Synthesis of N-(2,3,4,5,6-pentafluorobenzyloxy)-γ-lactams by rhodium-catalyzed cyclization of diazo amides

Article abstract of DOI:10.1002/ejoc.201402571

Rhodium-catalyzed cyclization of N-(2,3,4,5,6-pentafluoro-benzyloxy) diazo amides leading to the corresponding γ-lactams is described. The cyclization is based on the intramolecular catalytic insertion into the C-H bond. Fourteen lactams were obtained with up to 91 % yield and 88 % ee. Gabapentin hydrochloride, a GABA analog, was also synthesized by this method, which shows that deprotection of the 2,3,4,5,6-pentafluorobenzyloxy group is possible. The rhodium-catalyzed cyclization of diazo amides, derived from O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine, is reported. The reaction leads to a variety of lactams in up to 91 % yield and 88 % ee. The developed method was applied in the synthesis of gabapentin hydrochloride, an important GABA analog.

Full text of DOI:10.1002/ejoc.201402571

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402571
Synthesis of N-(2,3,4,5,6-Pentafluorobenzyloxy)-γ-lactams by Rhodium-
Catalyzed Cyclization of Diazo Amides
[a]
[a]
[a]
[a]
Marcin Budny, Magdalena Nowak, Andrzej Wojtczak, and Andrzej Wolan*
Keywords: Diazo compounds / Insertion / Lactams / GABA analogs / Stereoselective synthesis
Rhodium-catalyzed cyclization of N-(2,3,4,5,6-pentafluoro-
benzyloxy) diazo amides leading to the corresponding γ-lact-
were obtained with up to 91% yield and 88% ee. Gabapen-
tin hydrochloride, a GABA analog, was also synthesized by
ams is described. The cyclization is based on the intramolec- this method, which shows that deprotection of the 2,3,4,5,6-
ular catalytic insertion into the C–H bond. Fourteen lactams
pentafluorobenzyloxy group is possible.
Introduction
used by Sintim and co-workers for intramolecular C–H in-
[
36,37]
sertions and cyclopropanation reactions.
Importantly,
γ-Lactams are important compounds forming a key in Sintim’s C–H insertion reaction, carbene attack occurs
structural feature in numerous biologically active sub- on the N–OR substituent located at the α- and γ-positions
stances, including many natural products.[
1–5]
There are nu- relative to the oxygen atom, and the selectivity of the inser-
merous synthetic approaches to the five-membered cyclic tion depends on the electronic character of the α- and γ-
[
6]
amides, including direct cyclization of γ-amino acids, hal- substituents. If the electrophilic CO Me group is in the α-
2
[
7]
[8]
olactamization, cycloisomerization of 1,6-enynes, intra- position, then insertion into the neighboring C–H bond is
[9]
molecular Tsuji–Trost reactions, atom transfer radical cy- not favored (Scheme 1). Despite this, products of carbene
clization (ATRC), and enyne metathesis.[11]
[10]
attack on the N–R substituent were not formed in any case.
Among these methods, rhodium-catalyzed cyclization of
diazo amides is a versatile tool used for the synthesis of γ-
[
12–26]
lactams
natural products and GABA analogs.
tion proceeds through a carbene–metal complex,
and biologically active compounds, including
[
18,24,25,27,28]
The reac-
[
29,30]
which undergoes intramolecular insertion into the C–H
bond to give the five-membered ring.
Cyclizations of diazo amides are often challenging reac-
tions in terms of the control of selectivity. Both the catalyst
and the nitrogen-protecting group should be chosen care-
fully to achieve good results. The suitable nitrogen-protect-
ing group for such cyclizations should be unreactive toward
Scheme 1. Sintim’s work.[36]
Herein, efficient cyclizations of N-(2,3,4,5,6-penta-
the carbene and should also enhance carbene attack on fluorobenzyloxy) diazo amides leading to the correspond-
the appropriate C–H bond. Many nitrogen-protecting ing γ-lactams are described. Achievement of this goal re-
[
14,18,26,31]
groups including tert-butyl,
bis(trimethylsilyl)- quired reversion of the C–H insertion selectivity in terms of
[
15,16,20,22,25]
[17,18,21,32]
[17,32]
methyl,
hydryl,
benzyl,
cumyl,
benz- elimination of carbene attack on the C–H bond α to the
[
22,32]
and aryl[32,33] have been proposed for such cy- oxygen and forcing carbene attack on the N–R substituent.
We expected that the 2,3,4,5,6-pentafluorobenzyl protecting
clizations.
Utilization of N-alkoxy diazo amides in such cyclizations group on the oxygen atom would be appropriate. Since the
[
38]
is an attractive approach because of their relatively simple
preparation and potential in further transformations of N- gen should be unreactive toward carbene. Previous reports
C F group is electrophilic, the C–H bonds α to the oxy-
6 5
[
34,35]
alkoxy amides.
Recently, N-alkoxy diazo amides were have shown examples of the influence of electrophilic sub-
[
25,31,39,40]
stituents on carbene C–H insertions.
Moreover, it
is known that perfluorinated arenes, such as hexafluoro-
benzene, exhibit lowered reactivity toward carbenes.[
The method developed in these studies has been applied to
the synthesis of gabapentin, the GABA analog exhibiting
anticonvulsant activity.
[
a] Faculty of Chemistry, Nicolaus Copernicus University,
41,42]
Gagarina 7, 87-100 Torun´
E-mail: wolan@chem.umk.pl
http://www.chem.umk.pl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402571.
[
43]
Eur. J. Org. Chem. 2014, 6361–6365
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Budny, M. Nowak, A. Wojtczak, A. Wolan
SHORT COMMUNICATION
Results and Discussion
distilled THF afforded 7 in 56% yield with only trace
amounts of 8 (Entry 4). Use of Rh (Oct) produced a sim-
ilar result (Entry 5).
2
4
N-(2,3,4,5,6-Pentafluorobenzyloxy) diazo amides were
prepared from the corresponding carbonyl compounds ac-
cording to the previously reported route,[36] as shown for
cyclopentyl derivative 1 (Scheme 2).
The reaction scope was explored under the optimized
conditions defined in entry 4 of Table 1, and the results are
shown in Table 2. Diazo amides selected for the study con-
tained primary, secondary, secondary benzylic, and tertiary
C–H bonds in the appropriate position. A series of cyclo-
hexyl-containing diazo amides, with the amide substituent
in the axial as well as equatorial positions, was also synthe-
sized to investigate the effects of conformation on the out-
come of the cyclization reaction.
Cyclopentanone 2 was converted into the corresponding
oxime ether 3 by reaction with O-(2,3,4,5,6-pentafluoro-
benzyloxy)hydroxylamine (4). Oxime ether 3 was then re-
duced to hydroxylamine 5, which was acylated with in situ
generated acylketene[ to give amide 6. The diazo transfer
reaction gave diazo compound 1.
44]
In the initial studies, the cyclization of model diazo com-
pound 1 was optimized (Table 1).
First, the selectivity of carbene insertion into the C–H
bond was investigated. Diazo amides 9, 11, and 13 were
subjected to cyclizations under the developed conditions,
yielding γ-lactams 10, 12, and 14. The secondary C–H bond
reacted preferentially over the primary C–H bond (Table 2,
Entry 1), and the tertiary C–H bond over the primary (En-
Table 1. A survey of the cyclization conditions.[a]
[
45]
try 2) and secondary ones (Entry 3). The high reactivity
of the tertiary C–H bond was confirmed in the reaction of
1
5, producing γ-lactam 16 in 73% yield on a 700 mg scale
Entry Conditions
7/8[b]
Yield [%][c]
(Entry 4). Cyclohexyl derivative 17, in which the nitrogen
substituent is in the equatorial position, gave a mixture of
diastereomeric lactams 18 in 57% yield and with 72:28
trans/cis selectivity (Entry 5). The diastereoselectivity was
even higher than for the previously reported cyclization of
N-(Me Si) CH-protected N-cyclohexyl diazo acetamide
1
2
3
4
5
Rh
Rh
Rh
Rh
Rh
2
2
2
2
2
(OAc)
(OAc)
(OAc)
(OAc)
4
4
4
4
, DCM
, (CH
, (CH
85:15
91:9
, MS (4 Å) Ͼ 99:1
Ͼ 99:1
55
58
51
56
55
2
Cl)
Cl)
2
2
2
, THF
(Oct)
4
, THF
Ͼ 99:1
3
3
[
a] General conditions: diazo compound 50–100 mg, solvent
–5 mL, catalyst 2 mol-%, time 2 h, room temp. [b] Determined by
[16]
(trans/cis = 57:43).
Diazo amides 19 and 21, in which
2
1
the nitrogen substituent is in the axial position, were also
cyclized. In contrast to the cyclohexyl derivative, they re-
acted smoothly and gave bicyclic lactams 20 and 22 as sin-
gle diastereomers in 91% and 78% yields, respectively (En-
tries 6 and 7). The structure of compound 22 was confirmed
H NMR spectroscopic analysis of crude reaction mixtures.
c] Combined yield of 7 and 8 after chromatography. Rh (Oct)
dirhodium tetraoctanoate.
[
2
4
/
The cyclization performed in DCM gave an inseparable by crystallographic analysis (Figure 1). In these cases, dia-
mixture of lactam 7 and amide 8 in 55% yield (Entry 1). stereoselectivity can be explained in terms of geometric re-
The product of carbene insertion into the benzylic C–H lationships, as the carbene in the axial position is too far
bond was not formed because of the electronic influence from the neighboring trans C–H bond and hence it can only
[
46]
of the perfluorophenyl ring. With 1,2-dichloroethane, better react with the cis C–H bond (Figure 2).
selectivity, 91:9, was achieved and the yield was 58% (Entry Methyl derivative 23 gave diastereomeric amides 24 in
). Addition of freshly activated molecular sieves (4 Å) to 66% yield with a lower diastereoselectivity of 65:35 (Entry
2
the reaction mixture gave 7 with high selectivity, Ͼ 99:1, 8). In this case, the methyl group is too small to control the
in 51% yield (Entry 3). Conducting the reaction in freshly conformation of the cyclohexyl ring, and hence the nitrogen
Scheme 2. The synthesis of diazo amide 1.
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Eur. J. Org. Chem. 2014, 6361–6365

Synthesis of N-(2,3,4,5,6-Pentafluorobenzyloxy)-γ-lactams
Table 2. Rh (OAc)
-catalyzed cyclizations of N-(2,3,4,5,6-pentafluorobenzyloxy) diazo amides.[a]
2
4
[
a] General conditions: A solution of diazo compound (50–100 mg) in THF was added dropwise to a suspension of the catalyst (2 mol-
) in THF. [b] dr = 77:23. [c] 700 mg scale. [d] 41% of trans-18 and 16% of cis-18. [e] 43% of β-H-24 and 23% of α-H-24. [f] No
%
conversion of starting material occurred at room temperature. [g] In toluene heated to reflux, a complex reaction mixture was formed.
substituent can occupy the equatorial position. Donor–ac- reflux a complex mixture of reaction products was formed
ceptor diazo amide 25 underwent efficient cyclization to af- (Entry 10). trans-Derivatives 28, 30, and 32 cyclized in a
ford 26 as a single diastereomer in 86% yield (Entry 9). trans-selective manner, producing bicyclic lactams 29, 31,
Interestingly, cyclization of 25 proceeded with migration of and 33, respectively, in low yields (Entries 11–13). Cycliza-
[
42]
the enol carbon–carbon double bond. Acceptor–acceptor tion of 34 gave only the Büchner reaction
product –
diazo compound 27 did not undergo any reaction under 1,3,5-cycloheptatriene 35 was formed in 56% yield (Entry
the developed reaction conditions, and in toluene heated to 14).
Eur. J. Org. Chem. 2014, 6361–6365
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6363

M. Budny, M. Nowak, A. Wojtczak, A. Wolan
SHORT COMMUNICATION
48% ee (Entry 2). The phenyl-substituted 21 was less reac-
tive, producing 22 only in 28% yield and with 53% ee (En-
try 3). Interestingly, donor–acceptor diazo amide 25 gave
bicyclic amide 26 in 80% yield and 88% ee (Entry 4).[
The N–O bond in 16 was reductively cleaved with
48,49]
[
50]
SmI2 to afford the corresponding NH-lactam 36 in 70%
yield, which was further hydrolyzed to gabapentin hydro-
chloride (37), an important GABA analog (Scheme 3).[
51,52]
Figure 1. An ORTEP plot of 22.
Scheme 3. The synthesis of gabapentin hydrochloride (37).
Conclusions
In summary, we have shown an unprecedented cycliza-
tion of N-(2,3,4,5,6-pentafluorobenzyloxy) diazo amides to
the corresponding protected γ-lactams. Products of carbene
insertion into the benzylic C–H bond were not detected.
Figure 2. Diastereoselective cyclizations of 19 and 21.
We found that the 2,3,4,5,6-pentafluorobenzyloxy group The cyclization outcome of cyclohexyl-substituted diazo
was not fully stable under the reaction conditions, as compounds depends on the cyclohexyl ring conformation.
2,3,4,5,6-pentafluorobenzaldehyde and 2,3,4,5,6-penta- When the nitrogen substituent is in the axial position, dia-
fluorobenzyl alcohol were detected in the reaction mixtures, stereoselective cyclization occurs with a high yield. Gabap-
which was confirmed by GC analysis (see Supporting Infor- entin hydrochloride, the GABA-analog, has been prepared
mation).
by the developed method.
The use of THF as a solvent was well tolerated, although
it is known to be potentially reactive toward carbenes.
[
47]
We detected products of carbene attack on THF only in a Experimental Section
few cases (e.g., in cyclizations of 9 and 13, see Supporting
Information).
Procedure for the Cyclization of Diazo Amide 1: To a stirred suspen-
sion of Rh (OAc) (2 mol-%, 2.5 mg) in THF (1 mL), was added a
2 4
Enantioselective cyclizations of diazo compounds 1, 19,
solution of 1 (0.286 mmol, 100 mg) in THF (2 mL) in one portion.
The resulting mixture was stirred until the starting material was
completely consumed (typically 2 h). The solvent was evaporated,
and the crude product was subjected to flash chromatography (hex-
ane/ethyl acetate: from 80:20 to 50:50), yielding 52 mg (56%) of 7
as a colorless oil.
2
1, and 25 were attempted in the presence of Rh [(S)-
2
TCPTTL] catalyst (Table 3).
4
Table 3. Enantioselective cyclizations of N-(2,3,4,5,6-pentafluoro-
benzyloxy) diazo amides.[
a]
Supporting Information (see footnote on the first page of this arti-
cle): Methods, experimental procedures, and characterization data,
1
13
as well as copies of H and C NMR spectra.
Acknowledgments
Entry
Diazo compound Product
Yield [%] ee [%]
Authors gratefully acknowledge Prof. Marek Zaidlewicz for valu-
able discussions. The study was supported by the National Science
Centre (grant DEC-2011/01/N/ST5/02539). Financial support from
the Ministry of Science and Higher Education (grant 2693/B/H03/
1
2
3
4
1
7
54[b]
71
39
48
53
88
19
21
25
20
22
26
28
80
2010/38) is also acknowledged.
[
a] General conditions: a solution of diazo compound (50–100 mg)
in THF was added dropwise to a solution of the catalyst (2 mol-
[
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Synthesis of N-(2,3,4,5,6-Pentafluorobenzyloxy)-γ-lactams
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Received: May 13, 2014
Published Online: August 27, 2014
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6365