Gold-Catalyzed Carboamination of Allenes by Tertiary Amines Proceeding with Benzylic Group Migration

Article abstract of DOI:10.1002/adsc.202100007

Tertiary amines bearing a benzyl-type group (CH₂Ar) undergo Au(I)-catalyzed intramolecular addition to allenes. A formal 1,3-transfer of the CH₂Ar group takes place during the cyclization. As demonstrated by both experimental and DFT studies, these unprecedented intramolecular carboaminations involve two consecutive [3,3] rearrangements via a dearomatized intermediate. Because of the poor stability of the enamine products, protocols were developed to convert them in situ to more stable polycyclic chiral compounds. (Figure presented.).

Full text of DOI:10.1002/adsc.202100007

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DOI: 10.1002/adsc.202100007
Gold-Catalyzed Carboamination of Allenes by Tertiary Amines
Proceeding with Benzylic Group Migration
Pierre Milcendeau,a Vincent Gandon,b, c,* and Xavier Guincharda,*
a
Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198, Gif-sur-Yvette, France
E-mail: xavier.guinchard@cnrs.fr
Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Université Paris-Saclay, Bâtiment 420, 91405
b
Orsay cedex, France
E-mail: vincent.gandon@universite-paris-saclay.fr
Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Institut Polytechnique de Paris, route de
c
Saclay, 91128 Palaiseau cedex, France
Manuscript received: January 4, 2021; Revised manuscript received: March 15, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100007
the intermediate gold species and promote an addi-
tional functionalization by a nucleophile resulting most
Abstract: Tertiary amines bearing a benzyl-type
group (CH2Ar) undergo Au(I)-catalyzed intramolec-
of the time into a formal double heterofunctionaliza-
ular addition to allenes. A formal 1,3-transfer of the
tion (Scheme 1, type B).[1h,8,9] However, reactions
CH2Ar group takes place during the cyclization. As
performed with functionalized nucleophiles (no XÀ H
demonstrated by both experimental and DFT stud-
bond), for which the protodeauration step cannot take
ies, these unprecedented intramolecular carboamina-
place, may lead to both cyclization and a transfer of
tions involve two consecutive [3,3] rearrangements
the functional group via intriguing mechanisms
via a dearomatized intermediate. Because of the
(Scheme 1, type C). In these reactions, no external
poor stability of the enamine products, protocols
oxidant is needed since no redox cycle operates. A
were developed to convert them in situ to more
stable polycyclic chiral compounds.
number of chemical functions have been shown to
efficiently transfer during the cyclizations of O-, N- or
S- centered nucleophiles to mostly alkynes electro-
philes, such as alkyl,[10] silyl,[11] sulfonyl,[12]
Keywords: Gold catalysis; Indoles; [3,3] rearrange-
arylidene,[13] propargyl[14] or allyl groups.[10a,15] All
ments; Heterocyclic chemistry; Carboaminations
these reactions raise questions regarding the associa-
After almost two decades of intense research, homoge-
neous gold catalysis has established itself as a
prominent field in organic synthesis.[1,2] The π-acidic
properties of Au(I) complexes enable a vast range of
catalytic reactions, leading to a huge structural diver-
sity. Among the popular reactivities of these com-
plexes, hydrofunctionalizations of unsaturated sub-
strates hold a salient position. The diversity of
nucleophiles combined with various unsaturated elec-
trophilic partners lead to an efficient access to a
Scheme 1. General heterocyclization processes with Au(I) cata-
lysts.
number of important heterocycles.[3] In most cases, the
reactions evolve through a generally similar pathway
combining 1) activation of the unsaturation, 2) addition
of the nucleophile, and 3) protodeauration reaction.
This strategy was very efficiently applied to tive of dissociative nature of the mechanism, which
hydrofunctionalization[4] of alkynes,[5] allenes[6] or appears to be strongly dependent on the heteroatom
alkenes (Scheme 1, type A).[7] In some reactions and the migratory group.
though (mainly from alkenes), it is possible to oxidize
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Over the last years, we have developed a number of
In this paper, we show that a range of CH2Ar
Au(I)-catalyzed strategies to the functionalization of groups can be efficiently transferred and lead to
indoles.[16,17] Recently, we pioneered a new type of valuable molecules. The whole process was also
intramolecular cyclizations from N-allyl tetrahydro-β- applied to different scaffolds. A DFT study assessed
carbolines that undergo gold-catalyzed carboamination the mechanistic hypothesis.[24]
of their allene moiety,[18] resulting in cyclization
We first prepared in good yields a series of
products with the concomitant 1,3-migration of the tetrahydro-β-carbolines 1 by using the Pictet-Spengler
allyl group (Scheme 2, eq. 1).[19] Seeking to question reaction[25] between a series of tryptamines protected
the possibility to do related cyclizations with more by a range of benzylic groups and hexa-4,5-dienal
challenging migrating groups, we hypothesized that (Scheme 3).
benzylic groups should lead to structurally resembling
A suitable catalytic system was sought using
compounds, with the migration of the whole CH2Ar tetrahydro-β-carbolines 1 as substrates (Table 1). We
group. To our knowledge, cyclizations occurring with first engaged 1a in the reaction with the
transfer of a benzyl group have been reported using JohnPhosAuSbF6.MeCN catalyst[26] 3a in toluene
platinum catalysis in the course of the synthesis of
benzofurans,[20] but there is only a single example of a
cyclization occurring with a transfer of a p-MeOBn
upon gold catalysis, reported only in a review.[21,22] In
addition, precedents from Hashmi evidenced the
difficulty to transfer benzyl groups in related
reactions,[15c] likely because of the energetically de-
manding dearomatization in intermediate i (Eq. 2).[23] It
is however not to exclude that some aryls groups may
be able to participate to such reactions, and we
anticipated that tetrahydro-β-carbolines 1 could lead to
indolo[2,3-a]quinolizidines 2 via the ammonium salt ii
and the dearomatized intermediate iii, that would
further undergo an additional [3,3] sigmatropic rear-
rangement (Scheme 2, eq. 3).
Scheme 3. Synthesis of tetrahydro-β-carbolines 1.
Table 1. Optimization of the catalytic system using 1a–d.
Entry
1
cat (mol %)
solvent
conv (%)[a]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3b (5)
3c (5)
3a (5)
3a (2.5)
PhMe
PhMe
PhMe
PhMe
DCE
THF
DMF
DCE
DCE
DCE
DCE
2a, 0
2b, 0
2c, 0
2d, 50
2d, 100
2d, 65
2d, 35
2d, 35
2d, 0
9
10
11
2d, 100[b]
2d, 60[c]
1
[a] Measured by H NMR. Reactions were performed for 16 h.
[b] Reaction performed over 4 h.
[c] Reaction performed over 24 h.
Scheme 2. Au(I)-catalyzed carboamination of allenes.
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(Table 1, entry 1), but no conversion was observed. Information for optimization of the reduction). NOESY
The effect of an electron donating group and a halogen studies revealed that compound 4d is cis-configured.
were checked using compounds 1b and 1c but, again,
In a second valorization strategy of the unstable
no reaction took place (Entries 2–3). Those results enamine product 3d, we added aqueous HCl to
confirmed that benzylic groups embedding a phenyl promote its hydrolysis and protected in situ the
ring do not undergo the dearomatization step included resulting amine with a Boc group to lead to the stable
in the mechanistic hypothesis. On the other hand, ketone 5d in 79% yield.[28] At the end, the product
when the naphthylmethyl-substituted tetrahydro-β-car- obtained results from a formal carbohydration of the
boline 1d was used, a high NMR conversion of 1d in allene, though the mechanism evolves through a
2d was monitored, in particular when the solvent was carboamination. This constitutes an interesting ap-
switched to DCE (entries 4–7). Both the Gagosz proach, since direct carbohydration of allenes systems
catalyst 3b[27] and the IPrAuBF4 complex 3c showed is, to our knowledge, not reported in the literature, in
lower activity (entries 8–9).
sharp
contrast
with
hydration[29]
and
Further studies revealed that the reaction necessi- carboalkoxylation[30] with gold, or other transition
tates shorter reaction time (4 h, entry 10) but that a metals.[31,32]
lower catalyst loading results in a significant decrease
in the catalytic activity despite prolonged reaction the gold-catalyzed carboamination and applied for
times (entry 11). each substrate both the reductive and the hydrolytic
We next engaged other tetrahydro-β-carbolines 1 in
As we observed in our previous studies,[19] the protocols. The reaction tolerated the presence of a
enamine nature of product 2d complicates its purifica- methoxy group at position 5 of the indole ring,
tion and isolation because of its high reactivity. For resulting in the isolation of both 4e and 5e, in 60%
this reason, we established two different protocols to and 56% yield, respectively. We also confirmed that
directly convert compounds 2d into a stable product the 7-methoxynaphthylmethyl group allows the carboa-
(Scheme 4). In a first approach, we directly reduced mination process to 4f in 69% yield. When the acidic
the enamine resulting from the carboamination to the workup was applied, product 5f was obtained in 65%
corresponding amine by addition of NaBH4 and MeOH yield. Finally, the 2-thienylmethyl moiety also partici-
after completion of the Au(I)-catalyzed reaction. This pated in the reaction, leading to 4g and 5g in good
resulted in the formation of compound 4d as a single yields.
diastereoisomer in 73% yield (See the Supporting
Scheme 4. Scope of the Reaction.
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Interestingly, the analogous compound 1h bearing a cleavage of the nitrogen-indolylmethyl bond, forming
furylmethyl group undergoes the cyclization but an azafulvenium ion ii and protodeauration of inter-
delivered very selectively compound 6 instead of the mediate iii by mean of the azafulvene ion. Finally,
expected compound 2h (Scheme 5, eq. 1), likely tetrahydro-β-carboline 1j featuring a 1,3-disubstituted
stemming from a direct rearomatization (see intermedi- allene (see the Supporting Information for its syn-
ate iii, Scheme 2) and not a [3,3] rearrangement. This thesis) also led to unique reactivity (eq. 4).[35] Upon
compound is however poorly stable on silica gel but exposure of 1j to Au(I)-catalyzed conditions com-
could be fully characterized as a mixture with the pound 9 was obtained in 28% yield as a single
catalyst (See the Supporting Information). When the diastereomer, along with other non-identified com-
hydrolysis workup B was applied to the crude mixture, pounds. NOESY experiments confirmed the trans
compound 7 was obtained in 42% yield after Boc configuration between both stereogenic centers and the
protection (eq. 2). Interestingly, the tetrahydro-β-carbo- E configuration for the olefin. This product again
line 1i also evolved through an original pathway, results from a 5-exo-trig cyclization with the delivery
leading to compound 8 as the main identifiable product of the benzylic moiety at the central carbon atom of
of the reaction, that we previously obtained using the initial 1,2-propadienic system.
palladium catalysis[33] (eq. 3). Most likely, this products
During the optimization process, an interesting
arises from the 5-exo-trig cyclization of the amine to observation arose from cyclization experiments per-
the allene[34] leading to intermediate i, followed by the formed from 1d in nitromethane with catalyst 3a
(Scheme 6, eq. 1). This reaction furnished the nitro
compound 10d with full conversion as a couple of
diastereomers (dr 75/25). This compound likely results
from the nucleophilic addition of nitromethane to the
intermediate enamine 2d. It is however not stable on
silica gel and undergoes elimination leading to the final
product 2d. Because of its intrinsic instability, com-
pound 10d could be characterized only as the crude
Scheme 5. Au(I)-catalyzed cyclizations with furyl and indolyl
substituents and 1,3-disubstituted allene.
Scheme 6. Using MeNO2 as solvent.
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product without removal of the catalyst (see the DFT computations with the JohnPhos ligand on the
Supporting Information) and its structure was also gold atom and compared with those reported earlier
confirmed by HRMS. Interestingly, when the reaction with a vinyl group[19] (see the Supporting Information
was performed in deuterated nitromethane, the 1H for details). All energies are Gibbs free energies in
NMR spectra of the product fitted that of 10d, with kcal/mol at 353 K including a solvent correction for
however the disappearance of the two protons adjacent dichloromethane. The computed mechanistic options
to the nitro group and of two additional CH2 (eq. 2).
are shown in Figure 1. Starting from the allene gold(I)
In order to confirm that 10d is indeed formed from complex A, a 6-exo-dig cyclization leads to the
enamine 2d and if the Au(I) catalyst plays a role in its allylgold species B. A suprafacial [3,3]-sigmatropic
formation, a batch of enamine 2d (as pure as possible shift of the CH2R group provides the exo-enamine gold
despite its instability, see the Supporting Information) complex C. A second [3,3]-sigmatropic shift trans-
°
was then stirred at 80 C in deuterated nitromethane in forms the latter into the endo-enamine gold complex
the presence or absence of the gold catalyst (eq. 3). In D. Alternatively, electrophilic cleavage of the Csp3À Au
the absence of the catalyst, despite the full conversion bond of B by the CH2R group leads to D directly, but
of 2d, the reaction showed only traces of 10d and led this could be only modeled with R=vinyl. From C,
mostly to degradation. On the contrary, in the presence one can imagine a proton elimination that would lead
of catalyst 3a, the formation of 10d was confirmed, to the allylgold species E. Protodemetalation finally
even if the reaction was not complete (ca 55% conv.), gives F, which is actually the isolated product when
confirming the role of the Au(I) catalyst in this step. R=vinyl. On the other hand, a simple dissociation of
Nitro-Mannich reactions have already been catalyzed the active species LAu+ from D delivers H (=
by Lewis acids,[36] but to our knowledge, this behavior compounds 2), which is experimentally obtained when
is not common for enamines in Au(I) catalysis and has R=2-naphthyl (Hd =2d). Another scenario to get 2
never been documented. Our hypothesis is that would be the dissociation of LAu+ from C to give G,
enamine 2d coordinates the Au(I) complex to generate followed by a [3,3]-sigmatropic shift (Cope rearrange-
iminium (i), that is trapped by the nitromethane in the ment).
course of the Aza-Henry reaction leading to (ii).
The formation of B through TSAB, appears kineti-
Finally, protodeauration generates the final product cally and thermodynamically much more favorable
10d (eq. 4). The cyclization performed in deuterated with R=vinyl. The second step requires 25.2 kcal/mol
nitromethane corroborates well this hypothesis.
of free energy of activation to reach TSBC with R=
Since these results in nitromethane showed that a vinyl, 22.1 kcal/mol with R=Ph and 18.1 kcal/mol with
C-centered nucleophile could act as a trapping agent, R=2-naphthyl.[37] There is a strong difference in the
we next attempted to trap the enamine product 2d with exergonicity of this step, which is very strong with R=
trimethylsilylcyanide. The addition of TMSCN after vinyl (À 31.4 kcal/mol), weak with R=Ph (À 2.7 kcal/
the Au(I)-catalyzed cyclization of 1d gratifyingly led mol) and average with R=2-naphthyl (À 12.5). This
to the formation of the cyanide 11d, isolated with 53% can be explained by the loss of aromaticity in the latter
yield as a single diastereomer (Scheme 7). NOESY two cases compared to the former. This loss is
NMR analysis showed that the cyanide was delivered complete with R=Ph, hence a weak exergonicity, and
on the same side of the enamine than when NaBH4 partial with R=2-naphthyl, meaning an average
was used. In contrast with compound 10d, 11d exergonicity.
showed great stability both on silica gel and upon
storage.
With R=vinyl, the third step seems inaccessible, as
reaching TSCD would necessitate 38.0 kcal/mol. Reach-
In order to secure the initial mechanistic hypothesis, ing D from B through TSBD is in fact even more
we first verified experimentally that the reaction difficult since a barrier of 39.5 kcal/mol would have to
operates solely via an intramolecular mechanism by be overcome. Complex C could then give G and
using cross experiments (see the Supporting Informa- finally H through TSGH, but this last step demands as
tion).
much as 31.2 kcal/mol of free energy of activation.
The model cyclization of tetrahydro-β-carbolines The last scenario in this case is the protodemetalation
1a (Ar=Ph) and 1d (Ar=2-naphthyl) were studied by via E to give F, which is indeed the product observed
experimentally with R=vinyl.[19]
The R=2-naphthyl showcases an interesting and
subtle balance that rationalizes the different outcome
compared to R=vinyl. On one hand, the loss of
aromaticity is only partial, so it does not hamper the
formation of C. On the other hand, the recovery of
aromaticity facilitates the final Cope transposition that
was impossible with R=vinyl.
Scheme 7. Extension of the reactivity to the cyanation of
intermediate product 2d. Ar=2-naphthyl.
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Figure 1. Free Energy Profile (ΔG353, kcal/mol) Relatively to Complex A (free energies of the transition states are in italics).
The case of R=2-furyl is also interesting and amines, leading to unstable enamine products that were
provides valuable confirmation of the existence of converted to stable polycyclic scaffolds via a reductive
dearomatized intermediates C since this compound treatment or an acidic hydrolysis protocol. This set of
necessarily stems from the A-B-C-E-F pathway, results is a proof of concept that allenes can undergo
similarly to the case of R=vinyl. The reaction from 1i carboaminations of amines with the transfer of a
leading to 8 also testifies that the 5-exo-trig initial benzylic group, with interesting mechanistic pathways
addition of the amine to the allene is thermodynami- ongoing and original elementary steps, such as the
cally favored over the 6-exo-dig addition, but is in dearomatization/cope rearrangement sequence. These
most cases unproductive and reversible. This was the steps could be assessed by DFT calculations and
case in our previous studies with allyl groups, where experimentally verified by the reaction of a number of
the 5-exo-trig addition (ΔG353 =1.6 kcal/mol, Ik starting material that probed the mechanistic pathways.
À 19.4 kcal/mol) was calculated to be favored over the
6-exo-dig addition (ΔG353 =7.3 kcal/mol, À 22.2 kcal/
Experimental Section
mol).[19] On the contrary, with R=indolyl, intermediate
Ii is probably formed easily but evolves to compound
8 because of the electron-density of the indolyl moiety
(see Scheme 5, eq. 3). Conversely, the formation of 9
would result from the same pathway, through the
formation of intermediate Ij (R=2-naphthyl, see the
Supporting Information for exact structure) and a
direct transfer of the benzylic group from the nitrogen
atom to the vinylgold(I), highlighting another possibil-
ity in this mechanistic puzzle.
General procedure 1for the synthesis of tetrahydro-β-carbo-
lines 1:
A mixture of N-Benzyl tryptamine (1 equiv.),
(PhO)2PO2H (0.1 equiv.) and 3 Å molecular sieves (70 mg for
0.15 mmol of starting material, powdered) in toluene was stirred
for 5 min at room temperature under an argon atmosphere.
Subsequently, aldehyde (2 equiv.) was added, and the mixture
°
was stirred at 50 C for the 16 h under an argon atmosphere.
After the reaction was completed, the reaction mixture was
filtered over Celite path. The filtrate was concentrated under
vacuum and purified by flash chromatography to give the
desired product 1.
In conclusion, we have reported a new type of
carboamination reaction of allenes with tertiary
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3.34–3.37 (m, 1H, H3b), 3.08–2.92 (m, 2H, H14), 2.88–2.76
(m, 2H, H3), 2.71–2.62 (m, 1H, H13a), 2.50–2.42 (m, 1H,
H13b) 2.14–2.02 (m, 2H, H10a and H11a) 2.02–1.89 (m, 2H,
H10b and H11b). 13C NMR (75 MHz, CDCl3) δ=144.6 (Cq,
Car), 139.9 (Cq, Car), 136.2 (Cq, Car), 135.3 (Cq, Car), 133.8 (Cq,
Car), 133.6 (Cq, Car), 132.1 (Cq, Car), 127.9 (CH, Car), 127.7
(CH, Car), 127.6 (CH, Car), 127.6 (CH, Car), 126.5 (CH, Car),
126.0 (CH, Car), 125.2 (CH, Car), 121.6 (CH, Car), 119.5 (CH,
Car), 118.2 (CH, Car), 111.0 (CH, Car), 109.3 (Cq, Car), C 102.3
(CH, C12), 54.4 (CH, C1), 44.4 (CH2, C3), 36.1 (CH2, C13),
35.1 (CH2, C14), 26.0 (CH2, C10), 22.3 (CH2, C11), 22.1 (CH2,
C4). HRMS (ESI) m/z: calc for C27H27N2 [M+H]+ 379.2174,
found 379.2174.
2-(naphthalen-2-ylmethyl)-1-(penta-3,4-dien-1-yl)-2,3,4,9-tetra-
hydro-1H-pyrido[3,4-b]indole 1d: Prepared according to the
general procedure 1 from 2-(1H-indol-3-yl)-N-(naphthalen-2-
ylmethyl)ethan-1-amine (415 mg, 1.38 mmol), hexa-4,5-dienal
(271 mg, 2.76 mmol), (PhO)2PO2H (34 mg, 0.138 mmol) and
3 Å molecular sieves (660 mg) in toluene (19 mL). 1d was
obtained after column chromatography on silica gel (eluent:
Petroleum ether/EtOAc, 90/10) as an oil (428 mg, 1.13 mmol,
82%).
General procedure 3for cyclization and in situ reduction:
The corresponding carboline 1 (1 equiv.) and 3a (5 mol%) were
placed in a Schlenk tube and flushed with cycles of vacuum/
argon (3 times). The DCE was added and the reaction mixture
IR (neat) νmax =3406, 3053, 2935, 2843, 1953, 1685, 1465,
1446, 857, 821, 741 cmÀ 1. 1H NMR (300 MHz, CDCl3) δ=
7.88–7.77 (m, 3H, Har), 7.73 (s, 1H, H15), 7.68 (brs, 1H, H9),
7.61 (dd, J=8.5, 0.5 Hz, 1H, Har), 7.57–7.52 (m, 1H, Har),
7.51–7.43 (m, 2H, Har), 7.36–7.30 (m, 1H, Har), 7.22–7.09 (m,
2H, Har), 5.08 (quint., J=6.6 Hz, 1H, H12), 4.61 (td, J=3.3,
6.7 Hz, 2H, H13), 3.93 (s, 2H, H14), 3.81–3.73 (m, 1H, H1),
3.35–3.22 (m, 1H, H3a), 3.06–2.90 (m, 2H, H3b and H4a),
2.65–2.54 (m, 1H, H4b), 2.28–2.09 (m, 2H, H11), 2.03–1.79
(m, 2H, H10). 13C NMR (75 MHz, CDCl3) δ=208.7 (Cq, Car),
137.5 (Cq, Car), 136.0 (Cq, Car), 135.3 (Cq, Car), 133.5 (Cq, Car),
133.0 (Cq, Car), 128.0 (CH, Car), 127.8 (CH, 2 Car), 127.5 (CH,
2 Car), 127.5 (Cq, Car), 126.1 (CH, Car), 125.7 (CH, Car), 121.6
(CH, Car), 119.5 (CH, Car), 118.2 (CH, Car), 110.8 (CH, Car),
108.1 (Cq, Car), 90.1 (CH, C12), 75.4 (CH2, C13), 57.7 (CH2,
C14), 55.9 (CH, C1), 44.6 (CH2, C3), 33.9 (CH2, C10), 24.7
(CH2, C11), 17.9 (CH2, C4). HRMS (ESI) m/z: calc for
C27H27N2 [M+H]+ 379.2174, found 379.2174.
°
was stirred at 80 C for 4 h. After completion, MeOH was added
°
and the reaction cooled to 0 C. Then NaBH4 (1.1 equiv.) was
°
added and the reaction mixture stirred at 0 C for 1 h. After
completion, the reaction mixture was concentrated under
vacuum. The crude mixture was purified by flash chromatog-
raphy to give the desired product 4.
4-(2-(naphthalen-2-yl)ethyl)-1,2,3,4,6,7,12,12b-octahydroindolo
[2,3-a]quinolizine (4d): Prepared according to the general
procedure 3 from 1d (138 mg, 0.36 mmol) and catalyst 3a
(2.0 mg, 18 μmol), in DCE (3.6 mL), NaBH4 (15.0 mg,
0.40 mmol) and MeOH (3.6 mL), 4d was obtained after column
chromatography on silica gel (eluent: Petroleum ether/EtOAc,
General procedure 2for cyclization: The corresponding
tetrahydro-β-carboline 1 (1 equiv.) and 3a (5 mol%) were
placed in a Schlenk tube and flushed with cycles of vacuum/
argon (3 times). The DCE was added and the reaction mixture
60/40) as an oil (100 mg, 0.26 mmol, 73%). IR (neat) νmax
=
1
3409, 3198, 2932, 1599, 1453, 1264, 816, 732, 700 cmÀ 1. H
NMR (500 MHz, CDCl3) δ=7.85–7.78 (m, 3H, 3 Har), 7.71 (br
s, 1H, H9), 7.68 (s, 1H, H15), 7.51 (d, J=7.6 Hz, 1H, Har),
7.48–7.43 (m, 2H, 2 Har), 7.40 (dd, J=0.9 and 8.2 Hz, 1H, Har),
7.31 (d, J=7.9 Hz, 1H, Har), 7.15 (t, J=7.6 Hz, 1H, Har), 7.11
(t, J=7.3 Hz, 1H, Har), 3.58–5.51 (m, 1H, H3a), 3.49 (d, J=
11.0 Hz, 1H, H1), 3.02–2.93 (m, 2H, H4a and H14a), 2.93–2.84
(m, 1H, H14b), 2.84–2.77 (m, 1H, H4b), 2.59–2.51 (m, 1H,
H22), 2.51–2.41(m, 1H, H3b), 2.15–1.92 (m, 4H, H10a, H11a
and H13), 1.85–1.78 (m, 1H, H12a), 1.75–1.53 (m, 3H, H10b,
H11b and H12b). 13C NMR (125 MHz, CDCl3) δ=140.3 (Cq,
Car), 136.1 (Cq, Car), 135.8 (Cq, Car), 133.7 (Cq, Car), 132.0 (Cq,
Car), 128.0 (CH, Car), 127.7 (CH, Car), 127.6 (Cq, Car), 127.5
(CH, Car), 127.4 (CH, Car), 126.2 (CH, Car), 126.1 (CH, Car),
125.2 (CH, Car), 121.3 (CH, Car), 119.3 (CH, Car), 118.1 (CH,
Car), 110.9 (CH, Car), 108.3 (Cq, Car), 58.1 (CH, C22), 52.7 (CH,
C1), 49.4 (CH2, C3), 33.6 (CH2, C14), 30.2 (CH2, C10), 28.4
(CH2, C13), 28.2 (CH2, C11), 21.1 (CH2, C4), 19.8 (CH2, C12).
HRMS (ESI) m/z: calc for C27H29N2 [M+H]+ 381.2331, found
381.2340.
°
was stirred at 80 C for 4 h. The reaction mixture was filtered
over celite and concentrated under vacuum to give the desired
product 2.
Application to the synthesis of 4-(2-(naphthalen-2-yl)ethyl)-
1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine 2d. Prepared
according to the general procedure 2 from 1d (20 mg,
0.053 mmol) and catalyst 3a (2.0 mg, 2.6 μmol), 2d was
obtained as a crude yellow solid (22 mg, 100% NMR yield) that
was not further purified. NMR data were obtained after a fast
1
purification on silica gel (eluent: PhMe/MTBE gradient): H
NMR (500 MHz, CDCl3) δ=7.83–7.74 (m, 3H, 3Har), 7.65 (s,
1H, H15), 7.50 (d, J=7.6 Hz, 1H, Har) 7.46–7.39 (m, 2H, Har),
7.37 (d, J=8.2 Hz, 1H, H21), 7.34–7.29 (m, 1H, Har) 7.15 (t,
J=7.7 Hz, 1H, Har), 7.10 (t, J=7.1 Hz, 1H, Har), 4.63 (s, 1H,
H12), 4.29 (d, J=8.9 Hz, 1H, H1), 3.44–3.38 (m, 1H, H3a),
General procedure 4for cyclization and in situ hydrolysis
and protection: The corresponding carboline 1 (1 equiv.) and
3a (5 mol%) were placed in a Schlenk tube and flushed with
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cycles of vacuum/argon (3 times). The DCE was added and the
raphy on silica gel (eluent: Petroleum ether/EtOAc, 70/30) to
°
reaction mixture was stirred at 80 C for 4 h. After completion,
give 10d as an oil (28.3 mg, 0.07 mmol, 53%).
°
the reaction cooled to 0 C and HClaq. 1.0 M (2.0 equiv.) was
IR (neat) νmax =3416, 2924, 2845, 2318, 1454, 1265, 819,
added dropwise. After 1 h Et3N (10 equiv.) was added and the
1
734 cmÀ 1. H NMR (500 MHz, CDCl3) δ=7.87–7.80 (m, 3H),
°
reaction mixture stirred at 0 C for 5 min. Then Boc2O
7.77 (brs 1H), 7.67 (s, 1H), 7.53–7.44 (m, 3H), 7.38–7.33 (m,
2H), 7.18 (t, J=7.6 Hz, 1H), 7.13 (t, J=7.5 Hz, 1H), 3.86 (d,
J=11.5 Hz, 1H), 3.51 (dd, J=5.1, 11.6 Hz, 1H), 3.06–2.90 (m,
3H), 2.85–2.79 (m, 1H), 2.62 (dt, J=3.8, 11.7 Hz, 1H), 2.45
(ddd, J=5.2, 12.1, 14.0 Hz, 1H), 2.32 (ddd, J=5.1, 12.0,
14.2 Hz, 1H), 2.16 (d, J=12.3 Hz, 1H), 2.10 (d, J=12.1 Hz,
1H), 2.02–1.87 (m, 3H), 1.61 (dq, J=4.8, 12.2 Hz, 1H). 13C
NMR (75 MHz, CDCl3) δ=138.4 (Cq), 136.3 (Cq), 134.6 (Cq),
133.8 (Cq), 132.8 (Cq), 128.5 (CH), 127.8 (CH), 127.6 (CH),
127.2 (Cq), 127.1 (CH), 126.5 (CH), 126.3 (CH), 125.6 (CH),
121.8 (CH), 119.8 (CH), 119.0 (Cq), 118.3 (CH), 111.0 (CH),
108.4 (Cq), 61.2 (Cq), 56.8 (CH), 45.5 (CH2), 40.2 (CH2), 34.6
(CH2), 30.0 (CH2), 29.4 (CH2), 22.1 (CH2), 21.3 (CH2). HRMS
(ESI) m/z: calc for C28H28N3 [M+H]+ 406.2283, found
406.2285.
(1.5 equiv.) was added and the reaction mixture was allowed to
warn up to room temperature and was further stirred for 3 h.
After completion, the layers were separated, the aqueous phase
was extracted with EtOAc (2x). The combined organics phases
were dried over MgSO4 and concentrated under vacuum. The
crude mixture was purified by flash chromatography to give the
desired product 5. The NMR spectra of these compounds
present the characteristic signals of rotamers.
tert-butyl 1-(6-(naphthalen-2-yl)-4-oxohexyl)-1,3,4,9-tetrahy-
dro-2H-pyrido[3,4-b]indole-2-carboxylate (5d): Prepared ac-
Acknowledgements
cording to the general procedure
4 from 1d (107 mg,
0.28 mmol) and catalyst 3a (10.9 mg, 14 μmol), in DCE
(2.8 mL), HClaq. 1.0 M (560 μL, 0.56 mmol), Et3N (393 μL,
2.82 mmol) and Boc2O (92 mg, 0.42 mmol) 5d was obtained
after column chromatography on silica gel (eluent: Petroleum
ether/EtOAc, 80/20) as an oil (110 mg, 0.26 mmol, 79%). IR
(neat) νmax =3320, 2972, 2934,1684, 1663, 1414, 1159, 1031,
733, 701 cmÀ 1.1H NMR (500 MHz, CDCl3) δ=8.36 and 8.06
(m, 1H), 7.82–7.78 (m, 1H),7.78–7.73 (m, 2H), 7.61 (s, 1H),
7.49–7.41 (m, 3H), 7.31 (d, J=7.8 Hz, 2H), 7.16 (t, J=7.0 Hz,
1H), 7.10 (t, J=7.4 Hz, 1H), 5.39–5.03 (m, 1H), 4.55–4.21 (m,
1H), 3.19–2.97 (m, 3H), 2.93–2.71 (m, 3H), 2.69–2.61 (m, 1H),
2.56–2.37 (m, 2H), 1.85–1.67 (m, 4H), 1.50 (s, 9H). 13C NMR
(125 MHz, CDCl3) δ=210.4 (Cq), 154.4 (Cq), 138.6 (Cq), 136.1
(Cq), 134.7 (Cq), 133.7 (Cq), 132.2 (Cq), 128.2 (CH), 127.8 (Cq),
127.7 (CH), 127.6 (CH), 127.2 (CH), 127.0 (Cq), 126.6 (CH),
126.2 (CH), 125.5 (CH),121.8 (CH), 119.5 (CH), 118.1 (CH),
111.7 (CH), 111.1 (CH), 80.1 (Cq), 51.3 and 50.3 (CH), 44.2
(CH2), 42.7 and 42.5 (CH2), 38.9 and 37.7 (CH2), 34.6 and 34.1
(CH2), 30.1 (CH2), 28.6 (CH3), 21.6 and 21.3 (CH2), 20.3
(CH2). HRMS (ESI) m/z: calc for C32H37N2O3 [M+H]+
497.2804, found 497.2813.
Pierre Milcendeau thanks the CHARMMMAT Laboratory of
Excellence (ANR-11-LABX0039) and the Université Paris-
Saclay for financial support. This work was granted access to
the HPC resources of CINES under the allocation 2020-
A0070810977 made by GENCI. We thank Valérian Gobé for his
contribution to the very early experiments of this project.
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Gold-Catalyzed Carboamination of Allenes by Tertiary
Amines Proceeding with Benzylic Group Migration
Adv. Synth. Catal. 2021, 363, 1–11
P. Milcendeau, V. Gandon*, X. Guinchard*