Mild metal-free tandem α-alkylation/cyclization of N-benzyl carbamates with simple olefins

Full text of DOI:10.1002/anie.201202379

Angewandte
Chemie
DOI: 10.1002/anie.201202379
Synthetic Methods
Mild Metal-Free Tandem a-Alkylation/Cyclization of N-Benzyl
Carbamates with Simple Olefins**
Heinrich Richter, Roland Frçhlich, Constantin-Gabriel Daniliuc, and Olga Garcꢀa MancheÇo*
The aminoalkyl moiety is one of the most frequently
occurring functionalities in natural products and synthetic
biologically active compounds.[1] Thus, the direct functional-
a Lewis acid or a strong acid and preactivation in the a-
position to the nitrogen atom, such that OR, OCOR,
+
NHCOR, NR2, NR3 , SiR3, or halogen act as a leaving
ization of C H bonds in the a-position to a nitrogen group is
group (Scheme 1B).[8,9] Therefore, the development of more
general and milder methods for the direct a-alkylation of
nitrogen compounds with olefins remains a challenge. Herein,
we describe the first mild metal-free method for the highly
selective direct oxidative a-alkylation/cyclization tandem
reaction of N-benzyl carbamates with simple olefins. More-
over, this oxidative approach makes it possible to avoid the
use of both metal catalysts and a-activated nitrogen reagents.
Since numerous olefins are readily available and cheap,
they are preferred reagents for conducting alkylation reac-
tions. It would be highly desirable to develop a new mild and
general method for the reaction of nonactivated olefins to
À
of special interest for both academia and industry.[2,3] Among
the various synthetic strategies for the introduction of these
aminoalkyl residues, the hydroamination of olefins and
alkynes[4] and the hydroaminoalkylation of olefins[5,6] have
attracted great interest in the past few years. Several methods
3
À
for the metal-catalyzed activation of a-C(sp ) H bonds in
amines and the subsequent addition to olefins, to form mostly
a,b-branched amines, have been developed recently
(Scheme 1A).[5–7] However, these procedures, usually cata-
lyzed by Group 4 and 5 metals, suffer from regioselectivity
issues and still require high temperatures (typically around
140–2008C) and long reaction times. On the other hand, the
related a-amidoalkylations of simple olefins typically require
À
form C C bonds in the a-position to a nitrogen atom.
Encouraged by our initial studies on the FeCl3-catalyzed
oxidative synthesis of quinolines from N-alkylanilines
(Scheme 1, middle),[10] we therefore decided to explore the
direct oxidative C(sp3)-H a-alkylation of simple carbamates
with nonactivated olefins, in which a subsequent nucleophilic
attack of the carbamate oxygen could lead to interesting
heterocyles such as oxazinones[11,12] (Scheme 1, bottom).
The reaction of N-protected tetrahydroisoquinolines
(THIQs) with styrene in the presence of Cu(OTf)2 as the
catalyst (10 mol%) and a 2,2,6,6-tetramethylpiperidine N-
oxide (TEMPO) salt[13,14] (R’ = H/T+BF4À, 1.1 equiv) as the
oxidant at room temperature was chosen as the starting point
for the optimization. Different simple alkyl-substituted car-
bamates such as methyl (1a), isopropyl (1b), and benzyl
derivatives (1c) were explored. In these cases no reaction was
observed or a complex reaction mixture formed in which we
identified a small amount of the corresponding Heck-type
product (Table 1, entries 1–3). These initial results at room
temperature were quite promising, although the necessity of
a good leaving group R at the carbamate was apparent. Thus,
when the Boc-protected THIQ 1d was reacted with styrene,
the desired cyclic product 3a was formed in 57% yield
(Table 1, entry 4). We were surprised to observe the con-
comitant formation of product 3b (35% yield), derived from
Scheme 1. a-Alkylation of nitrogen compounds with olefins. LG=leav-
ing group, LA=Lewis acid, Nu=nucleophile.
[*] Dr. H. Richter, Dr. R. Frçhlich, Dr. C.-G. Daniliuc,
Dr. O. Garcꢀa MancheÇo
À
Universitꢁt Mꢂnster, Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢂnster (Germany)
E-mail: olga.garcia@uni-muenster.de
a formal C H bond functionalization of the tBu group. This
compound is, however, more likely to be formed by the
reaction of 1d with isobutene generated in situ upon the
partial decomposition of the substrate.[12] As expected, 3b was
also obtained in the absence of an external olefin in 48% yield
(Table 1, entry 5).[15] The reaction in the absence of a tran-
sition-metal catalyst, using 4 equivalents of styrene, was next
carried out. Surprisingly, the efficiency of the reaction was
[**] This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. H.R. thanks the DFG for
support within the IRTG/SFB858 Program. We thank Dr. Peter
Nesvadba (BASF Schweiz AG) for the donation of various TEMPO
derivatives and Prof. D. P. Curran and Dr. J. Alemꢃn for interesting
discussions and suggestions.
À
retained (Table 1, entry 6). When we switched from T+BF4
to the 4-acetamido derivative of TEMPO (4-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202379.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Substrate scope.[a]
Variation of the olefin
Entry 1 (R)
2a
Cu(OTf)2 Oxidant
Yield [%][b]
[equiv] [mol%]
3a 3b
[c]
1
2
3
4
5
6
7
8
1a (Me)
2.0
2.0
2.0
2.0
–
4.0
4.0
2.0
1.2
1.2
1.2
1.2
1.2
10
10
10
10
10
–
–
–
–
–
R’T+BF4À(R’=H)
R’T+BF4À(R’=H)
R’T+BF4À(R’=H)
R’T+BF4À(R’=H)
R’T+BF4À(R’=H)
R’T+BF4À(R’=H)
–
1b (iPr)
1c (Bn)
1d (tBu)
1d
1d
1d
1e (Ad)
1e
1e
1e
1e
–
–
57
–
35
48
22
15
58
R’T+BF4À(R’=NHAc) 63
R’T+BF4À(R’=NHAc) 93
R’T+BF4À(R’=NHAc) 93[d]
9
10
11
12
13
–
–
6
–
–
–
–
–
DDQ
tBuOOH
[e]
1e
O2
[a] 1 (0.1 mmol), 2a (1.2–4.0 equiv), and oxidant (1.1 equiv) in CH2Cl2
(0.2m) at RT for 24 h. [b] Yield of isolated product. [c] A complex mixture
was formed. [d] Same yield was obtained in a 0.5 mmol scale reaction.
[e] 1 atm of O2 was used.
NHAcT+BF4 ),[16] 3a was obtained in a slightly improved
À
Variation of the tetrahydroisoquinoline
yield of 63% (Table 1, entry 7).[17] However, certain amounts
of 3b were still formed. To avoid this and achieve high
chemical selectivity, we ultimately envisioned the use of an
adamantyl (Ad) group as a substituent on the carbamate
moiety. Owing to the high stability of the adamantyl cation[18]
it should be a good leaving group and, according to Bredtꢀs
rule, it would not undergo elimination to introduce another
olefin to the reaction mixture. Consequently, when the
reaction was carried out using 1e, with 2 equivalents of
styrene, 3a was obtained in an excellent yield of 93%
(Table 1, entry 8). The same efficiency was obtained by
reducing the amount of styrene to 1.2 equivalents and by
scaling up the reaction by a factor of 5 (Table 1, entry 9).
Moreover, it is worth mentioning that other common oxidants
like DDQ, tBuOOH, and O2, which are used for the
formation of iminium-type intermediates in dehydrogenative
couplings, were not efficient in promoting the reaction
(Table 1, entries 11–13).[3,19] This fact underlines the unique
action of the TEMPO-derived salts as oxidants in this
alkylation coupling reaction.
[a] 1 (0.1 mmol), 2 (1.2 equiv), and 4-NHAcT+BF4À (1.1 equiv) in CH2Cl2
(0.2m) at RT for 24 h. (The relative configuration of the major isomer is
represented.[21]) [b] A solution of the styrene in CH2Cl2 was slowly added
(over 5 h). [c] 3l’ was also isolated in 12% yield. [d] 5 equiv of olefin
used.
With the optimized conditions in hand, we investigated
the scope of the reaction (Table 2). Initially, styrene deriva-
tives bearing either electron-withdrawing (EGW) (3c–g) or
electron-donating groups (EDG) (3h–j) were explored. The
desired oxazinones 3 were generally furnished in good to
excellent yield (83–99%), with the exception of substrates
with strong EWGs (e.g. R = m-CF3: 3g, 51%; or p-NO2:
traces). On the other hand, highly electron-rich substrates
such as the p-MeO-substituted derivative (3h, 38%) suffer
from the favored competitive oxidative polymerization of the
styrene.[20] Most of the generated diastereomeric mixtures
obtained with styrenes could be separated by chromatogra-
phy (e.g. 3a, 3 f, 3g, and 3h).[21]
Next, a-branched styrenes were tested. a-Methylstyrene
gave 3k in almost quantitative yield, while the reaction with
the more hindered 1,1-diphenylethylene produced 3l in
a lower yield of 68% (along with 12% yield of the olefinated
compound 3l’, see Scheme 3). The reaction of 1e with trans-b-
methylstyrene proceeded smoothly and 3m was isolated in
68% yield and 10.5:1 d.r. On the other hand, the reaction with
isoprene gave exclusively 3n, indicating the chemoselective
coupling of the more substituted double bond.
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To further establish the scope of this transformation,
aliphatic olefins were next investigated. Interestingly, a simple
olefin like 1-octene was also a suitable substrate and
compound 3o was formed in 66% yield. Moreover, the use
of methylenecyclohexane as the coupling partner provided
selectively the spiro compound 3p in a good yield of 71%.
Next, we addressed the synthesis of trisubstituted oxazinones.
Although it is reported in the literature that oxoammonium
salts undergo ene-like addition to trisubstituted alkenes,[22]
under our conditions the reaction of 1e with 1-methyl-1-
cyclohexene gave exclusively the tetracyclic compound 3q in
a remarkable 84% yield. After demonstrating the generality
of the nucleophile, we explored several THIQ derivatives.
Substrates containing either electron-donating or electron-
withdrawing groups were efficiently employed (Table 2,
bottom). To show the variation at the saturated N-hetero-
cyclic unit, an enantiomerically pure compound having an
ester in the C3 position of the THIQ was prepared starting
from l-phenylalanine. The ester group was well tolerated and
3x was obtained in 89% yield with the complete preservation
of chirality. Our method is thus compatible with optically
active compounds and suitable for the synthesis of complex
molecules.
method to the synthesis of the racemic form of the analgesic
drug Methopholine (7)[26] in three steps from oxazinone 3u.
The direct reduction of 3u with LiAlH4 to generate the N-
methyl derivative of type 5 was not selective, and we observed
À
the concomitant significant reduction of the aromatic C Cl
bond. However, when initial carbamate deprotection with
base (NaOH) was followed by a one-pot treatment with HCl
(conc.), reduction with the H2 on Pd/C, and a final N-
methylation, 7 was obtained in good overall yield (Scheme 2).
The more challenging acyclic benzyl carbamates were also
suitable substrates for this transformation. Thus, when the
reaction was performed at 608C in the presence of 4-
NHAcT+BF4 (1.5 equiv), the corresponding oxazinones
À
4a–f were obtained in moderate to excellent yield (66–99%,
Figure 1).[23] Moreover, more hindered 1,1-disubstituted ole-
fins could also be employed, leading to the products 4e and
4 f, which possess a quaternary center, in 40–42% yield.
Scheme 2. Modification of oxazinones and synthetic applications.
Finally, based on experimental observations,[27] we pro-
pose a mechanism for the alkylation/cyclization reaction in
which an initial a-oxidation with the TEMPO salt generates
the N-acyliminium ion 8,[8] which undergoes nucleophilic
addition of the olefin (Scheme 3). Subsequently, the cleavage
À
of the O adamantyl bond and the concomitant attack of the
carbamate oxygen atom at the carbocation center in 9 release
oxazinone 3 and an adamantyl cation.[28,29] The participation
of the cationic intermediate 9 in the course of the reaction was
confirmed by the formation of the 3l’ (Scheme 3).[28] Thus, in
the reaction with sterically hindered 1,1-diphenylethylene, the
b-proton elimination from the proposed intermediate 9 can
compete with the intramolecular cyclization (3l/3l’). How-
ever, because of the selectivities observed and the complete
retention of the stereochemistry in the reactions with both
trans- and cis-b-methylstyrene (Scheme 3, bottom), a fast
cyclization of the highly reactive cationic intermediates of
type 9, or even a concerted cycloaddition pathway, can be
assumed. Moreover, if one considers that the reaction with
the different styrenes proceeded in similar reaction times (14–
18 h) and that the acyclic substrates required higher reaction
temperatures,[30] the generation of the active iminium species
8 might be involved in the rate-determining step. Thus, to
differentiate between a proton- or hydrogen-abstraction
mechanism in the formation of 8 after an initial single-
electron transfer (SET) to form an N-centered radical cation
Figure 1. Products obtained from the reaction with acyclic benzyl
carbamates.
Oxazinones 3 derived from THIQ were next easily
transformed into other valuable biologically active deriva-
tives such as the corresponding substituted aminoalcohols 5
and 6.[24,25] Thus, the two separated diastereomers of 3a were
reduced with LiAlH4 to give the corresponding N-methyl-1-
alkyl-THIQ compounds trans-5a and cis-5a in excellent yield
(90% and 94%, respectively). These b-hydroxy-THIQ struc-
tures are interesting since they are present in several natural
and synthetic bioactive compounds such as NMDA-NR2B
receptor antagonists.[25] Additionally, treatment of cis-3a with
NaOH in an ethanol/water mixture gave the free amino-
alcohol cis-6a in good yield (71%). Finally we applied our
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[4] Recent review on hydroaminations: T. E. Mꢁller, K. C.
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[5] For a recent overview on catalytic hydroaminoalkylations, see:
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À
[6] For the initial studies, involving activation of a C H bond in a-
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6069.
Scheme 3. Mechanistic observations and proposal. SET=single-elec-
tron transfer.
intermediate, we carried out kinetic isotope studies with 1e
and a,a-dideuterated [D2]-1e (see the Supporting Informa-
tion). A high kinetic isotope effect (KIE) of 4.6 was observed,
[11] For some examples of bioactive 1,3-oxazin-2-ones, see: a) Z. Xu,
PCT Int. Appl., 2009, WO 2009017671; b) A. Nardi, K. L.
Troelsen, H. K. Erichsen, PCT Int. Appl., 2010, WO
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[13] Reviews on oxoammonium chemistry: a) Oxoammonium- and
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À
suggesting that hydrogen abstraction (C H cleavage) is more
likely to be the rate-determining step.
In summary, we have developed a novel and general
tandem a-alkylation/cyclization of N-benzyl carbamates with
nonactivated olefins in the absence of metal catalysts. More-
À
over, a C H bond in the a-position to a nitrogen group can be
directly functionalized, and thus no preactivation of the
substrate is required. The reaction takes place under mild
conditions in the presence of 4-NHAcT+BF4 as a unique
À
nontoxic mild oxidant. This method constitutes the first
example of metal-free direct a-alkylation of N-benzyl carba-
mates using simple mono-, di-, and trisubstituted olefins. We
also demonstrated the generality of this reaction and its
applicability to the synthesis of a variety of oxazinones and
other different bioactive derivatives.
À
[14] For our recent work on dehydrogenative C C coupling reactions
using TEMPO salts, see: a) H. Richter, O. G. MancheÇo, Eur. J.
Org. Chem. 2010, 4460 – 4467; b) H. Richter, R. Rohlmann, O.
Garcꢂa MancheÇo, Chem. Eur. J. 2011, 17, 11622 – 11627. See
also ref. [10].
Received: March 26, 2012
Revised: May 30, 2012
Published online: && &&, &&&&
[15] See the Supporting Information for the X-ray structures:
CCDC 872907 (3b), CCDC 882424 (3m, major isomer) and
CCDC 883598 (4e, major isomer) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
À
Keywords: alkenes · alkylation · C H bond functionalization ·
metal-free methods · nitrogen heterocycles
.
[16] J. M. Bobbitt, N. Merbouh, Org. Synth. 2005, 82, 80 – 86.
[17] The use of 4-NHAcT+BF4À has several benefits. In the course of
the reaction its corresponding N-hydroxy salt precipitates as
a white solid, which can be collected by filtration (see the
Supporting Information for analytical data) and easily recycled
to 4-NHAcT+BF4À as described by Bobbitt et al. (see Ref. [13]).
[18] G. A. Olah, G. K. S. Prakash, J. G. Shih, V. V. Krishnamurthy,
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a) C.-X. Song, G.-X. Cai, T. R. Farrell, Z.-P. Jiang, H. Li, L.-B.
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3
À
[2] Review on C(sp ) H bond functionalization adjacent to nitro-
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3
À
including amino a-C(sp ) H bond functionalizations: a) C.-J. Li,
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example on the use of styrenes in cross-dehydrogenative
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A 1993, 31, 1505.
[21] The relative configuration of the major diastereoisomers was
determined by X-ray structure analysis and/or 1D NOESY
studies (for more details see the Supporting Information).
[22] P. P. Pradhan, J. M. Bobbitt, W. Bailey, Org. Lett. 2006, 8, 5485 –
5487.
[23] Reactions were carried out in CH2Cl2 at 608C in a pressure
Schlenk tube. Similar results for 4a were obtained using 1,2-
dichloroethane as solvent.
[27] The presence of radical inhibitors like BHT and the TEMPO
free radical dramatically hampered the reaction, whereas
galvinoxyl radical had only a slight influence on the efficiency
(64%, 3a). Moreover, the reaction with tritylium cation
(Ph3CSbCl6) as a hydrogen abstractor, known in N-acyliminium
chemistry, did not proceed. This indicates that a single-electron
transfer might be involved in the formation of the active iminium
intermediate.
[24] See for example: a) H.-Y. Wang, L. B. Barbier, J. Wang, PCT Int.
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[28] As a side product, 1-fluoroadamantane, generated by the
reaction of adamantyl cation with the BF4À, was isolated in
50 – 80% yield. A. Fokin, P. A. Gunchenko, A. I. Yaroshinsky,
A. G. Yurchenko, P. A. Krasutsky, Tetrahedron Lett. 1995, 36,
4479 – 4482.
[29] The possible in situ generated BF3 is not a promoter, since the
reaction with added BF3–Et2O (1 equiv) did not deliver the
desired products. The addition of HBF4 or TfOH led to complex
mixtures.
[30] Only traces of products 4 were detected at room temperture
after 18–24 h.
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Communications
Synthetic Methods
H. Richter, R. Frçhlich, C.-G. Daniliuc,
O. Garcꢁa MancheÇo*
&&&& — &&&&
Mild Metal-Free Tandem a-Alkylation/
Cyclization of N-Benzyl Carbamates with
Simple Olefins
Easy does it! The chemoselective oxida-
TEMPO oxoammonium salt serves as the
oxidant, making it possible to carry out
the reaction at low temperatures. Neither
a metal catalyst nor preactivation in the
a-position to the nitrogen group are
needed.
3
À
tive a-C(sp ) H alkylation/cyclization
reaction of N-benzyl carbamates using
simple mono-, di-, and trisubstituted
olefins provides functionalized N-hetero-
cycles such as oxazinones (see picture). A
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!