Rhodium-catalyzed sequential allylic amination and olefin hydroacylation reactions: Enantioselective synthesis of seven-membered nitrogen heterocycles

Article abstract of DOI:10.1002/anie.201310354

Dynamic kinetic asymmetric amination of branched allylic acetimidates has been applied to the synthesis of 2-alkyl-dihydrobenzoazepin-5-ones. These seven-membered-ring aza ketones are prepared in good yield with high enantiomeric excess by rhodium-catalyzed allylic substitution with 2-amino aryl aldehydes followed by intramolecular olefin hydroacylation of the resulting alkenals. This two-step procedure is amenable to varied functionality and proves useful for the enantioselective preparation of these ring systems. A two-step process has been developed for the formation of enantioenriched seven-membered-ring aza ketones under mild conditions. The approach consists of a rhodium-catalyzed asymmetric amination of allylic trichloroacetimidates with 2-aminobenzaldehydes (C-N bond) followed by intramolecular hydroacylation (C-C bond) of the alkenal products and exhibits broad substrate scope and functional-group tolerance (see example).

Full text of DOI:10.1002/anie.201310354

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Communications
DOI: 10.1002/anie.201310354
Asymmetric Catalysis
Hot Paper
Rhodium-Catalyzed Sequential Allylic Amination and Olefin
Hydroacylation Reactions: Enantioselective Synthesis of Seven-
Membered Nitrogen Heterocycles**
Jeffrey S. Arnold, Edward T. Mwenda, and Hien M. Nguyen*
Abstract: Dynamic kinetic asymmetric amination of branched
allylic acetimidates has been applied to the synthesis of 2-alkyl-
dihydrobenzoazepin-5-ones. These seven-membered-ring aza
ketones are prepared in good yield with high enantiomeric
excess by rhodium-catalyzed allylic substitution with 2-amino
aryl aldehydes followed by intramolecular olefin hydroacyla-
tion of the resulting alkenals. This two-step procedure is
Scheme 1. Sequential amination and alkene hydroacylation.
amenable to varied functionality and proves useful for the
enantioselective preparation of these ring systems.
and enantioselective synthesis of allylic arylamines.[12–16]
C
hiral nitrogen-containing heterocycles are important struc-
Herein, we extend our DYKAT process to challenging
anilines 2 bearing an ortho-aldehyde functionality to form
enantioenriched allylic amines 3 (Scheme 1), which could
participate in an intramolecular alkene hydroacylation. The
resulting two-step process, based on allylic trichloroacetimi-
dates 1 with 2-aminobenzaldehydes 2, would provide chiral
medium-sized-ring aza ketones 4. The unique feature of this
approach is that the asymmetric induction is controlled during
the amination step, rather than during the hydroacylation
step.[5–9]
tural motifs embedded in a wide variety of bioactive natural
products and pharmaceuticals.[1] Despite many efficient
strategies toward their construction,[2,3] methods that allow
the catalytic asymmetric synthesis of medium-sized-ring aza
ketones remain underdeveloped.[2,3] Transition-metal-cata-
lyzed intramolecular alkene hydroacylation with 2-amino-
benzaldehydes would be a novel way to prepare this motif.[4,5]
This strategy has not been fully investigated, in part because
of strong metal–nitrogen bonding. Other less-basic heteroa-
toms, however, have been utilized to assist the intramolecular
hydroacylation of alkenes.[6–8] Dong and co-workers reported
the first example of a chiral rhodium-catalyzed amine-
directed hydroacylation of alkenal ketones for the enantio-
selective preparation of seven- and eight-membered-ring
nitrogen-containing lactones.[9] Recently, Bendorf et al. dem-
onstrated the feasibility of amine-directed intramolecular
alkene hydroacylation, which provided the corresponding
racemic medium-size aza heterocycles.[10] Herein, we describe
a new strategy for the catalytic enantioselective synthesis of 2-
alkyl-dihydrobenzoazepin-5-ones 4 by a sequential rhodium-
catalyzed asymmetric allylic amination followed by an intra-
molecular alkene hydroacylation reaction (Scheme 1).
Although the use of 2-aminobenzaldehydes 2 as nucleo-
philes in the sequential reactions highlights the efficacy of our
DYKAT method, this approach could be challenging. It is
well-established that RhI catalysts undergo oxidative addition
of aldehydes to form the acyl-RhIII complexes.[17] This path-
way would be more favorable because of the presence of the
ortho-nitrogen atom.[6–8] To our knowledge, there is only one
example of the use of 2-aminobenzaldehydes 2 as substrates
for hydroacylation with alkynes.[18] To test our hypothesis, the
regioselective amination of allylic trichloroacetimidate 6a
with 2-aminobenzaldehyde (5) was investigated (Table 1). We
discovered that the neutral rhodium catalyst [{RhCl(cod)}2],
was more effective than cationic rhodium complexes at
promoting the reaction (entries 1–3). Allylic arylamine 7a
(entry 3) was formed in 77% yield with excellent regioselec-
tivity (b/l > 99:1). Next, we focused on the rhodium(I)-
catalyzed DYKAT of imidate 6a with aniline 5. Under
previously optimized conditions,[11a] the amination product
7a was isolated in 14% yield (entry 4) and with poor
selectivities (b/l = 2:1, 29% ee). Decreasing the reaction
temperature to 258C (entry 5) significantly improved the
selectivity (b/l = 2:1!29:1, 29!67% ee). The outcome of this
result can be rationalized in terms of competition between the
rate of p-allylrhodium interconversion and nucleophilic
attack by aniline 5.[11a] Changing to MTBE as the solvent
(entry 8) afforded 7a in higher yield (11!61%), while
retaining the selectivity. To further optimize the reaction
conditions, a number of Hayashiꢀs chiral diene ligand
analogues were examined (entries 9–13).[19,20] As expected
Our group recently reported the chiral-diene-ligated
rhodium-catalyzed dynamic kinetic asymmetric transforma-
tion (DYKAT) of racemic allylic trichloroacetimidates with
a range of anilines.[11] This method allows the high-yielding
[*] J. S. Arnold,[+] E. T. Mwenda,[+] Prof. Dr. H. M. Nguyen
Department of Chemistry, The University of Iowa
Iowa City, IA 52242 (USA)
E-mail: hien-nguyen@uiowa.edu
Homepage: http://chem.uiowa.edu/nguyen-research-group
[+] These authors contributed equally to this work.
[**] This research was supported by the University of Iowa. J.S.A. is the
recipient of an A. Lynn Anderson Outstanding Research Award.
E.T.M. is a McCloskey Fellow.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310354.
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Table 1: Studies of rhodium-catalyzed asymmetric amination.[a]
(nbd = 2,5-norbornadienedetracts from their util-
ity.[7] Commercially available [Rh(cod)(dppb)]BF4
(entry 6) was equally effective, affording seven-
membered-ring aza ketone 9a in 99% yield after
1 h at 1058C. On the other hand, cyclization to form
nitrogen heterocycle 9a progressed slowly at 708C
(entry 7), and full conversion was observed after
20 h. In all cases, 9a was produced without any
observable racemization.[21] The results in Table 2
highlights that cyclization can take place effectively
in the absence of additional substituents on the
nitrogen atom of allylic amines; such amines are
unsuitable substrates under Bendorfꢀs conditions.[10]
We also subjected linear allylic amine 8a to the
hydroacylation reaction (Scheme 2a). Cyclization of
the minor amination isomer 8a did not proceed in
the presence of the [Rh(cod)(dppb)]BF4 catalyst,
which effectively promoted hydroacylation of the
branched allylic arylamine 7a (Table 2). Alterna-
tively, the use of [Rh(cod)2]OTf provided six-mem-
bered-ring aza ketone 10 in 58% yield.[22] Encour-
aged by this result, we performed the cyclization of
branched amination isomer 7a (Scheme 2b), which
afforded six-membered-ring product 11 in 84%
yield, albeit with low diastereoselectivity (d.r. =
ca. 2:1).
Entry Rh-ligand complex
Solvent T [8C] t [h] Yield [b/l][c] ee [%][d]
[%][b]
1
2
3
4
5
6
7
8
[Rh(cod)2]OTf
[Rh(cod)2]BF4
[{RhCl(cod)}2]
[{RhCl(ethylene)2}2]/L1 dioxane 40
[{RhCl(ethylene)2}2]/L1 dioxane 25
THF
THF
THF
25
25
25
3
3
3
66
59
77
14
11
44
22
61
34
35
46
64
59
10:1
6:1
>99:1
–
–
–
22
22
22
22
22
22
22
22
22
22
2:1 29
29:1 67
82:1 71
30:1 53
29:1 67
26:1 59
20:1 70
53:1 65
>99:1 84
6:1 62
[{RhCl(ethylene)2}2]/L1 THF
[{RhCl(ethylene)2}2]/L1 toluene 25
25
[{RhCl(ethylene)2}2]/L1 MTBE
[{RhCl(ethylene)2}2]/L2 MTBE
[{RhCl(ethylene)2}2]/L3 MTBE
[{RhCl(ethylene)2}2]/L4 MTBE
[{RhCl(ethylene)2}2]/L5 MTBE
[{RhCl(ethylene)2}2]/L6 MTBE
25
25
25
25
25
25
9
10
11
12
13
[a] All amination reactions were conducted at 0.2m with 1 equiv imidate 6a.
[b] Yields of isolated products. [c] The branched to linear ratio (b/l) was determined
by 1H NMR spectroscopy. [d] Determined by HPLC on a chiral stationary phase.
cod=1,5-cyclooctadiene, Tf=triflate, MTBE=methyl tert-butyl ether.
Table 2: Hydroacylation of branched allylic arylamine.[a]
on the basis of our previous studies,[11a] electron-deficient
ligands induced excellent asymmetric induction. The best
result was achieved using chiral ligand L5 (entry 12) with
3,4,5-trifluorophenyl groups (b/l > 99:1, 84% ee), thus dem-
onstrating the successful extension of the DYKAT method[11]
to challenging 2-aminobenzaldehydes in the asymmetric
amination. In no case was the decarbonylation of alkenal 7a
observed. In addition, the hydroacylation product (e.g. 4,
Scheme 1) was not formed even at elevated temperatures or
when the neutral rhodium-L5 complex was converted into
a more reactive cationic rhodium species with silver salts.
Next, we focused on evaluating rhodium catalysts to effect
the intramolecular hydroacylation of alkenal 7a (Table 2). We
anticipated that coordination of the amine group in 7a to
a rhodium center to form a five-membered amino-acyl
rhodacycle is important to promote olefin hydroacylation
over aldehyde decarbonylation.[9,10] Accordingly, we tested
a number of bisphosphine-ligated rhodium catalysts (Table 2)
in various solvents at elevated temperatures.[6–10] Table 2
demonstrates that the ligand bite angle plays a critical role in
the hydroacylation.[7b] The efficiency of the cyclization of 7a
decreased (96% versus 72%, entries 2 and 1, respectively) as
the bite angle of the bisphosphine ligand becomes smaller.
This result is consistent with the reported rhodium-catalyzed
enantioselective hydroacylation of ketones.[7b] Even though
rhodium–bisphosphine complexes (entries 1–5) performed
well in the reaction, the need to generate them by the
hydrogenation of [Rh(nbd)2]BF4/bisphosphine complexes
Entry RhI catalyst
Solvent T [8C] t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
[Rh(dppe)]2(BF4)2
PhCF3
PhCF3
PhCF3
105
105
105
1
1
1
1
1
1
72
96
82
99
99
99
84
84
84
84
84
84
84
[Rh(dppp)]2(BF4)2
[Rh(dppb)]2(BF4)2
[Rh(dppp)]2(BF4)2
[Rh(dppp)]2(BF4)2
[Rh(cod)(dppb)]BF4 dioxane 105
[Rh(cod)(dppb)]BF4 dioxane 70
toluene 105
dioxane 105
20 99
[a] All reactions, except for entries 6 and 7, were conducted in the
presence of 5 mol% [Rh(nbd)2]BF4, 5.5 mol% bisphosphine ligand, and
H2 (g).[7b] [b] Yield of isolated product. [c] Determined by HPLC on
a chiral stationary phase. dppe=ethane-1,2-diylbis(diphenylphos-
phane), dppp=propane-1,3-diylbis(diphenylphosphane), dppb=bu-
tane-1,4-diylbis(diphenylphosphane).
Scheme 2. Formation of six-membered-ring aza ketones.
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Table 3: Scope of sequential amination and hydroacylation.[a]
To illustrate the scope of the sequential process, we turned
our attention to assessing the rhodium-catalyzed asymmetric
amination of racemic secondary allylic imidates 6b–h
(Table 3, entries 1–7), which contain a variety of functional
groups, and found that they were able to react with 2-
aminobenzaldehyde (5). The allylic amines 7b–h were
isolated in 40–95% yield and 80–92% ee, with complete
selectivity for the branched product. Notably, a-substituted
imidate 6h (entry 7) reacted efficiently to afford amine 7h
with excellent regioselectivity; this substrate was previously
reported to form amination products with low regioselecti-
vely.[13a] Furthermore, the amination is compatible with
electron-donating and electron-deficient 2-amino aryl alde-
hydes (entries 8–10), thereby giving access to 7i–k in 61–91%
yield with excellent enantioselectivity (84–94% ee). A cyclic
aniline nucleophile (entry 11) also provides allylic amine 7l in
83% yield and 88% ee. To establish the generality of the
process, we examined the amination with disubstituted olefin
6j (entry 12), which had not previously been explored under
our DYKAT conditions. This imidate presents an additional
challenge in that both the syn- and anti-p-allylrhodium
intermediates need to be considered.[23] Although the 2-
methyl group on the p-allyl system destabilizes the syn isomer
through a 1,2 steric interaction, the anti isomer suffers from
A(1,3)interaction. As expected, allylic arylamine 7m was
isolated in 10% yield with 13% ee (entry 12). This low
selectivity suggests that the Rh-L5 complex was not effective
at controlling the relative population of the syn and anti
isomers.[23] Overall, Table 3 illustrates the generality of this
class of 2-amino aryl aldehyes with our DYKAT method.
With alkenyl aldehydes 7b–m in hand, we subsequently
subjected these amination products to the intramolecular
olefin hydroacylation conditions of 5 mol% [Rh(cod)-
(dppb)]BF4 at 1058C for 1 h (Table 3). The cyclization of
alkenals 7b–m proceeded smoothly to afford seven-mem-
bered aza heterocycles 9b–m in high yields (50–99%) without
any observable racemization. A range of functional groups
are tolerated in the b-substituted alkenal. Notably, the a-
substituted cyclohexyl alkenal 7h (entry 7) efficiently under-
went cyclization to provide seven-membered-ring aza ketone
9h in nearly quantitative yield. In the case of amine substrate
7j (entry 9), we observed that the hydroacylation occurred
preferentially at the allyl position at 1058C to yield a nitro-
gen-containing heterocycle, with simultaneous isomerization
of the g-vinyl substituent.[24] On the other hand, cyclization of
arylamine 7j at 708C provided aza ketone 9j (entry 9) and the
exclusive Z-isomerization product as a 1:1 inseparable
mixture of isomers.[25] Electron-deficient alkenal 7k
(entry 10) significantly slowed down the cyclization process.
Even after 24 h, only 62% yield of the nitrogen-containing
heterocycle 9k (entry 10) was obtained in the reaction.
Cyclization of substrate 7l, which contains a secondary aniline
functionality, also reacted slowly and took 24 h to reach
completion (entry 11). Seven-membered-ring product 9l was
obtained in 66% yield. Interestingly, intramolecular hydro-
acylation of the challenging allylic arylamine 7m (entry 12)
proceeded smoothly to afford aza heterocyle 9m in 99% yield
with d.r. = 4:1 and without racemization. Although the major
diastereomer of 9m was isolated with 15% ee, the minor
Trichloroacetimidates Allylic amines
Aza ketones
yield [%][b] (ee[%])[c] yield [%],[b] (ee [%])[c]
1
2
3
4
5
6
6b: R=BnOCH2
6c: R=TBSOCH2
6d: R=BnO
6e: R=4-F-PhO
6 f: R=Ph
7b: 95 (87)
7c: 67 (83)
7d: 81 (86)
7e: 77 (80)
7 f: 59 (92)
7g: 40 (80)[e]
9b: 99 (89)
9c: 90 (83)
9d: 99 (86)
9e: 99 (80)
9 f: 95 (92)
9g: 96 (78)
6g: R=(CH3)2CH
7
8
9
6h
7h: 41 (80)[e]
9h: 99 (80)
6 f
7i: 91 (94)
9i: 92 (95)
6i
7j: 61 (84)
9j: 50 (86)[d]
10
11
6b
6d
7k: 64 (93)[e]
9k: 62 (94)[f]
7l: 83 (88)
9l: 66 (84)[g]
12
6j
7m: 10 (13)[e]
9m: 99, d.r.=4:1
[a] All amination reactions were conducted with 1 equiv allylic acetimi-
date and 1.5 equiv 2-amino aryl aldehyde. [b] Yield of isolated product.
[c] Determined by HPLC on a chiral stationary phase. [d] Reaction
conducted at 708C for 18 h. [e] Reaction carried out with 7.5 mol% Rh-L5
complex at 408C for 24 h. [f] Hydroacylation carried out with 10 mol%
[Rh(cod)(dppb)]BF4 for 24 h. [g] Hydroacylation conducted with 5 mol%
[Rh(cod)(dppb)]BF4 at 1058C for 24 h. Bn=benzyl, TBS=tert-butyldi-
methylsilyl.
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[2] a) T. E. Mꢁller, K. C. Hultzch, M. Yus, F. Foubelo, M. Tada,
isomer was obtained with 11% ee. Additionally, no competing
b-hydride elimination product was observed in this reaction.
As a further demonstration of the robust nature and
operational simplicity of the sequential catalytic events, the
enantioselective amination of tertiary allylic trichloroaceti-
midate 6k (Scheme 3) was attempted. The reaction pro-
Chem. Rev. 2008, 108, 3795; b) P. Thansandote, M. Lautens,
Chem. Eur. J. 2009, 15, 5874.
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[4] For reviews on alkene hydroacylation, see a) B. Bosnich, Acc.
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[5] For representative first examples of rhodium-catalyzed enantio-
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James, C. G. Young, J. Chem. Soc. Chem. Commun. 1983, 1215;
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[6] For ether-, sulfide-, and sulfoxide-assisted intramolecular alkene
hydroacylation reactions, see a) H. D. Bendorf, C. M. Colella,
E. C. Dixon, M. Marchetti, A. N. Matukonis, J. F. Musselman,
T. A. Tiley, Tetrahedron Lett. 2002, 43, 7031; b) M. M. Coulter,
P. K. Dornan, V. M. Dong, J. Am. Chem. Soc. 2009, 131, 6932.
[7] For Rh-catalyzed asymmetric intramolecular ketone hydroacy-
lation, see a) Z. Shen, H. A. Khan, V. M. Dong, J. Am. Chem.
Soc. 2008, 130, 2916; b) Z. Shen, P. K. Dorna, H. A. Khan, T. K.
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Phan, B. Kim, V. M. Dong, J. Am. Chem. Soc. 2009, 131, 15608.
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co-catalyst, see a) Y. J. Park, J.-W. Park, C.-H. Jun, Acc. Chem.
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J. Org. Chem. 2012, 77, 5884.
Scheme 3. Studies with tertiary allylic trichloroacetimidate substrate.
ceeded slowly under standard conditions to generate 7n,
which contains a nitrogen-substituted quaternary center, in
poor yield. Increasing the catalyst loading (5!7.5 mol%) and
reaction temperature (25!408C) provided amine 7n in 54%
yield and 96% ee.[26] Subsequent cyclization of alkenal 7n
with 10 mol% [Rh(cod)(dppb)]BF4 at 1058C for 12 h
afforded nitrogen-containing heterocycle 9n in 94% yield
without observable racemization (95% ee).
In summary, a new strategy for the enantioselective
synthesis of seven-membered-ring aza ketones has been
developed. Construction of the enantioenriched nitrogen-
containing heterocycles was carried out by a rhodium-cata-
lyzed DYKAT of allylic trichloroacetimidates with 2-amino
ꢀ
aryl aldehydes (C N bond) followed by intramolecular
ꢀ
hydroacylation (C C bond) of the alkenal products. This
[9] H. A. Khan, K. G. M. Kou, V. M. Dong, Chem. Sci. 2011, 2, 407.
[10] H. D. Bendorf, K. E. Ruhl, A. J. Shurer, J. B. Shaffer, T. O.
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[11] a) J. S. Arnold, H. M. Nguyen, J. Am. Chem. Soc. 2012, 134,
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two-step process proceeds under mild conditions, and exhibits
broad substrate scope and functional-group tolerance. The
corresponding seven-membered aza heterocycles are formed
in high yields and with excellent levels of selectivity without
any observable racemization of the enantioenriched allylic N-
arylamines containing an ortho-aldehyde functionality. As the
enantioselective synthesis of medium-sized-ring heterocycles
continues to develop, we anticipate that this sequential
reaction will have an impact on the strategies used for the
preparation of biologically active natural products and
potential pharmaceutical agents.
[12] For a review, see B. M. Trost, T. Zhang, J. D. Sieber, Chem. Sci.
2010, 1, 427.
[13] For representative examples of the transition-metal-catalyzed
regio- and enantioselective/enantiospecific amination with ani-
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Received: November 28, 2013
Revised: February 2, 2014
Published online: March 3, 2014
Keywords: allylic amination · asymmetric catalysis ·
.
intramolecular hydroacylation · nitrogen heterocycles · rhodium
[14] For kinetic resolution of racemic secondary allylic acetates/
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Communications
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J. Am. Chem. Soc. 2001, 123, 7471; b) C. Defieber, M. A. Ariger,
P. Moril, E. M. Carreira, Angew. Chem. 2007, 119, 3200; Angew.
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[23] B. M. Trost, M. R. Machacek, H. C. Tsui, J. Am. Chem. Soc.
2005, 127, 7014.
[24] The cyclization of the alkenal product 7j with 5 mol% [Rh-
(cod)(dppb)]BF4 at 1058C for 1 h provided 99% yield of the
nitrogen heterocycle 12 as a 2:1 mixture of E/Z isomers.
[16] For rhodium-catalyzed enantioselective intermolecular hydro-
amination of allenes with aniline nucleophiles, see M. L. Cooke,
K. Xu, B. Breit, Angew. Chem. 2012, 124, 11034; Angew. Chem.
Int. Ed. 2012, 51, 10876.
[17] J. Tsuji, K. Ohno, Tetrahedron Lett. 1965, 6, 3969.
[18] For Rh-catalyzed alkyne hydroacylation using 2-aminobenzal-
dehydes, see M. Castaing, S. L. Wason, B. Estepa, J. F. Hooper,
M. C. Willis, Angew. Chem. 2013, 125, 13522; Angew. Chem. Int.
Ed. 2013, 52, 13280.
[25] At 708C, a 1:1 mixture of the desired nitrogen-containing
heterocycle 9j and Z isomer 12 was obtained in the reaction.
[19] N. Tokunaga, Y. Otomaru, K. Okamoto, K. Ueyama, R.
Shintani, T. Hayashi, J. Am. Chem. Soc. 2004, 126, 13584.
[20] a) C. Defieber, H. Grutzmacher, E. M. Carreira, Angew. Chem.
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Xu, G.-Q. Lin, Synlett 2011, 1345.
[21] We also attempted a one-pot amination and hydroacylation
reaction without isolating the branched alkenyl aldehyde 7a.
Poor conversions were observed in the reaction. As a result, it is
imperative to isolate the allylic aryl amine products prior to
cyclization.
[22] It is not clear why the [Rh(cod)(dppb)]BF4 catalyst does not
effect the hydroacylation of linear allylic aryl amine 8a and why
[Rh(cod)2]OTf catalyst provides six-membered aza heterocycle
with branched allylic aryl amine 7a. We hypothesize that this is
probably due to bite-angle effects that impart steric and
electronic influences on metal catalysts, see Z. Freixa,
P. W. N. M. van Leeuwen, Dalton Trans. 2003, 1890.
[26] In previous studies, we observed that tertiary allylic imidates
lacking an oxygen substitutent at the b-position provided the
a,a-disubstituted allylic arylamines in low selectivity (see
Ref. [11a]). As a result, we did not explore this type of
acetimidate in the rhodium-catalyzed sequential reactions.
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