Iron(II) pincer-catalyzed synthesis of lactones and lactams through a versatile dehydrogenative domino sequence

Article abstract of DOI:10.1002/cctc.201402967

The synthesis of lactones and lactams by using iron(II) pincer-catalyzed dehydrogenative methodology was developed. Starting from 1,n-diols or 1,n-amino alcohols, this domino transformation takes place through initial dehydrogenation of the substrates, subsequent intramolecular cyclization, and final oxidation to afford the desired products in good yields. The ability to access heterocycles of different sizes makes this protocol especially versatile, in which two consecutive oxidation reactions are performed without requiring an external oxidant. In this paper, we report the application of the Fe-MACHO-BH complex [carbonylhydrido(tetrahydroborato)[bis(2-diisopropylphosphinoethyl)amino]iron(II)] in this atom-efficient and environmentally benign process, for which molecular hydrogen is formed as the only stoichiometric side product. Just a little pinch: The iron(II) pincer-catalyzed synthesis of lactones and lactams from easily available 1,n-diols and 1,n-amino alcohols is explored. The use of a nontoxic metal as well as the generation of molecular hydrogen as the only stoichiometric byproduct makes this method a highly atom-efficient and environmentally benign process.

Full text of DOI:10.1002/cctc.201402967

DOI: 10.1002/cctc.201402967
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Iron(II) Pincer-Catalyzed Synthesis of Lactones and
Lactams through a Versatile Dehydrogenative Domino
Sequence
Miguel PeÇa-Lꢀpez, Helfried Neumann, and Matthias Beller*[a]
The synthesis of lactones and lactams by using iron(II) pincer-
catalyzed dehydrogenative methodology was developed. Start-
ing from 1,n-diols or 1,n-amino alcohols, this domino transfor-
mation takes place through initial dehydrogenation of the sub-
strates, subsequent intramolecular cyclization, and final oxida-
tion to afford the desired products in good yields. The ability
to access heterocycles of different sizes makes this protocol es-
pecially versatile, in which two consecutive oxidation reactions
are performed without requiring an external oxidant. In this
paper, we report the application of the Fe-MACHO-BH complex
[carbonylhydrido(tetrahydroborato)[bis(2-diisopropylphosphi-
noethyl)amino]iron(II)] in this atom-efficient and environmen-
tally benign process, for which molecular hydrogen is formed
as the only stoichiometric side product.
Introduction
Nowadays, one of the most relevant scientific challenges is the
development of efficient, low-costing, and environmentally
friendly processes.[1] In fact, the discovery of more sustainable
methodologies has become even more important than high-
yielding synthetic protocols. Towards this end, the designed
routes should involve, in terms of green chemistry, a reduced
number of steps, the use of renewable resources, high atom
economy, and waste minimization.[2] In this context, catalytic
reactions performed with the use of nontoxic and easily acces-
sible metallic complexes usually offer versatile and efficient
strategies that can satisfy the prior requirements.
responding lactones and lactams, respectively.[7,8] In this case,
a dehydrogenative step followed by an intramolecular reaction
gives rise to the formation of the mentioned compounds in
a sustainable way.
These dehydrogenative coupling protocols are generally cat-
alyzed by transition-metal complexes such as ruthenium, iridi-
um, and palladium. However, the application of nonprecious
metals would still provide greater environmental benefits to
this methodology.[9] Specifically, the use of iron-based catalysts
in such synthetic strategies is of particular interest owing to
the low toxicity and bioavailability of iron. On this basis, vari-
ous iron complexes have already been shown to be active in
the dehydrogenation of different alcohols into the correspond-
ing carbonyl compounds,[10] reactivity which might be effec-
tively used in coupling processes.
Among the numerous chemical transformations developed
to date for the synthesis of valuable molecules from cheap
and abundant feedstock, metal-catalyzed dehydrogenative
coupling methodologies represent a powerful tool box consis-
tent with the principles described above.[3] The well-estab-
lished hydrogen autotransfer protocol allows the formation of
new CÀN and CÀC bonds from simple alcohols to be per-
formed by using amines or C nucleophiles as reagents.[4,5] For
such a reaction, H2O is formed as the only byproduct, which
makes it a benign and highly atom-economic process. In addi-
tion, the synthesis of heterocycles by sequential dehydrogena-
tive coupling processes has also been developed.[6] More spe-
cifically, several compound classes such as pyrroles, pyridines,
and indoles have been prepared, and only molecular hydrogen
and water were formed as waste products. On the other hand,
it is noteworthy that this methodology can also be applied to
the cyclization of diols and amino alcohols to provide the cor-
In function of these precedents and following the experi-
ence of our group with iron(II) complexes bearing aliphatic
noninnocent PNP pincer ligands,[11] we planned to study their
activity in dehydrogenative processes with a focus on the syn-
thesis of heterocycles. In particular, the Fe-MACHO-BH complex
[carbonylhydrido(tetrahydroborato)[bis(2-diisopropylphosphi-
noethyl)amino]iron(II)], see structure in Scheme 1) was success-
fully applied in the selective hydrogenation of esters and ni-
triles, as well as in hydrogen production from methanol. After
our initial work, other uses of this catalyst were published by
different groups,[12] whereas its activity for the acceptorless re-
versible dehydrogenation–hydrogenation of alcohols and ke-
tones was very recently analyzed.[13] On the basis of these fea-
tures, we initially considered to develop a general study on the
iron pincer-catalyzed lactonization of diols. In agreement with
the mechanism proposed for such transformations, the synthe-
sis of lactones would proceed by the following domino se-
quence (Scheme 1). First, the iron-catalyzed mono-dehydro-
genation of the diol would provide the corresponding hydroxy
aldehyde. Subsequent intramolecular nucleophilic addition
[a] Dr. M. PeÇa-Lꢀpez, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢁr Katalyse e.V. an der Universitꢂt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402967.
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played no conversion. Hence, after the screening of
the best conditions, we selected the reaction of 1,2-
benzenedimethanol (1a, 100 mol%) with Fe-MACHO-
BH (0.5 mol%) and K2CO3 (10 mol%) in tert-amyl alco-
hol at 1508C for 5 h as the optimal catalytic system.
It is important to note the high atom economy of
this process, as the diol was completely converted
into the product to afford only 2 equivalents of mo-
lecular hydrogen as the byproduct. In addition, no
external oxidants were required for this transforma-
tion, and the only used additive is cheap, safe, and
employed in catalytic amounts.
Scheme 1. Iron(II) pincer-catalyzed dehydrogenative lactonization of diols.
Table 1. Optimization of the reaction conditions for the synthesis of
phthalide (2a) from 1,2-benzenedimethanol (1a).[a]
would result in the formation of the intermediate lactol, which
after a new oxidation step would afford the desired lactone.
Two equivalents of molecular hydrogen would be formed as
the only byproduct to regenerate the catalytic species.
This fact together with the use of a nontoxic metal and no
need for external stoichiometric oxidants make this atom-effi-
cient strategy environmentally benign. Under these premises,
we present herein versatile application of the previously
shown iron complex to the dehydrogenative synthesis of lac-
tones and lactams from simple and available substrates such
as diols and amino alcohols.
Entry
Catalyst
Base
Solvent
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
FeBr3
Fe(acac)2
–
–
–
–
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
toluene
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
130
130
130
150
130
150
150
150
150
150
–
–
Fe-MACHO-BH
Fe-MACHO-BH
Fe-MACHO-BH
Fe-MACHO-BH
Fe-MACHO-BH
Fe-MACHO-BH
Fe-MACHO-BH
–
79
82
85
99
81
96
98
–
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Results and Discussion
8[c]
9[c,d]
10[c,d]
Our research started by selecting the best iron-based catalytic
system for the model transformation of 1,2-benzenedimetha-
nol (1a) into phthalide (2a). Initially, we observed that the re-
action of 1a (1 mmol) with 1 mol% of classical iron salts such
as FeBr3 and Fe(acac)2 (acac=acetylacetonate) in tert-amyl al-
cohol at 1308C for 18 h did not provide the expected lactone
(Table 1, entries 1 and 2). Nevertheless, the same experiment
performed in the presence of the Fe-MACHO-BH complex af-
forded 2a in a good 79% yield (Table 1, entry 3), whereas
higher temperatures only resulted in a slight change in the
yield (82%; Table 1, entry 4). After this first approach, we con-
sidered that the addition of a base in a catalytic amount could
favor the cyclization step, which would lead to an increase in
the efficiency of the process. Thus, the reaction of 1,2-benzene-
dimethanol with the iron(II) pincer complex in the presence of
K2CO3 (10 mol%) at 1308C provided the desired g-butyrolac-
tone in 85% yield; in this case, a quantitative result for the re-
action at 1508C was observed (Table 1, entries 5 and 6). The
solvent showed a high relevance in the transformation, as the
use of a less polar, aprotic medium such as toluene resulted in
a considerable decrease in the yield (81%; Table 1, entry 7). For
further optimization, we decided to analyze other parameters
such as the catalyst loading and time. The experiment per-
formed with 0.5 mol% Fe afforded a very good result (96%;
Table 1, entry 8), whereas a decrease in the reaction time to
5 h allowed phthalide (2a) to be obtained in an excellent 98%
yield (Table 1, entry 9). As expected, the same reaction per-
formed in a basic medium in the absence of a catalyst dis-
[a] Unless otherwise specified, all reactions were performed with the diol
(1 mmol), base (0.1 mmol), and the Fe catalyst (0.01 mmol) in solvent
(1 mL) at the indicated temperature for 18 h. [b] GC yields with hexade-
cane as an internal standard. [c] Catalyst loading: 0.005 mmol. [d] Reac-
tion time: 5 h.
With the aim of expanding the scope of this methodology,
the next step consisted in the study of the reactivity of differ-
ent 1,4-diols that would allow a variety of substituted g-butyro-
lactones to be prepared.[14] As shown in Table 2, we observed
that aryl substrates such as 1,2-benzenedimethanol (1a) and
2,3-naphtalenedimethanol (1b) were effectively converted into
the corresponding lactones following the previously developed
conditions (products 2a and 2b, 92 and 84% yield, respective-
ly; Table 2, entries 1 and 2). In the case of 4-methyl-1,2-benze-
nedimethanol (1c), the reaction proceeded quantitatively to
afford a 1:1 mixture of regioisomers with the methyl group in
the 5,6-positions (2c; Table 2, entry 3). This result suggests that
this substituent of the aromatic group does not influence the
preferential formation of one intermediate hydroxy aldehyde,
so the dehydrogenation of the two alcoholic groups takes
place at the same rate. Electron-deficient substrates such as
4,5-dichlorobenzene derivative 1d required an increase in the
catalyst loading and an increase in the reaction time to get
a good 72% yield (2d; Table 2, entry 4). The same experiment
under the initially established conditions afforded the desired
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(1g) took place to afford the product in 79% yield (Table 2,
entry 7). In the latter case, the use of 1 mol% Fe-MACHO-BH
was again necessary to achieve a good result, because applica-
tion of the standard loading led to the desired product in
a moderate 42% yield. Other aliphatic linear and cyclic diols
were also used for this transformation, and the corresponding
lactones were obtained in good yields (products 2h–j, 65–83%
yield; Table 2, entries 8–10). The chemoselectivity of this iron-
catalyzed methodology is notable, as the C=C bonds are not
reduced under these conditions, although molecular hydrogen
is generated as a side product (Table 2, entry 10). This fact con-
trasts with the well-known ability of ruthenium complexes to
promote the isomerization or even the reduction of multiple
bonds in such transformations.[15]
Table 2. Iron-catalyzed synthesis of substituted g-butyrolactones 2a–j.[a]
Entry
1
Diol
Product
Yield [%][b]
92
1a
1b
1c
2a
2
3
4
2b 84
At this point and after the general development of the de-
hydrogenative synthesis of five-membered lactones from the
corresponding 1,4-diols, we proposed to extend this methodol-
ogy to different sized structures. Using terminal diols of suit-
able length would allow the versatility of this protocol to be
increased. Lactones are present in nature as building blocks in
a large variety of relevant compounds, especially five- and six-
membered compounds as a result of their high stability.[16] In
addition, a- and b-lactones are also found in different mole-
cules,[17] but their synthesis and isolation is more complicated
because of their reactivity. On this basis, we initially considered
the synthesis of b-propiolactones from 1,3-diols. For this pur-
pose, we chose 2-hydroxybenzyl alcohol (3a) as the substrate,
but unfortunately, its treatment with the iron(II) pincer com-
plex (0.5 mol%) at 1508C in the presence of K2CO3 did not
lead to the desired product (Table 3, entry 1). After this first at-
tempt, we decided to deal with the synthesis of a more stable
structure such as six-membered valerolactone. In this case, the
reaction of 2-[2-(hydroxymethyl)phenyl]ethanol (3b) under the
previously optimized conditions afforded isochromanone 4b in
very good yield as a mixture of regioisomers (81% yield, 85:15;
Table 3, entry 2). The isochroman-1-one depicted in the table
was shown to be the major isomer, because dehydrogenation
of the benzyl position is favored as a result of the formation of
a conjugated and non-enolizable aldehyde instead of the cor-
responding aliphatic one. In a similar way, other aromatic de-
rivative such as 1,8-naphthalenedimethanol (3c) allowed tricy-
clic lactone 4c to be prepared in quantitative yield (98%;
Table 3, entry 3). Additionally, this protocol was also assayed
for the synthesis of simple d-valerolactone (4d) from 1,5-pen-
tanediol (3d). In this case, the application of the standard con-
ditions afforded low yields and a lack of selectivity. However,
for the case in which the reaction was catalyzed by Fe-
MACHO-BH (1 mol%) in an aprotic solvent such as toluene, the
desired compound was obtained in a moderate 55% yield, as
determined by NMR spectroscopy (Table 3, entry 4). To demon-
strate the versatility of the process, the synthesis of other ali-
phatic lactones was accomplished. Thus, the transformation of
alkyl-substituted 1,5-diols 3e and 3 f was performed efficiently
to give rise to six-membered lactones 4e and 4 f in yields of
61 and 82%, respectively (Table 3, entries 5 and 6). The next
step was to examine the possibility of preparing larger-ring lac-
tones,[18] which sometimes require the use of special methods
2c
98[c]
1d
2d 72[d]
5
6
7
1e
1 f
1g
2e
2 f
93
80[e]
2g 79[f]
8
1h
2h 65
9
1i
1j
2i
2j
83
81
10
[a] Unless otherwise specified, all reactions were performed with the diol
(1 mmol), K2CO3 (0.1 mmol), and Fe-MACHO-BH (0.005 mmol) in tert-amyl
alcohol (1 mL) at 1508C for 5 h. [b] Yield of isolated product. [c] Mixture
of regioisomers: 5-Me/6-Me (1:1). [d] Catalyst loading: 1 mol%; reaction
time: 24 h. [e] Yield was determined by NMR spectroscopy by using
durene as an internal standard. [f] Catalyst loading: 1 mol%.
product in only 28% yield, and a substantial amount of the un-
altered starting material was recovered. Following analysis of
the aromatic derivatives, the use of a substrate with primary
and secondary hydroxyl moieties allowed access to trisubstitut-
ed lactone 2e in excellent 93% yield (Table 2, entry 5). In this
case, oxidation of the primary alcohol to the corresponding
conjugated aldehyde and subsequent intramolecular attack of
the secondary one to form the intermediate lactol is favored.
On the other hand, lactonization of 1,4-butanediol (1 f) afford-
ed general g-butyrolactone (2 f) under the optimized condi-
tions (80% yield, as determined by NMR spectroscopy; Table 2,
entry 6), whereas the reaction with 1-phenylbutane-1,4-diol
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Table 3. Iron-catalyzed synthesis of different-sized lactones 4a–h.[a]
Table 4. Iron-catalyzed synthesis of different-sized lactams 6a–i.[a]
Entry
1
Diol
Product
Yield [%][b]
n.d.[c]
Entry
1
Amino alcohol
Product
Yield [%][b]
n.d.[c]
3a
3b
4a
4b
5a
5b
5c
6a
6b
6c
81[d]
2
3
n.d.[c]
2
3
86 (83)[d]
3c
4c
98
4
5d
6d
75 (64)[d]
4
5
3d
3e
4d
4e
55[e,f]
5
6
7
5e
5 f
5g
6e
6 f
6g
49 (91)[e,f]
61
92[g]
85 (77)[d,e]
6
3 f
4 f
82
8
9
5h
5i
6h
6i
82 (74)[d]
41 (95)[e,f]
7
8
3g
3h
4g
4h
72
63[e,f]
[a] Unless otherwise specified, all reactions were performed with the
amino alcohol (1 mmol), K2CO3 (0.1 mmol), and Fe-MACHO-BH
(0.01 mmol) in tert-amyl alcohol (1 mL) at 1508C for 5 h. [b] Yield was de-
termined by NMR spectroscopy by using durene as an internal standard.
[c] n.d.: not detected. [d] Yield of the isolated product is given in paren-
theses. [e] Catalyst loading: 2 mol%. [f] Yield based on recovered starting
material is given in parentheses. [g] Decomposition observed during iso-
lation by chromatography on silica gel.
[a] Unless otherwise specified, all reactions were performed with the diol
(1 mmol), K2CO3 (0.1 mmol), and Fe-MACHO-BH (0.005 mmol) in tert-amyl
alcohol (1 mL) at 1508C for 5 h. [b] Yield of isolated product. [c] n.d.: not
detected. [d] Yield of the mixture of isolated regioisomers: isochroman-1-
one/isochroman-3-one (85:15). [e] Yield was determined by NMR spec-
troscopy by using durene as an internal standard. [f] Reaction was per-
formed in toluene with Fe-MACHO-BH (1 mol%).
of other biologically relevant compounds. The similarity of
their structures led us to focus on analogous lactams
(Table 4).[19] These cyclic amides can be obtained by using nu-
merous synthetic methods starting from a wide variety of syn-
thons,[20] but there is still a necessity for the development of
versatile techniques that allow access to different-sized lactams
from simple substrates. Applying the methodology proposed
in this article, their synthesis was visualized from the corre-
sponding easily available amino alcohols. In this case, the sub-
strate would be first transformed into the amino aldehyde by
iron-catalyzed dehydrogenation, and this would be followed
by cyclization through reaction of the amine with the aldehyde
moiety to finally generate the lactam after a second oxidation
step.
for their synthesis. In this direction, we envisaged the conver-
sion of 1,6-diols into the corresponding e-caprolactones. Aro-
matic 1,1’-biphenyl-2,2’-dimethanol (3g) was transformed into
seven-membered compound 4g in 72% yield (Table 3, entry 7),
whereas 1,6-hexanediol (3h) needed again the addition of
a higher amount of catalyst and toluene as the solvent with
the aim of getting good conversion (4h, 63% yield, as deter-
mined by NMR spectroscopy; Table 3, entry 8). These results
show the versatility of this iron-based procedure, which pro-
vides access to a variety of lactones simply by selecting appro-
priately sized diols.
Once having performed the synthesis of lactones from
simple diols, we applied this domino sequence to the synthesis
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Within this group of compounds, the four-membered b-lac-
tams have special relevance, as they are present in many drugs
with antibiotic, anti-inflammatory, and antitumor properties.[21]
Owing to this biological significance, we initially proposed
their synthesis starting from the corresponding 1,3-amino alco-
hols. Unfortunately, the reaction of 3-amino-3-pheny-1-propa-
nol (5a) with the iron(II) pincer complex (0.5 mol%) in the
presence of a catalytic amount of K2CO3 at 1508C in tert-amyl
alcohol proved to be ineffective in the formation of desired
compound 6a (Table 4, entry 1). Only remaining starting mate-
rial was observed together with the formation of some decom-
position product, whereas the application of other substrates
and different reaction conditions did not alter this result. The
high ring strain makes these compounds very reactive and sus-
ceptible to hydrolysis,[22] whereby specific conditions are some-
times required to perform their synthesis. Later, we focused on
the synthesis of the corresponding g-butyrolactams, but in
contrast to the homologous synthesis of the five-membered
lactones, the reaction of aromatic substrate 5b under the stan-
dard conditions only showed the presence of the unreacted
amino alcohol (Table 4, entry 2). The study of higher catalyst
loadings and longer reaction times did not allow the attain-
ment of better outcomes. Interestingly, aniline 5c displayed
good reactivity in the first oxidation and cyclization steps, but
then the H2O elimination was faster than the second dehydro-
genation reaction, which gave rise to indole 6c in excellent
yield (Table 4, entry 3).
tained in an excellent yield (85%; Table 4, entry 7). Finally, we
proposed to analyze the feasibility of preparing seven-mem-
bered lactams. Among this group of cyclic amides, the rele-
vance of e-caprolactam should be highlighted as a very useful
intermediate in the industry for the synthesis of the polyamide
nylon 6.[24] Hence, the application of the developed methodol-
ogy to 1-amino-6-hexanol (5h) gave rise to desired product 6h
in a very good 82% yield (Table 4, entry 8). In contrast to the
six-membered analogue, the reaction with benzyl derivative 5i
only proceeded moderately, and protected caprolactam 6i was
provided in 41% yield by using the iron(II) pincer complex
(2 mol%; 95% yield based on recovered starting material;
Table 4, entry 9). Overall, we applied this domino sequence for
the first time to the synthesis of six- and seven-membered lac-
tams that generally require higher catalyst loadings than the
corresponding cyclic esters previously described.
Conclusion
In conclusion, we developed the synthesis of lactones and lac-
tams by using iron(II) pincer-catalyzed dehydrogenative meth-
odology. This versatile protocol allows a broad scope of
heterocyclic compounds to be prepared in good to excellent
yields by using simple and easily available substrates such as
1,n-diols and 1,n-amino alcohols. It is important to remark the
high atom economy of this reaction, as molecular hydrogen is
the only stoichiometric waste, and the fact that two sequential
dehydrogenation reactions can be performed in the absence
of external oxidants.
After these failed experiments, we turned our attention to
six-membered lactams, which are in principle more stable com-
pounds and for this reason potentially easier to synthesize.
Thus, the reaction of 1-amino-5-pentanol (5d) catalyzed by Fe-
MACHO-BH (0.5 mol%) gave basic d-valerolactam (6d) in
a moderate 47% yield, as determined by NMR spectroscopy.
As we observed in the reaction with simple and lineal diols
(Table 3, entries 4 and 8), a larger amount of catalyst (1 mol%)
improved the transformation and delivered a good 75% yield
Experimental Section
General methods
Unless otherwise stated, all reactions were conducted under an
argon atmosphere with exclusion of moisture from reagents and
glassware by using standard techniques for manipulation of air-
sensitive compounds. Reaction temperatures refer to external bath
temperatures. TLC was effected on silica gel 60 F254 (layer thickness
0.2 mm), and components were located by observation under UV
light and/or by treating the plates with a phosphomolybdic acid or
p-anisaldehyde reagent followed by heating. Column chromatogra-
phy was performed on silica gel (230–400 mesh) by using 30%
ethyl acetate/heptane as eluent. NMR spectra were recorded with
a Bruker Avance 400 spectrometer by using the residual solvent
signal as the internal standard [chloroform: d=7.26 ppm (1H),
77.0 ppm (13C)]. All measurements were performed at room tem-
perature unless otherwise stated, and DEPT was used to assign
carbon types. Mass spectra were in general recorded with a MAT
95XP or a HP 5973N mass selective detector. Gas chromatography
was performed with a HP 6890N chromatograph with a HP5
column. Infrared spectra were taken with a Bruker Alpha with at-
tenuated total reflectance (ATR). Unless otherwise stated, commer-
cial reagents were used as received without purification.
(Table 4, entry 4). Following, we tested
a substrate with
a heteroatom in its structure such as 2-(2-aminoethoxy)ethanol
(5e). Curiously, the reactivity changed drastically; a very low
conversion was observed, but it was slightly improved by
using double the amount of the iron pincer complex with re-
spect to the previous reaction. Lactam 6e was obtained in
a modest 49% yield, as determined by NMR spectroscopy, but
considering the amount of recovered starting material, the
yield could be set at 91% (Table 4, entry 5). Next, we decided
to study the behavior of an aromatic amino alcohol such as [2-
(2-aminoethyl)phenyl]methanol (5 f). As it was shown for the
aryl substrate in entry 3 of Table 4, the iron-catalyzed dehydro-
genative oxidation and subsequent intramolecular reaction
took place effectively, but again the corresponding dehydra-
tion provided 3,4-dihydroisoquinoline (6 f) in 92% yield, as de-
termined by NMR spectroscopy (Table 4, entry 6). On the other
hand, the N-substituted derivatives have been shown to be
useful synthetic intermediates for the preparation of different
analogues of lactam-based pharmaceuticals.[23] For this reason,
we also assayed this strategy with secondary benzyl amine 5g,
and in this case, respective N-protected lactam 6g was at-
Synthesis of noncommercially available diols
General procedure: In a 100 mL, oven-dried, two-necked flask, the
commercially available dicarboxylic acid (1 equiv.) was dissolved in
dry THF. LiAlH4 (2m in THF, 3 equiv.) was added carefully at 08C by
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SusChem 2009, 2, 551–557; e) D. Hollmann, A. Tillack, D. Michalik, R.
Jackstell, M. Beller, Chem. Asian J. 2007, 2, 403–410.
syringe. After this addition, the mixture was stirred at room tem-
perature overnight. After that time, saturated NH4Cl aqueous solu-
tion (20 mL) was added carefully at 08C to quench the reaction.
The resulting mixture was filtered over Celite, and the solid residue
was washed with Et2O (3ꢂ40 mL). The organic phase was later
washed with saturated NH4Cl, and the aqueous layer was extracted
with EtOAc (3ꢂ20 mL). The combined organic extract was washed
with H2O (2ꢂ25 mL) and brine (50 mL), dried (MgSO4), filtered, and
concentrated under vacuum to afford the corresponding diol,
which was used in the next step without further purification.
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Iron-catalyzed dehydrogenative reactions
General procedure: In a glass pressure tube (25 mL) under an
argon atmosphere, [Fe-MACHO-BH] (2.1 mg, 0.005 mmol), K2CO3
(13.8 mg, 0.10 mmol), and the diol/amino alcohol (1.0 mmol) were
dissolved in t-amyl alcohol (1 mL). Next, the pressure tube was
closed, and the resulting mixture was stirred at 1508C in an oil
bath for 5 h. After cooling to room temperature, the crude material
was directly purified by flash chromatography on silica gel to
afford, after concentration and high-vacuum drying, the corre-
sponding lactone/lactam.
Acknowledgements
We thank the State of Mecklenburg-Vorpommern and the Bun-
desministerium fꢁr Bildung und Forschung (BMBF) for financial
support. M.P.L. thanks the European Commission for a Marie
Curie Intra-European Fellowship within the 7th Framework Pro-
gramme (PIEF-GA-2012–328500). We also thank Dr. Christine
Fischer, Susann Buchholz, Susanne Schareina, Andreas Koch, and
Sandra Leiminger (LIKAT) for analytical and technical support.
Keywords: dehydrogenative oxidation
lactones · pincer complexes
· iron · lactams ·
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Received: December 1, 2014
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M. PeÇa-Lꢀpez, H. Neumann, M. Beller*
&& – &&
Iron(II) Pincer-Catalyzed Synthesis of
Lactones and Lactams through
a Versatile Dehydrogenative Domino
Sequence
Just a little pinch: The iron(II) pincer-
catalyzed synthesis of lactones and lac-
tams from easily available 1,n-diols and
1,n-amino alcohols is explored. The use
of a nontoxic metal as well as the gen-
eration of molecular hydrogen as the
only stoichiometric byproduct makes
this method a highly atom-efficient and
environmentally benign process.
&
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ÝÝ These are not the final page numbers!