, we disclose an interesting iron-catalyzed approach for the functionalization via 1,5-HAT to the synthesis of pyrrolidine
carbonylation of tertiary carbon radical. The tertiary carbon derivatives.8 This nitrogen radical reaction now was named as
radical generated from a 1,5-hydrogen atom transfer can be Hofmann-Löffler-Freytag (HLF) reaction. While various
captured by CO gas smoothly. Various six-membered lactams improvements about this reaction were explored by different
were constructed chemo-selectivity in high yields.
groups over the last hundreds years, most of these methods
provide access to construct C-halogen, and C-heteroatom
bonds. For the less reported C-C bond formation, activated
alkenes were normally selected to capture the new generated
carbon radical.9 Using CO gas as radical acceptor gives another
route for the synthesis of carbonyl-containing compounds has
not been reported. Last but not least, important lactam
compounds can be directly produced.
Since the first example of free radical carbonylation was
discovered by Coffman and co-workers in 1951,1 the free
radical carbonylation reaction has received much attention
during the past decades.2 There is no doubt that the direct
carbon radical carbonylative transformation is an efficient
method for the synthesis of carbonyl-containing compounds.
Among all the types of carbon radicals, primary and secondary
carbon radicals are more frequently studied in carbonylation
reactions compared with tertiary carbon radical. In general,
there are two reasons might explain the challenge: 1) the
tertiary carbon radical is easy to be oxidized into the
corresponding olefins; 2) CO trapping is difficult due to the
obvious steric hindrance and the formed tertiary acyl radical
undergoes a rapid decarbonylation process (Scheme 1a). This
phenomena was described by Ryu and co-workers in 1998.3
They described a δ-C-H carbonylation reaction of saturated
alcohols through 1,5-hydrogen atom transfer to synthesis δ- Scheme 1. Tertiary carbon radical carbonylation.
lactones. However, the carbonylation of tertiary carbon radical
was failed. Except one successful case with special
Based on these backgrounds and our continuing interest in
adamantane carbon radical.4
carbonylation chemistry, we turn our attention on the tertiary
carbon radical related carbonylative transformation. Initially,
5-methylhexan-2-one O-benzoyl oxime10 1a was selected as
the model substrate for testing this tertiary carbon radical
carbonylative transformation. The reaction was performed by
using 1a, copper as the catalyst in 1,4-dioxane under pressure
of CO (40 bar) at 100 °C. Unfortunately, no desired
carbonylation product was detected and the start material was
also decomposed (Table 1, entries 1-2). With the changing of
the catalyst from copper to Fe(OTf)2, a mixture of two isomers
2a and 3a can be obtained in 45% yield (Table 1, entry 3). To
our delight, the start material 1a can be transferred into the
desired product in 85% yield (Table 1, entry 8) when Fe(acac)3
was applied as the catalyst. Many other iron catalysts were
also explored, but the results were inferior to Fe(acac)3 (Table
On the other hand, the selective activation of diverse
alkane C-H bonds is general challenging. Most of the successful
examples depend on the activation of symmetrical alkanes
such as methane, ethane, and cyclic alkanes.5,6 1,5-Hydrogen
atom transfer offers an effective and applicable approach for
the selective activation and functionalization at δ-C-H bond.7 In
1883, Hoffman reported the first example of C-H
a.Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße
29a, 18059 Rostock, Germany; E-mail: xiao-feng.wu@catalysis.de
b.Catalyse et Organométalliques, Institut Sciences Chimiques de Rennes, UMR
6226-CNRS-Université de Rennes, Av. Général Leclerc, 35042 Rennes, France
Electronic Supplementary Information (ESI) available: [General comments, general
procedure, optimization details, analytic data and NMR spectrums]. See
DOI: 10.1039/x0xx00000x
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1, entries 4-7). Then we continued to optimize this reaction
Journal Name
a
Reaction conditions: 1a (0.20 mmol), catalysts (10 mol%), solvents (3 mL),
View Article Online
b
DOI: 10.1039/C9CC02112D
with different solvents. The yield can be further improved to additives, CO (40 bar), 100 °C, 20 h. GC yields of the mixture 2a and 3a were
c
88% by using CH3CN as the solvent (Table 1, entry 9). Other determined by using hexadecane as the internal standard. Isolated yield is in
solvents, such as DCE, DMSO, DMF, THF, and toluene gave a parenthesis. d 20 bar CO. e Fe(acac)3 (5 mol%). DCE = 1,2-dichloroethane; DMSO
little lower yields or no conversion (Table 1, entries 10-14). As = dimethyl sulfoxide; DMF = N,N-dimethylmethanamide; THF = tetrahydrofuran;
it is difficult to purify the two isomers 2a and 3a, and part of Et3N
= triethylamine; DIPEA = N,N-Diisopropylethylamine; TMEDA =
iminyl product 2a will decompose during purification process Tetramethylethylenediamine.
in silica column. We try to explore other condition which can
transfer 2a into 3a absolutely. After screening various organic
bases, we found that adding 1.2 equivalent of pyridine into the
reaction mixture produced the single product 3a at 89% yield
(Table 1, entry 15, 81% isolated yield). Furthermore, the
reaction efficiency dropped slightly when decreasing the
loading of Fe(acac)3 and the pressure of CO (Table 1, entries
Figure 1. Molecular structure of 3a in the crystal. Displacement
ellipsoids correspond to 30% probability (CCDC 1886524).
19-20). The molecular structure of the observed products
could be unambiguously determined by X-ray diffraction
analysis of 3a as shown in figure 1.11 The final optimized
conditions were found to be: 10 mol% Fe(acac)3 and 1.2
equivalent of pyridine in CH3CN under 40 bar CO at 100 °C
which gave 3a in 81 % isolated yield.
With the optimized reaction conditions in hand, we next
examined the substrate scope of this reaction with a range of
oxime esters. As shown in Table 2, the reaction tolerated
different size of aliphatic rings on the ketone moiety. Both
cyclopropane and cyclobutane substituted substrates gave the
corresponding desired lactams in 70% and 68% yields
Table 1. Optimization of the reaction conditions.a
respectively (3b, 3c). It is interesting that cyclopentane
substrate gave the tetra-substitution lactam as the major
product in 54% yield, which is very hard to access by other
method (3d). The ester functional group also worked well in
the standard condition and gave the target product in 50%
yield (3e). In addition, we changed the tert-alkyl moiety and
found that the carbonylation of tertiary radical in cyclic and
acyclic systems proceed smoothly to deliver the corresponding
Catalysts
Cu(OTf)2
CuI
Solvents
1.4-dioxane
1.4-dioxane
1.4-dioxane
1.4-dioxane
1.4-dioxane
1.4-dioxane
1.4-dioxane
1.4-dioxane
CH3CN
Additives
Yieldb
0%
Entry
1
0%
2
Fe(OTf)2
Fe(OTf)3
FeSO4 H2O
Fe(acac)2
Fe(Pc)2
45%
31%
60%
71%
26%
85%
88%
0%
3
4
spiro-lactams and lactams in moderate yields (3f, 3g, 3h, 3i).
5
Subsequently, we examined the left moiety scope with
aromatic systems. In the beginning, some cyclohexanone
byproducts were detected when the reactions were performed
at standard conditions, which might derive from the direct
addition of iminyl radical to the aromatic ring systems.12 After
changing the reaction condition into lower concentration and
higher pressure of CO, the byproducts were almost inhibited.13
The phenyl group bearing electron-donating groups such as
methyl, tert-butyl, and methoxy group at para or meta position
6
7
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
8
9
Toluene
10
11
12
13
14
15
DCE
65%
83%
68%
60%
DMSO
gave the desired product in good yield (3j, 3k, 3l, 3m),
DMF
especially for the methoxy group at para position producing
the product in 90% yield (3n). The methoxy functional group at
ortho position only gave the product in 53% yield due to part
of decomposition of start material (3o). The substrates with
electron-withdrawing groups (bromide, fluoride) at ortho and
para position only gave moderate yields compared with
THF
CH3CN
Pyridine
(1.2 equiv)
89%
(81%)c
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Et3N
(1.2 equiv)
DIPEA
(1.2 equiv)
TMEDA
(1.2 equiv)
Pyridine
(1.2 equiv)
Pyridine
69%
76%
72%
81%d
84%e
16
17
18
19
20
electron-donating groups
(3p-3s). Moreover, 4-methyl-1-
(naphthalen-1-yl)pentan-1-one O-benzoyl oxime and 4-methyl-
1-(thiophen-3-yl)pentan-1-one O-benzoyl oxime also worked
well in the standard condition and gave the corresponding
product in 40% and 71% respectively (3t, 3u). Finally, we
further tested this carbonylative transformation with
secondary carbon radical. As we expected, 45% yield of the
(1.2 equiv)
2 | J. Name., 2012, 00, 1-3
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desired product can be produced from the corresponding
carbon radical (3v).
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DOI: 10.1039/C9CC02112D
13
14
74%b
Table 2. Scope of carbonylation of tertiary carbon radicals.a,b
3m
1m
90%b
3n
1
2
81%a
70%a
1n
1o
1a
1b
3a
15
16
53%b
3b
3o
3p
79%b,
3q
3
4
68%a
54%a
3c
1c
62%b
3d
1d
17
18
56%b
3r
50%a
51%a
1r
5
6
3e
1e
51%b
3s
3f
1f
1s
1t
40%b
53%b
56%a
19
20
7
8
3t
3g
1g
71%b
3u
1u
1v
1h
3h
21
45%a
3v
a
Reaction condition A: 1a (0.20 mmol), Fe(acac)3 (10 mol%, 7.0 mg),
pyridine (1.2 equiv., 19.3 mg), CH3CN (3 mL), CO (40 bar), 100 °C, 20
h. b Reaction condition B: 1a (0.20 mmol), Fe(acac)3 (10 mol%, 7.0 mg),
pyridine (1.2 equiv., 19.3 mg), CH3CN (6 mL), CO (50 bar), 100 °C, 20
h.
9
62%b
3i
1i
10
11
70%b
71%b
3j
1j
In our control experiments, the model reaction was totally
inhibited by adding 1.5 equivalents of TEMPO, and the
oxidation alkene product 3a' could be detected by GC-MS
(Scheme 2). Based on our results and literature,14 a potential
mechanism is proposed (Scheme 3). The catalytic cycle begins
with the formation of a reduced iron species Fe(n), which is
generated from the reduction of the Fe(acac)3 precatalyst in
the presence of CO. Then, the Fe(n) species induced a SET
3k
1k
1l
12
87%b
reduction of oxime esters to give the iminyl radical
Fe(n+1). The iminyl radical next undergoes a 1,5-hydrogen atom
transfer to produce the new tertiary carbon radical , which
A and
3l
B
will be captured by CO gas to form the intermediate
C.
Subsequently, the Fe(n) is regenerated by means of single
This journal is © The Royal Society of Chemistry 20xx
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2017, 10, 1341-1345; c) Y. H. Li, F. X. Zhu, Z. C. Wang, X. F.
electron oxidation of radical C to acyl carbocation intermediate
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. Finally,
D
undergoes a nucleophile ring close process to
which will be
through a
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provide the six-membered product
transformed into the final six-membered lactams
facile base-mediated double bond isomerization.
E
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In summary, an interesting protocol for the carbonylation
of tertiary carbon radical has been developed. Various oxime
esters were synthesized from easily accessible ketones, which
can be reduced by cheap iron catalyst to provide the
corresponding iminyl radical. The unstable tertiary carbon
radical was generated through a 1,5-hydrogen atom transfer.
We succeed to capture this tertiary carbon radical with CO to
construct different six-membered lactams in high yields and
excellent chemo-selectivity, which is very difficult to access via
other methods.
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11 CCDC 1886524 contains the supplementary crystallographic
data for this paper. These data are provided free of charge
by The Cambridge Crystallographic Data Centre.
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Conflicts of interest
There are no conflicts to declare.
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Graphic abstract:
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