Enhancement of 5-aminopenta-2,4-dienals electrophilicity via activation by O,N-bistrifluoroacetylation. Application to an N-acyl Pictet-Spengler reaction

Article abstract of DOI:10.1021/jo9019545

(Chemical Equation Presented) Aminopentadienals resulting from the condensation of tryptamine or homoveratrylamine with glutaconaldehydes were treated with trifluoroacetic anhydride, allowing the formation of tetrahydro-β-carbolines and tetrahydroisoquino

Full text of DOI:10.1021/jo9019545

pubs.acs.org/joc
Enhancement of 5-Aminopenta-2,4-dienals Electrophilicity via Activation
by O,N-Bistrifluoroacetylation. Application to an N-Acyl
Pictet-Spengler Reaction†
Philippe Nuhant,*,‡ Sanjay B. Raikar, Jean-Charles Wypych, Bernard Delpech,* and
Christian Marazano§
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse,
91198 Gif-sur-Yvette Cedex, France. ‡Present address: The Scripps Research Institute, Scripps Florida,
130 Scripps Way #A, Jupiter, FL 33458. §Deceased November 12, 2008.
pnuhant@scripps.edu; bernard.delpech@icsn.cnrs-gif.fr
Received September 11, 2009
Aminopentadienals resulting from the condensation of tryptamine or homoveratrylamine with glutaco-
naldehydes were treated with trifluoroacetic anhydride, allowing the formation of tetrahydro-β-carbolines
and tetrahydroisoquinolines bearing an enal function. In this N-acyl Pictet-Spengler reaction the electro-
philicity of the aminopentadienals was dramatically increased by O,N-bistrifluoroacetylation. Recovery of
the nitrogen nucleophilicity was achieved using a reductive process, and the heterocyclic amines were
converted into aminonitriles by a Strecker reaction in the presence of butanal. Cyclization, by intramolecular
Michael addition of the in situ generated enamines onto the enal moiety, was achieved in the presence of zinc
triflate and involved cyanide ion trapping. In this manner, compounds related to protoemetine and
dihydrocorynantheal were obtained, and a reduction step led to a short synthesis of (()-protoemetinol.
Introduction
However, aminopentadienals such as 1, which are bisviny-
logous formamides and donor-acceptor dienes, also have
electrophilic sites located at positions 1, 3, and 5. The difference,
from an electronic point of view, between these centers and the
nucleophilic carbons C-2 and C-4 is evident from the values of
the corresponding chemical shifts in the 13C NMR spectrum.
Our interest in the 5-alkylaminopenta-2,4-dienals1 arose
from the idea that manzamine alkaloids might originate
from a biosynthetic pathway involving these species.2 In this
context, the nucleophilicity of both nitrogen and carbon C-4
of aminopentadienal 1 was exploited some years ago in our
laboratory in its reaction with a 2,3-dihydropyridinium salt.3
† This article is dedicated with respect to the memory of Christian Marazano to
pay tribute to his contribution to the development of the Zincke reaction and of 5-
aminopenta-2,4-dienal chemistry for biomimetic approaches to marine alkaloids.
(1) (a) For a review on aminopentadienals, see: Becher, J. Synthesis 1980,
589–612. For recent work concerning aminopentadienal pericyclic reactions,
see: (b) Steinhardt, S. E.; Silverston, J. S.; Vanderwal, C. D. J. Am. Chem.
Soc. 2008, 130, 7560–7561. (c) Steinhardt, S. E.; Vanderwal, C. D. J. Am.
Chem. Soc. 2009, 131, 7546–7547.
(2) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano, C.; Das, B. C. J.
Am. Chem. Soc. 1998, 120, 8026–8034.
(3) Jakubowicz, K.; Ben Abdeljelil, K.; Herdemann, M.; Martin, M.-T.;
Gateau-Olesker, A.; Al Mourabit, A.; Marazano, C.; Das, B. C. J. Org.
Chem. 1999, 64, 7381–7387.
The electrophilic character of N,N-disubstituted aminopenta-
dienals (Zincke aldehydes), especially at C-1, was earlier shown
DOI: 10.1021/jo9019545
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Published on Web 11/19/2009
J. Org. Chem. 2009, 74, 9413–9421 9413
2009 American Chemical Society

Nuhant et al.
JOCArticle
SCHEME 1. Rearrangement Occuring during Acetylation of
Aminal 2
CDCl3, with monitoring by 1H NMR spectroscopy, was
examined, and no change was observed at room tempera-
ture. Only heating to reflux for several hours led to the
disappearance of the signals corresponding to 1 with the
formation of a complex mixture of presumed isomers of O,
N-diacetylated products. With trifluoroacetic anhydride as
an acylating agent, the transformation was very fast at room
temperature, the presence of diacylated species being sus-
pected (vide infra). Therefore, TFAA was chosen to increase
the electrophilicity of aminopentadienals to promote the
intramolecular additions of nucleophiles onto the activated
intermediates, with the initial goal of achieving an N-acyl
Pictet-Spengler reaction.10,11
With this aim in mind, the aminopentadienal 4 derived
from tryptamine was prepared using 2-methylglutaconalde-
hyde potassium salt in the presence of trifluoroacetic acid
(Scheme 2).6 Reaction of 4 with TFAA was first tested in
CDCl3, in order to monitor it by 1H NMR spectroscopy, and
the formation of compounds probably corresponding to
structure 8 was noted. Subsequent basic hydrolysis led to
the isolation of the N-acylated tetrahydro-β-carboline 5 with
an enal function and as the exclusive (E) isomer. It is
interesting to note that the yield of 5 was only 47% when
1 equiv of anhydride was used but reached 82% with 2 equiv,
suggesting that a diacylated species such as 7, with an
N-acyliminium moiety, is involved in the Pictet-Spengler-
type reaction.12,13 It is likely that O-trifluoroacetylation of 4
is the first step, with the imino compound (6) undergoing
subsequent rapid acylation.
The reaction with 4 was therefore conducted using 2 equiv
of TFAAand in CH2Cl2 as a solvent. The same procedure was
applied to the aminopentadienal 9 obtained with 80% yield
from tryptamine and glutaconaldehyde sodium salt.1a,14 Basic
hydrolysis of the enol esters led to the tetrahydro-β-carbolines
5 and 10 with, respectively, 87% and 58% yields (Scheme3). It
should be noted that the conjugation of the olefin with the
carbonyl group was observed during this process with forma-
tion of the (E) isomer only.
in condensation reactions with some nucleophilic reagents.4
Very recently, Vanderwal reported an annelation reaction
involving an intramolecular anionic cyclization onto the carbon
C-5 of an aminopentadienal.5
In a study related to a biomimetic approach toward
manzamine alkaloids, a rearrangement was observed during
acetylation of the bicyclic aminal 2.6 This sequence might
imply the intramolecular addition of an enamine onto an N,
O-diacetylated aminopentadienal (see intermediate 3) as
illustrated in Scheme 1.6
These results prompted us to examine the possibility of
increasing aminopentadienal electrophilicity by acylation
and thereby of broadening the scope of their reactivity.
The activation of Zincke aldehydes with phosphorus oxy-
chloride, for a Vilsmeier-Haack-type reaction, has been
reported by Jutz.7 O-Acylation of these aldehydes, leading to
very reactive electrophilic compounds, was also described by
€
8
Krohnke and co-workers. Starting from 5-(dialkylamino)-
penta-2,4-dien-1-ones, O-activation and subsequent treatment
by nucleophiles were used for the synthesis of pentamethine
derivatives.9 Very recently, 5-arylaminopenta-2,4-dienals were
transformed into aminopentadieneiminiums via silylation.9c
However, to the best of our knowledge, activation of N-mono-
substituted aminopentadienals by acylation has not been
reported. Our results in this area and their application in the
context of the Pictet-Spengler reaction are presented here.10
Aminopentadienals 11 and 12, readily prepared from
homoveratrylamine, led in the same conditions to the
tetrahydroisoquinolines 13 and 14 with 78% and 62%
yields, respectively. It should be emphasized that, for both
series, the reaction was less efficient with the unsubstituted
dienal moiety. This is a general problem with amino-
pentadienals without a substituent at C-2, which are more
prone to cyclization to pyridiniums salts under acidic
conditions.
Results and Discussion
Acylation of 5-Alkylaminopenta-2,4-dienals and the N-Acyl
Pictet-Spengler Reaction. The behavior of the aminopenta-
dienal 1 in the presence of an excess of acetic anhydride in
This new use of aminopentadienals with a Pictet-Spengler-
type reactivity supplements Vanderwal’s recent work in the
indole field.5
(4) (a) Jutz, C. Chem. Ber. 1958, 91, 1867–1880. (b) Malhotra, S. S.;
Whiting, M. C. J. Chem. Soc. 1960, 3812–3822. (c) Grewe, R.; von Bonin, W.
€
Chem. Ber. 1961, 94, 234–241. (d) Kobrich, G.; Breckoff, W. E. Liebigs Ann.
Chem. 1967, 704, 42–50. (e) Michels, T. D.; Rhee, J. U.; Vanderwal, C. D.
Org. Lett. 2008, 10, 4787–4790.
(5) Martin, D. B. C.; Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131,
3472–3473.
ꢀ ꢀ
(6) Wypych, J.-C.; Nguyen, T. M.; Nuhant, P.; Benechie, M.; Marazano,
C. Angew. Chem., Int. Ed. 2008, 47, 5418–5421.
(7) Jutz, C. Chem. Ber. 1958, 91, 850–861.
(11) For reviews, see: (a) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431–1628. (b) Royer,
J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311–2352.
(12) In an attempt to realize a Diels-Alder reaction with a Zincke
aldehyde derived from tryptamine, with catalysis by Bronsted or Lewis
acids, Vanderwal recently raised the possibility of Pictet-Spengler-like
reactivity, but no details were reported (see ref 5).
ꢀ
€
(8) (a) Dickore, K.; Krohnke, F. Chem. Ber. 1960, 93, 1068–1074. (b)
€
(13) The behavior reported here is reminiscent of Pictet-Spengler reac-
tions observed with N-acylated enaminoketones, in the presence of Brønsted
or Lewis acids, or by treatment of a 2-(3-acetamidoallylidene)malonate with
Nordmann, H. G.; Krohnke, F. Liebigs Ann. Chem. 1970, 731, 80–90.
€
(9) (a) Jutz, C.; Wagner, R.-M.; Kraatz, A.; Lobering, H.-G. Liebigs Ann.
Chem. 1975, 874–900. (b) Voitenko, Z.; Mazieres, M. R.; Sanchez, M.; Wolf,
ꢁ
BF3 Et2O, see: (a) Tietze, L. F.; Schimpf, R.; Wichmann, J. Chem. Ber. 1992,
125, 2571–2576. (b) Rosenmund, P.; Hosseini-Merescht, M.; Bub, C. Liebigs
Ann. Chem. 1994, 151–158.
3
J. G. Tetrahedron 2001, 57, 1059–1066. (c) Korinek, M.; Rybackova, M.;
€
Bohm, S. Synthesis 2009, 1291–1296.
(10) For reviews, see: (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95,
1797–1842. (b) Youn, S. W. Org. Prep. Process Int. 2006, 38, 505–591.
(14) Becher, J. Organic Synthesis; Wiley: New York, 1988; Collect. Vol.
VI, pp 640-644.
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SCHEME 2. Formation of Aminopentadienal 4 and Its Reaction with TFAA
SCHEME 3. N-Acyl Pictet-Spengler Reaction by Treatment of Tryptamine and Homoveratrylamine Derived Aminopentadienals with
TFAA
SCHEME 4. Retrosynthetic Scheme for Protoemetinol (15)
Application to Syntheses of Protoemetinol and of Tetrahy-
droisoquinoline and Indole Alkaloids Homologues. As the
Pictet-Spengler reaction is a useful transformation for the
synthesis of indole and tetrahydroisoquinoline alkaloids,10
an application of the present methodology to this field was
envisioned. Initially the construction of (()-protoemetinol
(15),15 which is a pivotal intermediate in total syntheses of
emetine and related biologically active alkaloids, was cho-
sen.16 Thus, it was considered that compound 14 might be a
precursor for C-ring formation, possibly by an intramole-
cular Michael addition of an enamine onto the enal moiety of
16 (Scheme 4).
(15) (a) For isolation of (-)-protoemetinol, see: Battersby, A. R.; Kapil,
R. S.; Bhakuni, D. S.; Popli, S. P.; Merchant, J. R.; Salgar, S. S. Tetrahedron
Lett. 1966, 4965–4971. (b) For a recent total synthesis of (()-protoemetinol,
see: Chang, J.-K.; Chang, B.-R.; Chuang, Y.-H.; Chang, N.-C. Tetrahedron
2008, 64, 9685–9688.
(16) For reviews, see : (a) Fujii, T.; Ohba, M. In The Alkaloids; Cordell, G.
A., Ed.; Academic Press: New York, 1998; Vol. 51, pp 271-321. (b) The
Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1983; Vol. 22, pp
1-50. For selected syntheses, see: (c) Hirai, Y.; Terada, T.; Hagiwara, A.;
Yamazaki, T. Chem. Pharm. Bull. 1988, 36, 1343–1350. (d) Fujii, T.; Ohba,
M.; Yoshifuji, S. Heterocycles 1988, 27, 1009–1033. (e) Ihara, M.; Yasui, K.;
Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1990, 1469–1476.
(f) Takacs, J. M.; Boito, S. C. Tetrahedron Lett. 1995, 36, 2941–2944. (g) Tietze,
L. F.; Rackelmann, N.; M€uller, I. Chem.-Eur. J. 2004, 10, 2722–2731. (h) Itoh,
T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1295–
1297.
To avoid a vinylogous retro-Michael reaction, under basic
conditions, or the liberation of the secondary amine in the
presence of the enal function, a reductive procedure was used
for the removal of the trifluoroacetyl moiety.17 A protected
(17) Weygang, F.; Frauendorfer, E. Chem. Ber. 1970, 103, 2437–2449.
J. Org. Chem. Vol. 74, No. 24, 2009 9415

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SCHEME 5. Access to Protoemetinol via Intramolecular Michael Addition
form of the labile open-chain enamine was introduced before
restoring the correct oxidation level. This goal was achieved
by the formation of an aminonitrile via a Strecker reaction.
Transformation of the allylic alcohol 18 into the enal 19
was problematic, but use of the Dess-Martin periodinane in
the presence of NaHCO3 proved to be a good solution. To
the best of our knowledge, no Michael-type addition invol-
ving an enal and an open chain aminonitrile has been
described.18,19 In the case of the desired reaction, in which
the sensitive enamine 16 might be an intermediate, a Lewis
acid could also increase the enal electrophilicity by oxygen
coordination. A method was therefore developed for the
gradual generation of the enamine and the achievement of
the 1,4-addition. It was found that the treatment of 19 with
0.5 equiv of Zn(OTf)2, in the presence of NaHCO3 (a complex
mixture was obtained without base) and in refluxing CDCl3,
led to cyclization with trapping of the intermediate iminium
salt, by the cyanide ion, as an aminonitrile (1H NMR spectro-
scopic assessment).20 However, the product was not stable in
these conditions and could not be isolated; therefore, both the
aldehyde and the masked iminium functions were reduced by
the addition of methanol and NaBH4 (Scheme 5).
Following this procedure, a concise synthesis of (()-
protoemetinol (15)15b and its C-3 epimer (20)21 was estab-
lished, albeit with a moderate 28% overall yield, which is
attributed to the low stability of the intermediates. However,
15 was the major product and its 1H and 13C NMR spectral
data fit well with the values reported recently for this
compound.15b The stereochemistry of 20 was deduced from
its 13C NMR spectra by the upfield shift, relative to 15, of C-1
and C-12, due to the γ-effect of the axial ethyl group.22 The
formation of C-ring is considered to proceed via the transi-
tion states ii or iii (rather than i) or by equilibration of
iminium ions involving B-ring opening.23 The position of the
ethyl group (equatorial for 15 and axial for 20) can be
considered as resulting from reduction of the iminium ions
obtained by cyclization via ii and iii, respectively, or after
their epimerization via the enamine 21.
Other conditions aimed at transforming the aminonitrile
19 into the enamine 16 (via an iminium ion), such as treat-
ment with AgBF4,24 TMSOTf,25 BF3 Et2O26 or alumina,27
3
were unsuccessful.28
If the methyl at C-2 of the aminopentadienal has a
beneficial effect on the yield of the Pictet-Spengler reaction
(see Scheme 3), its influence is also positive for the cyclization
by Michael addition, as illustrated by the synthesis of
homologues of 4-cyano-protoemetine from the tetrahydroi-
soquinoline 13 (Scheme 6). It should be noted that, in a
sequence that is analogous to those depicted in Scheme 5,
addition of NaHCO3 was not necessary either for the oxida-
tion step or for the treatment of the aminonitrile 25 with
Zn(OTf)2. Here, unlike the reaction with 19, the tricyclic
aminonitrile 26 could be isolated. Moreover, only two
epimers, differing in the relative position of the methyl on
the oxoethyl side chain, were obtained, although five stereo-
genic centers are present in the molecule.
(18) An intermolecular Michael-type addition, involving a cyclic enam-
ine, protected as an aminonitrile, and methyl vinyl ketone has been reported:
Mitch, C. H. Tetrahedron Lett. 1988, 29, 6831–6834.
(19) A related enantioselective organocatalytic intramolecular Michael
addition involving an enal was reported recently, but only for the case of the
relatively unreactive enamine of indoles: (a) Li, C.-F.; Liu, H.; Liao, J.; Cao,
Y.-J.; Liu, X.-P.; Xiao, W.-J. Org. Lett. 2007, 9, 1847–1850. (b) For a recent
€
review on iminium catalysis, see: Erkkila, A.; Majander, I.; Pihko, P. M.
Chem. Rev. 2007, 107, 5416–5470.
(23) Takano, S.; Hatakeyama, S.; Takahashi, Y.; Ogasawara, K. Hetero-
cycles 1982, 17, 263–284.
(20) Baldwin showed that the use of zinc bromide allowed the in situ
formation of a 2,3-dihydropyridinium from the corresponding aminonitrile
and that the cyanide ion, released in that process, was reintroduced in the
product structure after a Diels-Alder reaction: Baldwin, J. E.; Spring, D. R.;
Whitehead, R. C. Tetrahedron Lett. 1998, 39, 5417–5420.
(21) Kametani, T.; Suzuki, Y.; Terasawa, H.; Ihara, M. J. Chem. Soc.,
Perkin Trans. 1 1979, 1211–1217.
(24) Kempe, U. M.; Das Gupta, T. K.; Blatt, K.; Gygax, P.; Felix, D.;
Eschenmoser, A. Helv. Chim. Acta 1972, 55, 2187–2198.
(25) Yue, C.; Royer, J.; Husson, H.-P. J. Org. Chem. 1992, 57, 4211–4214.
(26) Koskinen, A.; Lounasmaa, M. J. Chem. Soc., Chem. Commun. 1983,
821–822.
ꢁ
(27) (a) Bonin, M.; Besselievre, R.; Grierson, D. S.; Husson, H.-P.
Tetrahedron Lett. 1983, 24, 1493–1496. (b) Bonin, M.; Royer, J.; Grierson,
D. S.; Husson, H.-P. Tetrahedron Lett. 1986, 27, 1569–1572.
(22) Reimann, E.; Renz, M. Monatsh. Chem. 2007, 138, 211–218.
9416 J. Org. Chem. Vol. 74, No. 24, 2009

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SCHEME 6. Access to Homologues of 4-Cyano-protoemetine
13C NMR spectroscopy is the method of choice for structural
analysis of these compound types, and it is clear from NMR
analysis that the relative configurations at C-11b, C-2, C-3, and
C-4 are the same for the two compounds. The chemical shifts
for C-2 (δc 21.7 and 22.5) and the coupling constants for H-4
(J = 4.4 Hz) indicate an equatorial position for the ethyl
group22 and a cis relationship for H-3 and H-4 and, therefore,
an axial cyano group.30 In the case of the major compound, the
coupling constants between H-2 and H-1ax and H-3 (12 Hz for
both) showed a trans-diaxial relationship for these hydrogens,
and therefore an equatorial position for the 1-oxopropan-2-yl
group. The values of δc for C-11b being very close for both
major and minor products (57.0 and 57.3, respectively), the
position of the 1-oxopropan-2-yl group on C-ring is the same
for the two compounds.22 The relative stereochemistry of the
C-ring is then the same as that of protoemetine. However, the
configuration R to the carbonyl could not be determined.
The stereochemical outcome of the reaction might be
attributed to a thermodynamically controlled process
(equatorial ethyl and axial cyano groups), via an iminium-
enamine equilibrium, with the relative configurations at
C-11b and C-2 involving a transition state analogous to ii.
The axial configuration for the cyano group is in accordance
with a stabilizing anomeric-like effect.31
The aforementioned sequence could be applied in the
indole series, starting from compound 5, to give the homo-
logues of 21-cyano-18,19-dihydrocorynantheal (28) (Scheme
7). In this case, the oxidation step was less efficient (42%
yield), probably due to competitive indole participation, but
as previously, only two epimers (28) were obtained after the
Michael-type addition, which also proceeded with a lower
yield (53%). Equilibration during the latter process is likely
1
since four isomeric enals were detected by H NMR spec-
troscopy after the Strecker reaction. The rationale developed
for determining the relative configuration of aminonitriles 26
was also applied for 28.32 It is noteworthy that the major
product has the same relative stereochemistry at C-3, C-15,
and C-20 as that of corynantheal.33
The methodology reported here could be extended to the
synthesis of alkaloids such as dihydroisoalangine34 or 3-epi-
antirhine.35 It is also possible to envision the formation of
the D- and E-rings of yohimbine and corynantheine deriva-
tives,36 starting from the Pictet-Spengler products, with the
Michael addition procedure or using other methods.37
(28) An attempt to improve the effectiveness of the Michael addition was
made using the more stable R,β-unsaturated ester 22, which was readily
prepared by Corey oxidation-esterification ( Corey, E. J.; Gilman, N. W.;
Ganem, B. E. J. Am. Chem. Soc. 1968, 90, 5616–5617. ) of enal 19. However,
heating 22 in CDCl3 in the presence of Zn(OTf)2 did not lead to the desired
cyclization, owing perhaps to the intervention of a cationic 2-aza-Cope [3,3]
sigmatropic rearrangement29 involving iv (signals corresponding to the vinyl
and to the iminium moieties of v in the 1H NMR spectrum of the reaction
mixture).
Conclusions
The scope of 5-alkylaminopenta-2,4-dienals reactivity has
been broadened by increasing their electrophilicity via acyla-
tion with TFAA. O,N-Bistrifluoroacetylation was probably
involved, and the putative N-acyliminium ions were used to
realize N-acyl Pictet-Spengler reactions affording heterocycles
(32) (a) For 13C NMR analysis of indoloquinolizine alkaloids, see:
€
€
Lounasmaa, M.; Hameila, M. Tetrahedron 1978, 34, 437–442. (b) For a
similar stereochemical outcome, see: Putkonen, T.; Valkonen, E.; Tolvanen,
A.; Jokela, R. Tetrahedron 2002, 58, 7869–7873.
(33) (a) For preparation of corynantheal and dihydrocorynantheal from
corynantheine, see: Janot, M.-M.; Goutarel, R. Bull. Soc. Chim. France
1951, 588–602. (b) For a synthesis of (()-corynantheal and (()-dihydrocor-
ynantheal, see: Kametani, T.; Kanaya, N.; Hino, H.; Huang, S.-P.; Ihara, M.
J. Chem. Soc. Perkin Trans 1 1981, 3168–3175.
(34) Itoh, A.; Tanahashi, T.; Tabata, M.; Shikata, M.; Kakite, M.; Nagai,
M.; Nagakura, N. Phytochemistry 2001, 56, 623–630.
(35) Kan-Fan, C.; Brillanceau, M.-H.; Husson, H.-P. J. Nat. Prod. 1986,
49, 1130–1132.
ꢀ
ꢀ
€
(36) Szantay, C.; Blasko, G.; Honty, K.; Dornyei, G. In The Alkaloids;
Brossi, A., Ed.; Academic Press: Orlando, 1986; Vol. 27, pp 131-268.
(37) (a) For a radical cyclization toward geissoschizine, see: Takayama,
H.; Watanabe, F.; Kuroda, A.; Kitajima, M.; Aimi, N. Tetrahedron 2000, 56,
6457–6461. For intramolecular Diels-Alder reactions, see: (b) Martin, S. F.
Acc. Chem. Res. 2002, 35, 895-904 and references therein. (c) Mergott, D. J.;
Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10, 745–748.
(29) Overman, L. E. Acc. Chem. Res. 1992, 25, 352–359.
(30) For 13C NMR of piperidine derived R-aminonitriles, see: Jokela, R.;
Tamminen, T.; Lounasmaa, M. Heterocycles 1985, 23, 1707–1722.
(31) (a) Takahashi, K.; Tachiki, A.; Ogura, K.; Iida, H. Heterocycles
1986, 24, 2835–2840. (b) Bonin, M.; Chiaroni, A.; Riche, C.; Beloeil, J.-C.;
Grierson, D. S.; Husson, H.-P. J. Org. Chem. 1987, 52, 382–385.
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SCHEME 7. Access to Homologues of 21-Cyano-18,19-dihydro-
corynantheal
60/40) afforded 5 (281 mg, 87%) as an orange gum: FTIR 3356,
1
2923, 1678, 1453, 1201, 1174, 1138 cm-1; H NMR (300 MHz,
CDCl3) δ 1.74 (s, 3 H), 2.93 (m, 2 H), 3.00 (m, 2 H), 3.58 (ddd, J =
14.0, 10.0, 6.0 Hz, 1 H), 4.28 (dt, J = 14.0, 2.5 Hz, 1 H), 5.87 (t, J =
7.0 Hz, 1 H), 6.59 (tq, J = 7.5, 1.0 Hz, 1 H), 7.15 (td, J = 8.0,
1.0 Hz, 1 H), 7.23 (td, J = 8.0, 1.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz,
1 H), 7.49 (d, J = 8.0 Hz, 1 H), 8.19 (br s, 1 H), 9.39 (br s, 1 H); 13
C
NMR (75 MHz, CDCl3) δ 9.4, 22.1, 33.9, 41.0, 50.2, 108.4, 111.2,
118.3, 120.2, 122.8, 126.1, 130.6, 136.3, 142.1, 146.8, 194.7 (the
carbons of the trifluoroacetyl group were not detected); HRMS
(ESI) m/z calcd for C18H17F3N2NaO2 (M þ Na)þ 373.1140, found
373.1152.
(2E,4E)-5-(2-(1H-Indol-3-yl)ethylamino)penta-2,4-dienal (9).
This compound was obtained with the procedure described
for the preparation of 4, using glutaconaldehyde sodium salt,14
in 80% yield and as an orange gum: FTIR 3256, 1566, 1557,
1145 cm-1; 1H NMR (500 MHz, CDCl3) δ 3.07 (t, J = 6.5 Hz,
2 H), 3.47 (q, J = 6.5 Hz, 2 H), 4.70 (br s, 1 H), 5.46 (t, J =
12.5 Hz, 1 H), 5.85 (dd, J = 14.0, 8.5 Hz, 1 H), 6.79 (dd, J =
12.5, 9.0 Hz, 1 H), 7.05 (br s, 1 H), 7.07 (dd, J = 14.0, 12.5 Hz,
1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.39 (d,
J = 7.5 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 H), 8.25 (br s, 1 H), 9.30
(d, J = 8.5 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 24.9, 44.5,
98.2, 111.4, 112.0, 118.5, 119.7, 120.9, 122.3, 122.4, 127.1, 136.4,
148.6, 156.5, 192.7; HRMS (ESI) m/z calcd for C15H17N2O
(M þ H)þ 241.1341, found 241.1330.
with an enal function. Another advantage of the trifluoroacetyl
moiety, as an activating group, is its easy removal from oxygen
or nitrogen, allowing further transformations of the cyclized
products. This feature was taken advantage of in an unprece-
dented intramolecular Michael addition of enamines, starting
from their aminonitrile equivalents, onto enals. For the Pic-
tet-Spengler reaction, as well as for the Michael addition,
substitution at position 2 of the aminopentadienal moiety
seems to be an important factor, since the procedures were less
effective with unsubstituted compounds. Sequences combin-
ing these two reactions were applied in a short synthesis of
(()-protoemetinol and to access tetrahydroisoquinoline and
indole alkaloid homologues. The N-acyl Pictet-Spengler reac-
tion reported here could be useful for synthesis in the isoquino-
line or indole alkaloids field. Finally, the aminonitrile moiety,
present in intramolecular Michael addition products, might
allow further functionalization.
(E)-4-(2-(2,2,2-Trifluoroacetyl)-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indol-1-yl)but-2-enal (10). This compound was obtained
using the procedure described for the preparation of 5, starting
from 9, in 58% yield and as an orange gum: FTIR 3362, 2918,
1681, 1453, 1203, 1176, 1141 cm-1; 1H NMR (300 MHz, CDCl3)
δ 2.93 (m, 2 H), 3.00 (m, 2 H), 3.56 (ddd, J = 14.0, 11.0, 5.0 Hz,
1 H), 4.28 (dt, J = 14.0, 2.0 Hz, 1 H), 5.88 (dd, J = 8.5, 5.0 Hz,
1 H), 6.19 (ddt, J = 15.5, 8.0, 1.0 Hz, 1 H), 6.87 (dt, J = 15.5,
8.0 Hz, 1 H), 7.15 (td, J = 8.0, 1.0 Hz, 1 H), 7.23 (td, J = 8.0,
1.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 1 H),
8.13 (br s, 1 H), 9.50 (d, J = 8.0 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 22.1, 37.8, 41.0, 50.1, 108.6, 111.2, 118.4, 120.2, 122.9,
126.2, 130.4, 135.6, 136.3, 151.0, 193.3 (the carbons of the
trifluoroacetyl group were not detected); HRMS (ESI) m/z calcd
for C17H15F3N2NaO2 (M þ Na)þ 359.0983, found 359.0973.
(2E,4E)-5-(3,4-Dimethoxyphenylethylamino)-2-methylpenta-
2,4-dienal (11). To a solution of homoveratrylamine (1.1 mL,
6.52 mmol) in CH2Cl2 (2 mL) at rt was added 2-methylgluta-
conaldehyde potassium salt6 (1.0 g, 6.66 mmol). TFA (513 μL,
6.66 mmol) was added dropwise over a period of 5 min, and the
reaction mixture was stirred for an additional 30 min at rt. The
mixture was diluted by CH2Cl2, washed successively with a
solution of saturated K2CO3 and with brine, dried over
Na2SO4, filtered, and concentrated. The resulting residue was
purified by flash chromatography on silica gel (CH2Cl2/MeOH
95/5) to afford 11 (1.45 g, 80%) as a viscous light yellow colored
oil: FTIR 3600, 1610, 1558, 1515, 1456, 1260, 1235, 1206, 1025,
763, 667, 608 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.72 (s, 3 H),
2.83 (t, J = 7.5 Hz, 2 H), 3.37 (q, J = 6.5 Hz, 2 H), 3.83 (s, 3 H),
3.84 (s, 3 H), 5.08 (br s, 1 H), 5.45 (t, J = 12.5 Hz, 1 H),
6.66-6.75 (m, 2 H), 6.76-6.87 (m, 3 H), 9.11 (s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 8.96, 34.6, 45.6, 55.8, 95.6, 111.3, 111.8,
120.6, 126.4, 130.6, 147.8, 149.0, 153.9, 192.8; HRMS (ESI) m/z
calcd for C16H22NO3 (M þ H)þ 276.1600, found 276.1593.
(E)-4-(6,7-Dimethoxy-2-(2,2,2-trifluoroethanoyl)-1,2,3,4-tetra-
hydroisoquinolin-1-yl)-2-methylbut-2-enal (13). To a solution of
11 (1.37 g, 4.98 mmol) in CH2Cl2 (16 mL) was added TFAA
(1.51 mL, 10.69 mmol) over a period of 5 min at rt. The resulting
solution was stirred for an additional 10 min at rt and quenched
by the addition of 1 N HCl (15 mL). The mixture was stirred for
45 min and quenched by solid K2CO3 until becoming basic, then
diluted by CH2Cl2. The two phases were separated, and the
Experimental Section
(2E,4E)-5-(2-(1H-Indol-3-yl)ethylamino)-2-methylpenta-2,4-
dienal (4). To a solution of 98% tryptamine (500 mg, 3.06 mmol)
in CH3CN (31 mL) at 0 °C was slowly added TFA (236 μL,
3.06 mmol), and the mixture was brought to room temperature.
2-Methylglutaconaldehyde potassium salt6 (482 mg, 3.21 mmol)
was added, and the reaction mixture was stirred for 30 min. The
mixture was taken up in CH2Cl2 and washed successively with
saturated K2CO3 solution and brine, dried over Na2SO4, filtered,
and concentrated. The resulting residue was purified by flash
chromatography on silica gel (CH2Cl2/AcOEt 70/30) to afford 4
(588 mg, 76%) as an orange gum: FTIR 3292, 1568, 1201 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.77 (s, 3 H), 3.07 (t, J = 6.5 Hz,
2 H), 3.48 (q, J = 6.5 Hz, 2 H), 4.87 (br s, 1 H), 5.48 (t, J =
12.5 Hz, 1 H), 6.78 (dd, J = 12.5, 8.0 Hz, 1 H), 6.82 (d, J =
12.5 Hz, 1 H), 7.05 (br s, 1 H), 7.14 (t, J = 7.0 Hz, 1 H), 7.22 (t,
J = 7.0 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.59 (d, J = 8.0 Hz,
1 H), 8.65 (br s, 1 H), 9.17 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ
9.1, 24.9, 44.6, 95.7, 111.5, 111.9, 118.4, 119.4, 122.2, 122.5, 126.4,
127.1, 136.5, 148.1, 154.3, 193.0; HRMS (ESI) m/z calcd for
C16H19N2O (M þ H)þ 255.1497, found 255.1509.
(E)-2-Methyl-4-(2-(2,2,2-trifluoroacetyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indol-1-yl)but-2-enal (5). To a solution of 4 (235 mg,
0.92 mmol) in CH2Cl2 (3 mL) was added TFAA (276 μL,
1.94 mmol) over a period of 5 min at rt. The resulting solution
was stirred for an additional 10 min at rt and quenched by the
addition of 1 N HCl (3 mL). The mixture was stirred for 45 min and
was quenched by solid K2CO3 until becoming basic, then diluted
by CH2Cl2. The two phases were separated, and the organic phase
was washed with brine and dried over Na2SO4. Concentration
followed by flash chromatography on silica gel (heptane/EtOAc
9418 J. Org. Chem. Vol. 74, No. 24, 2009

Nuhant et al.
JOCArticle
organic phase was washed with brine and dried over Na2SO4.
Concentration followed by flash chromatography on silica gel
(heptane/EtOAc 60/40) afforded 13 (1.44 g, 78%) as viscous light
yellow colored oil: FTIR 2939, 1690, 1681, 1611, 1519, 1462,
1256, 1196, 1141, 1116 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.68
(s, 3 H), 2.78 (dt, J = 16.0, 3.8 Hz, 1 H), 2.85-3.05 (m, 3 H,), 3.57
(ddd, J = 14.8, 11.2, 4.2 Hz, 1 H), 3.82 (s, 3 H), 3.84 (s, 3 H), 4.02
(br d, J = 15.0, 1 H), 5.66 (dd, J = 8.3, 5.4 Hz, 1 H), 6.52 (t, J =
7.1 Hz, 1 H), 6.60 (s, 1 H), 6.61 (s, 1 H), 9.36 (s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 9.2, 28.6, 35.7, 40.0, 52.8, 55.9, 56.0, 109.5,
111.2, 116.3 (q, J = 286.6 Hz), 124.8, 126.1, 141.3, 147.9, 148.1,
148.4, 156.2 (q, J = 34.6 Hz), 194.6; HRMS (ESI) m/z calcd for
C18H20F3NNaO4 (M þ Na)þ 394.1242, found 394.1234.
by flash chromatography on neutral alumina (heptane/EtOAc
50/50) to afford 18 (557 mg, 87%) as a viscous colorless oil. Only
the major product is described by 1H and 13C NMR: FTIR 3480,
2931, 1609, 1513, 1462, 1355, 1252, 1224, 1113, 1007, 973, 858,
1
732 cm-1; H NMR (300 MHz, CDCl3) δ 0.98 (t, J = 7.3 Hz,
3 H), 1.49 (sextet, J = 7.4 Hz, 2 H), 1.75-1.88 (m, 2 H),
2.49-2.57 (m, 2 H), 2.58-2.70 (m, 3 H), 3.08 (dt, J = 10.8,
4.6 Hz, 1 H), 3.84-3.87 (m, overlapping s at 3.84 and 3.85, 8 H),
3.98 (br t, J = 5.0 Hz, 2 H), 5.45-5.59 (m, 2 H), 6.56 (s, 1 H), 6.57
(s, 1 H); 13C NMR (75 MHz, CDCl3) δ 13.5, 19.2, 29.0, 33.5, 38.9,
42.7, 53.9, 55.8, 56.0, 60.6, 63.3, 109.9, 110.8, 118.4, 127.3, 128.3,
128.5, 131.5, 147.2 (2C); HRMS (ESI) m/z calcd for C20H28-
N2NaO3 (M þ Na)þ 367.1998, found 367.1996.
(2E,4E)-5-(3,4-Dimethoxyphenylethylamino)penta-2,4-dienal
(12). This compound was obtained using the procedure described
for the preparation of 11, using glutaconaldehyde sodium salt,14
in 80% yield and as an orange gum: FTIR 3420, 1608, 1557, 1514,
1260, 1140, 1024, 763 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.81
(t, J = 7.1 Hz, 2 H), 3.34 (q, J = 7.0 Hz, 2 H), 3.83 (s, 3 H), 3.84
(s, 3 H), 5.17-5.29 (br s, 1 H), 5.43 (t, J = 11.8 Hz, 1 H), 5.79 (dd,
J = 14.2, 8.3 Hz, 1 H), 6.66-6.86 (m, 4 H), 7.06 (dd, J = 14.1,
12.2 Hz, 1 H), 9.22 (d, J = 8.2 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 34.6, 45.6, 55.78, 55.82, 97.9, 111.4, 111.8, 120.2, 120.6,
130.4, 147.8, 149.0, 149.0, 157.0, 192.5; HRMS (ESI) m/z calcd
for C15H20NO3 (M þ H)þ 262.1443, found 262.1437.
(E)-2-(6,7-Dimethoxy-1-(4-oxobut-2-enyl)-3,4-dihydroisoqui-
nolin-2(1H)-yl)pentanenitrile (19). To a solution of 18 (163 mg,
0.47 mmol) in CH2Cl2 (0.5 mL) was added NaHCO3 (400 mg,
4.76 mmol) followed by the addition of Dess-Martin period-
inane (15% solution in CH2Cl2, 1.97 mL, 0.95 mmol) dropwise
over a period of 5 min. The mixture was stirred for 10 min and
quenched by the addition of a saturated solution of NaHCO3
(26 mL), a saturated solution of Na2S2O3 (26 mL), and ether
(52 mL). The mixture was stirred for 45 min whereupon the
initially formed precipitate dissolved and the phases became
clear. The two phases were separated, and the organic layer was
washed with brine, dried over Na2SO4, filtered, and concen-
trated to afford 19 (151 mg, 93%) as a viscous colorless oil:
FTIR 2958, 1685, 1610, 1514, 1463, 1250, 1222, 1136, 1113,
1025, 981, 862 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.96 (t, J =
8.0 Hz, 3 H), 1.46 (sextet, J = 7.3 Hz, 2 H), 1.72-1.90 (m, 2 H),
2.66 (td, J = 10.9, 4.0 Hz, 1 H), 2.64-2.87 (m, 4 H,), 3.09 (dt,
J = 10.8, 4.0 Hz, 1 H), 3.81 (t, J = 8.0 Hz, 1 H), 3.83 (s, 3 H),
3.85 (s, 3 H), 4.06 (br t, J = 4.0 Hz, 1 H), 6.00 (dd, J = 15.4,
7.8 Hz, 1 H), 6.49-6.63 (m, overlapping s at 6.55 and 6.57, 3 H),
9.34 (d, J = 7.8 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 13.4,
19.2, 28.5, 33.4, 38.3, 42.5, 53.8, 55.8, 56.0, 60.0, 109.5, 111.0,
118.0, 127.1, 127.9, 134.7, 147.7 (2C), 154.2, 193.4; HRMS
(ESI) m/z calcd for C20H26N2NaO3 (M þ Na)þ 365.1841, found
365.1848.
(E)-4-(6,7-Dimethoxy-2-(2,2,2-trifluoroethanoyl)-1,2,3,4-tetra-
hydroisoquinolin-1-yl)but-2-enal (14). This compound was ob-
tained using the procedure described for the preparation of 13,
starting from 12, in 62% yield and as a yellow gum: FTIR 2938,
1
1681, 1611, 1518, 1462, 1252, 1194, 1173, 1115, 1137 cm-1; H
NMR (300 MHz, CDCl3) δ 2.78 (dt, J = 15.9, 3.2 Hz, 1 H),
2.84-3.06 (m, 3 H), 3.54 (ddd, J = 15.9, 12.0, 4.4 Hz, 1 H), 3.85
(s, 6 H), 4.05 (br d, J = 15.8, 1 H), 5.68 (dd, J = 9.0, 5.1 Hz, 1 H),
6.10 (dd, J = 15.6, 7.8 Hz, 1 H), 6.61 (s, 2 H), 6.82 (ddd, J = 15.4,
8.1, 6.7 Hz, 1 H), 9.49 (d, J = 7.7 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 28.5, 39.8 (2C), 52.5, 55.9, 56.0, 109.4, 111.3, 116.3 (q,
J = 289.0 Hz), 124.7, 125.9, 135.2, 148.2, 148.5, 151.9, 156.3 (q,
J = 35.3Hz), 193.2; HRMS(ESI)m/z calcdfor C17H18F3NNaO4
(M þ Na)þ 380.1086, found 380.1034.
(()-Protoemetinol (15) and (()-3-epi-Protoemetinol (20). To a
solution of 19 (427 mg, 1.24 mmol) in CDCl3 (4.1 mL) were added
NaHCO3 (1.04 g, 12.4 mmol) and 98% Zn(OTf)2 (230 mg,
0.62 mmol). The mixture was heated at 70 °C for 1 h (reaction
monitored by NMR) and then cooled to room temperature.
MeOH (2 mL) and 96% NaBH4 (122 mg, 3.10 mmol) were
added, and the mixture was heated at 70 °C for 1 h. The mixture
was cooled again to room temperature, washed with saturated
K2CO3 solution, driedover Na2SO4, andconcentrated. Thecrude
residue was flash chromatographed on silica gel (acetone/EtOAc/
heptane 5/3/2) to afford 15 (70 mg, 17.6%) and 20 (41 mg, 10.4%)
as viscous colorless oils. 15: FTIR 3344, 2932, 1512, 1463, 1253,
1228 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, J = 7.0 Hz,
3 H), 1,12 (m, 1 H), 1.25 (m, 1 H), 1.43 (m, 2 H), 1.67 (m, 1 H),
1.94 (m, 2 H), 2.01 (t, J =11.0Hz, 1 H), 2.33 (dt, J = 13.0, 3.0 Hz,
1 H), 2.47 (td, J = 11.5, 4.0Hz, 1 H), 2.61 (br dd, J = 16.0, 4.0Hz,
1 H), 2.96 (ddd, J = 11.5, 6.0, 1.5 Hz, 1 H), 3.06 (m, 2 H), 3.10
(ddd, J = 16.0, 11.0, 6.0 Hz, 1 H), 3.75 (t, J = 7.0 Hz, 2 H), 3.83
(s, 3 H), 3.84 (s, 3 H), 6.56 (s, 1 H), 6.68 (s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 11.1, 23.5, 29.1, 35.9, 37.2, 37.6, 41.3, 52.4,
55.8, 56.1, 60.5, 61.4, 62.7, 108.3, 111.5, 126.7, 130.0, 147.1, 147.4;
HRMS (ESI) m/z calcd for C19H30NO3 (M þ H)þ 320.2226,
found 320.2223. 20: FTIR 3331, 2932, 1513, 1462, 1259, 1227
cm-1; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, J = 7.5 Hz, 3 H),
1,30 (m, 2 H), 1.46 (m, 1 H), 1.60 (m, 1 H), 1.61 (m, 2 H), 1.90 (m,
1 H), 2.00 (ddd, J = 13.0, 3.5, 2.0 Hz, 1 H), 2.27 (dd, J = 11.5,
2.4 Hz, 1 H), 2.43 (td, J =11.5, 4.0Hz, 1 H), 2.56 (brdd, J = 16.0,
4.0 Hz, 1 H), 2.83 (dd, J = 11.5, 6.0 Hz, 1 H), 2.98 (dd, J = 11.5,
6.0 Hz, 1 H), 3.07 (m, 1 H), 3.09 (m, 1 H), 3.75 (t, J = 7.0Hz, 2 H),
3.84 (s, 3 H), 3.85 (s, 3 H), 6.57 (s, 1 H), 6.69 (s, 1 H); 13C NMR
(E)-4-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)but-2-
en-1-ol (17). To a solution of 14 (460 mg, 1.29 mmol) in ethanol
(5 mL) at rt was added 96% NaBH4 (254 mg, 6.44 mmol). The
mixture was heated at reflux overnight and quenched by the
addition of 1 N HCl. Unreacted 14 and other neutral impurities
were removed by extracting the reaction mixture with CH2Cl2.
The aqueous phase was neutralized by the addition of saturated
K2CO3 solution and extracted with CH2Cl2. The organic layer
was washed with brine, dried over Na2SO4, and evaporated to
afford 17 (291 mg, 86%) as a viscous colorless oil. Further
purification was not necessary since the product was found to
be sufficiently pure by spectral analysis: FTIR 3520, 2930, 1608,
1511, 1450, 1255, 1220, 1111, 1010, 974, 855, 786, 730 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.96-2.23 (br s, 2 H), 2.38-2.51 (m,
1 H), 2.56-2.81 (m, 3 H), 2.92 (ddd, J = 11.8, 4.9, 2.4 Hz, 1 H),
3.19 (dt, J = 11.8, 5.0 Hz, 1 H), 3.84 (s, 6 H), 3.96 (dd, J = 9.0,
3.5 Hz, 1 H), 4.10 (d, J = 4.6 Hz, 2 H), 5.65-5.85(m, 2 H), 6.56 (s,
1 H), 6.63 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 29.4, 39.1, 41.0,
54.9, 55.8, 56.0, 63.2, 109.0, 111.8, 127.3, 129.0, 130.4, 132.6,
147.2, 147.4; HRMS (ESI) m/z calcd for C15H22NO3 (M þ H)þ
264.1600, found 264.1589.
(E)-2-(1-(4-Hydroxybut-2-enyl)-6,7-dimethoxy-3,4-dihydroiso-
quinolin-2(1H)-yl)pentanenitrile (18). To a solution of 17 (490 mg,
1.86 mmol) in CH2Cl2 (6 mL) at rt were added butyraldehyde
(200 μL, 2.22 mmol), H2O (70 μL), and 97% KCN (250 mg,
3.72 mmol). TFA (310 μL, 4.17 mmol) was added, and the
reaction mixture was stirred for 3 h. CH2Cl2 was added, and
the mixture was washed with saturated K2CO3 solution, dried
over Na2SO4, and concentrated. The crude residue was purified
J. Org. Chem. Vol. 74, No. 24, 2009 9419

Nuhant et al.
JOCArticle
(75 MHz, CDCl3) δ 12.6, 17.6, 29.4, 33.3, 36.4, 36.7, 39.1, 53.1,
55.9, 56.1, 59.1, 60.9, 63.4, 108.1, 111.6, 127.1, 130.7, 147.1, 147.3;
HRMS (ESI) m/z calcd for C19H30NO3 (M þ H)þ 320.2226,
found 320.2223.
60.5, 68.4, 109.9, 110.4, 118.4, 121.6, 127.6, 128.8, 136.2, 147.13,
147.14; HRMS (ESI) m/z calcd for C21H30N2NaO3 (M þ Na)þ
381.2154, found 381.2160.
(E)-2-(6,7-Dimethoxy-1-(3-methyl-4-oxobut-2-enyl)-3,4-dihy-
droisoquinolin-2(1H)-yl)pentanenitrile (25). To a solution of 24
(75 mg, 0.21 mmol) in CH2Cl2 (1 mL) was added dropwise
Dess-Martin periodinane (15% solution in CH2Cl2, 0.89 mL,
0.43 mmol) over a period of 5 min. The reaction mixture was
stirred for an additional 10 min and quenched by the addition of
a saturated solution of NaHCO3 (11 mL), a saturated solution
of Na2S2O3 (11 mL), and ether (22 mL). After the reaction
mixture stirred for 45 min, the initially formed precipitate
dissolved and the phases became clear. The two phases were
separated, and the organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated. Flash chromatogra-
phy on neutral alumina (heptane/EtOAc 60/40) afforded 25 as
two epimers (71/29) (57 mg, 76%) as a viscous colorless oil. Only
the major product is described by 1H and 13C NMR: FTIR 2935,
1682, 1611, 1518, 1461, 1256, 1196, 1142, 1117, 1018 cm-1; 1H
NMR (300 MHz, CDCl3) δ 0.91 (t, J = 7.3 Hz, 3 H), 1.34-1.54
(m, 2 H), 1.60 (s, 3 H), 1.70-1.87 (m, 2 H), 2.56-2.97 (m, 5 H),
3.07 (dt, J = 10.5, 3.7 Hz, 1 H), 3.75-3.84 (m, overlapping s at
3.76 and 3.81, 7 H), 4.05 (t, J = 4.3 Hz, 1 H), 6.32 (t, J = 6.5 Hz,
1 H), 6.54 (s, 1 H), 6.55 (s, 1 H), 9.21 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 9.4, 13.3, 19.0, 28.4, 33.3, 34.5, 42.4, 53.7, 55.6,
55.8, 59.7, 109.6, 110.8, 118.0, 127.4, 127.8, 140.1, 147.51,
147.53, 150.1, 194.5; HRMS (ESI) m/z calcd for C21H28N2NaO3
(M þ Na)þ 379.1998, found 379.1996.
(E)-Methyl 4-(2-(1-cyanobutyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinolin-1-yl)but-2-enoate (22). To a solution of 19
(621 mg, 1.81 mmol) in MeOH (36 mL) were successively added
activated MnO2 (3.15 g, 36.2 mmol), 97% KCN (487 mg,
7.25 mmol), and glacial AcOH (114 μL, 1.99 mmol). The organic
mixture was stirred for 3 h at ambient temperature and then
filtered on Celite. The filtrate was diluted by CH2Cl2 and
hydrolyzed with a solution of saturated K2CO3. The aqueous
phase was extracted by CH2Cl2, and the combined organic
phases were dried over Na2SO4, filtered, and concentrated to
afford 22 as a mixture of epimers (66/33) (603 mg, 88%) and as a
viscous colorless oil. Only the major product is described by 1H
and 13C NMR: FTIR 2957, 1716, 1514, 1463, 1251, 1226,
729 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.96 (t, J = 7.5 Hz,
3 H), 1.50 (m, 2 H), 1.81 (m, 2 H), 2.63 (m, 1 H), 2.66 (m, 3 H),
2.80 (m, 1 H), 3.08 (dt, J = 10.8, 4.0 Hz, 1 H), 3.66 (s, 3 H), 3.78
(t, J = 8.0 Hz, 1 H), 3.82 (s, 3 H), 3.84 (s, 3 H), 3.96 (br t, J =
5.0 Hz, 1 H), 5.72 (dt, J = 16.0, 1.0 Hz, 1 H), 6.52 (s, 1 H), 6.57 (s,
1 H), 6.76 (dt, J = 16.0, 7.0 Hz, 1 H); 13C NMR (75 MHz,
CDCl3) δ 13.5, 19.2, 28.3, 33.5, 38.5, 42.5, 51.3, 54.0, 55.8, 56.0,
60.3, 109.7, 111.0, 118.3, 122.9, 127.6, 127.9, 145.2, 147.5, 147.6,
166.5; HRMS (ESI) m/z calcd for C20H28NO4 (M - CN)þ
346.2018, found 346.2018.
(E)-4-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-2-
methylbut-2-en-1-ol (23). To a solution of 13 (50 mg, 0.14
mmol) in ethanol (2 mL) at rt was added 96% NaBH4 (27 mg,
0.69 mmol). The mixture was heated at reflux for 6 h and
quenched by the addition of 1 N HCl (5 mL). Unreacted 13 and
other neutral impurities were removed by extracting the reac-
tion mixture with CH2Cl2. The aqueous phase was neutralized
by the addition of saturated K2CO3 solution and extracted
with CH2Cl2. The organic layer was washed with brine, dried
over Na2SO4, and evaporated to afford 23 (31 mg, 83%) as a
viscous colorless oil. Further purification was not necessary
since the product was found to be sufficiently pure by spectral
analysis: FTIR 3455, 2905, 1609, 1513, 1462, 1356, 1325, 1258,
(2S*,3R*,4S*,11bS*)-3-Ethyl-9,10-dimethoxy-2-(1-oxopropan-
2-yl)-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline-4-car-
bonitrile (26). To a solution of 25 (57 mg, 0.16 mmol) in CDCl3
(2 mL) was added 98% Zn(OTf)2 (2 mg, 5.4 μmol), and the
mixture was heated at 80 °C in a sealed tube for 4 h. The reaction
mixture was washed with a saturated K2CO3 solution, dried over
Na2SO4, and concentrated. The crude residue was subjected
to flash chromatography on neutral alumina (heptane/EtOAc
70/30) to afford 26 as two epimers (66/34) (39 mg, 69%) and as a
viscous colorless oil: FTIR 2934, 1719, 1610, 1513, 1462, 1381,
1360, 1336, 1250, 1231, 1209, 1153, 1106, 1011, 855, 735 cm-1
;
HRMS (ESI-) m/z calcd for C21H27N2O3 (M - H)- 355.2022,
found 355.2029). Major epimer: 1H NMR (300 MHz, CDCl3) δ
1.01 (d, J = 7.2 Hz, 3 H), 1.03 (t, J = 7.5 Hz, 3 H), 1.26 (m, 1 H),
1.39 (m, 1 H), 1.73 (m, 1 H), 1.76-1.92 (m, 2 H), 2.39 (tt, J = 12.0,
3.0 Hz, 1 H), 2.65 (br d, J = 16.2 Hz, 1 H), 2.73 (qd, J = 7.0,
3.0 Hz, 1 H), 2.81-2.94 (m, 2 H), 3.01-3.15 (m, 1 H), 3.71 (br d,
J = 11.0 Hz, 1 H), 3.81 (s, 3 H), 3.83 (s, 3 H), 4.13 (d, J = 4.4 Hz,
1 H), 6.54 (s, 1 H), 6.57 (s, 1 H), 9.80 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 6.6, 11.1, 21.7, 29.1, 32.4, 37.5, 41.0, 46.2, 50.7, 55.8,
56.1, 57.0, 59.6, 108.3, 111.4, 115.1, 125.9, 128.4, 147.5, 147.7,
204.4. Minor epimer: 1H NMR (300 MHz, CDCl3) δ 0.96 (t, J =
7.5 Hz, 3 H), 1.16 (d, J = 7.1 Hz, 3 H), 1.27 (m, 1 H), 1.46 (m,
1 H), 1.55 (m, 1 H), 1.76-1.92 (m, 1 H), 2.18-2.31 (m, 2 H), 2.54
(qd, J =7.0, 2.0Hz, 1 H), 2.65 (br d, J =16.2 Hz, 1 H), 2.79-2.95
(m, 1 H), 2.99-3.16 (m,2 H), 3.71 (br d, J =11.0Hz, 1 H), 3.84 (s,
3 H), 3.85 (s, 3 H), 4.08 (d, J = 4.4 Hz, 1 H), 6.57 (s, 1 H), 6.64 (s,
1 H), 9.78 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 9.4, 11.0, 22.5,
29.1, 35.9, 39.7, 41.4, 48.6, 50.5, 55.8, 56.1, 57.3, 59.3, 108.3, 111.4,
115.0, 126.0, 128.4, 147.5, 147.7, 204.3.
1
1222, 1111, 1017, 853 cm-1; H NMR (300 MHz, CDCl3) δ
1.67 (s, 3 H), 2.41-2.59 (m, 1 H), 2.63-2.80 (m, 2 H),
2.87-3.05 (m, 4 H), 3.16 (dt, J = 12.6, 5.6 Hz, 1 H), 3.82 (s,
6 H), 3.97 (m, 3 H), 5.47 (t, J = 7.5 Hz, 1 H), 6.54 (s, 1 H), 6.61
(s, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.2, 29.0, 34.4, 40.6,
55.4, 55.9, 56.0, 68.2, 109.2, 111.8, 121.7, 127.0, 130.2, 138.1,
147.3, 147.5; HRMS (ESI) m/z calcd for C16H24NO3 (M þ H)þ
278.1756, found 278.1745.
(E)-2-(1-(4-Hydroxy-3-methylbut-2-enyl)-6,7-dimethoxy-3,4-
dihydroisoquinolin-2(1H)-yl)pentanenitrile (24). To a solution of
23 (30 mg, 0.11 mmol) in CH2Cl2 (1 mL) at rt were added
butyraldehyde (12 μL, 0.13 mmol), H2O (4 μL), and 97% KCN
(14 mg, 0.21 mmol). TFA (18 μL, 0.23 mmol) was added, and
the reaction mixture was stirred for 2 h. CH2Cl2 (10 mL) was
added, and the mixture was washed with a saturated K2CO3
solution, dried over Na2SO4, and concentrated. The crude
residue was purified by flash chromatography on neutral
alumina (heptane/EtOAc 50/50) to afford 24 as two epimers
(83/17) (35 mg, 90%) as a viscous colorless oil. Only the major
(E)-2-Methyl-4-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-
but-2-en-1-ol (27). Toa solutionof5 (1.19 g, 3.40 mmol) in ethanol
(34 mL) at rt was added 96% NaBH4 (669 mg, 16.98 mmol). The
mixture was heated at reflux for 6 h and quenched at 0 °C by the
addition of 1 N HCl. Unreacted 5 and other neutral impurities
were removed by extracting the reaction mixture with CH2Cl2.
The aqueous phase was neutralized by the addition of saturated
K2CO3 solution and extracted with CH2Cl2. The organic layer
was washed with brine, dried over Na2SO4, and evaporated to
afford 27 (814 mg, 94%) as an amorphous white solid. Further
1
product is described by H and 13C NMR: FTIR 3495, 2933,
1611, 1514, 1463, 1331, 1251, 1227, 1133, 1116, 1013, 860 cm-1
;
1H NMR (300 MHz, CDCl3) δ 0.93 (t, J = 7.3 Hz, 3 H), 1.45
(sextet, J = 7.3 Hz, 2 H) 1.51 (s, 3 H), 1.65-1.85 (m, 2 H), 2.47
(t, J = 5.5 Hz, 2 H), 2.60 (dd, J = 11.0, 3.0 Hz, 1 H), 2.73-2.91
(m, 2 H), 3.06 (dt, J = 11.0, 4.0 Hz, 1 H), 3.76-3.83 (m,
overlapping s at 3.78 and 3.80, 8 H), 3.85 (s, 2 H), 5.30 (t, J =
7.0 Hz, 1 H), 6.53 (s, 1 H), 6.55 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 13.3, 13.8, 19.0, 28.3, 33.4, 33.7, 42.6, 53.9, 55.6, 55.8,
9420 J. Org. Chem. Vol. 74, No. 24, 2009

Nuhant et al.
JOCArticle
purification was not necessary since the product was found to be
sufficiently pure by spectral analysis: FTIR 3263, 2922, 1451,
907 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.66 (s, 3 H), 2.45 (ddd,
J = 14.5, 7.0, 6.5 Hz, 1 H), 2.60 (ddd, J = 14.5, 7.0, 6.5 Hz, 1 H),
2.72 (m, 2 H), 2.97 (m, 1 H), 3.31 (dt, J = 13.0, 5.0 Hz, 1 H), 4.03
(s, 2 H), 4.08 (br t, J = 6.5 Hz, 1 H), 5.53 (br t, J = 7.0 Hz, 1 H),
7.09 (td, J = 7.0, 1.5 Hz, 1 H), 7.15 (td, J = 7.0, 1.5 Hz, 1 H), 7.30
washed with brine, dried over Na2SO4, filtered, and concentrated.
Column chromatography on neutral alumina (heptane/AcOEt 8/2)
afforded a mixture of four isomeric aldehydes (ratio ca. 5/2/2/1, as
assessed by integration of the formyl peaks in the 1H NMR
spectrum) (351 mg, 42%). To a solution of these compounds
(58 mg, 0.173 mmol) in CDCl3 (1.7 mL) was added Zn(OTf)2
(19 mg, 0.05 mmol), and the mixture was heated overnight at 80 °C
in a sealed tube. The reaction mixture was washed with saturated
K2CO3 solution, dried over Na2SO4, and concentrated to afford
quantitatively 28. However, the product was unstable during flash
chromatography on neutral alumina (heptane/EtOAc 8/2), and it
was just possible to obtain only a small amount of 28 as two epimers
(66/34) (31 mg, 53%) and as a viscous colorless oil. Only the major
product is described by 1H and 13C NMR: FTIR 3310, 2977, 2548,
1660, 1488, 1144 cm-1; 1H NMR (300 MHz, CDCl3) δ 1.02 (d, J =
7.0 Hz, 3 H), 1.06 (t, J = 7.0 Hz, 3 H), 1.33-1.50 (m, 2 H),
1.72-1.82 (m, 2 H), 1.90 (tt, J = 11.2, 4.3 Hz, 1 H), 2.40 (tt, J =
11.7, 3.0 Hz, 1 H), 2.73-2.84 (m, 2 H), 2.92-3.17 (m,
3 H), 3.86 (br d, J = 11.5 Hz, 1 H), 4.20 (d, J = 4.0 Hz, 1 H),
7.10 (br t, J = 7.0 Hz, 1 H), 7.16 (br t, J = 7.0 Hz, 1 H), 7.31 (d, J =
7.0 Hz, 1 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.82 (br s, 1 H), 9.78 (br s,
1H); 13C NMR (75 MHz, CDCl3) δ 6.7, 11.1, 21.6, 21.8, 30.6, 36.7,
41.3, 46.0, 51.4, 54.3, 58.8, 107.9, 110.9, 115.1, 118.2, 119.6, 121.9,
126.9, 133.1, 136.1, 204.3; HRMS (ESI) m/z calcd for C20H25N2O
(M - CN)þ 309.1967, found 309.1962.
(d, J = 7.0 Hz, 1 H), 7.47 (d, J = 7.0 Hz, 1 H), 8.31 (br s, 1 H); 13
C
NMR (75 MHz, CDCl3) δ 14.2, 22.5, 33.3, 42.4, 52.5, 67.9, 108.8,
110.8, 118.0, 119.2, 120.9, 121.5, 127.2, 135.6, 135.7, 138.4;
HRMS (ESI) m/z calcd for C16H19N2O (M - H)þ 255.1497,
found 255.1497.
(2S*,3R*,4S*,12bS*)- 3-Ethyl-2-(1-oxopropan-2-yl)-1,2,3,4,-
6,7,12,12b-octahydroindolo[2,3-a]quinolizine-4-carbonitrile (28).
To a solution of 27 (714 mg, 2.79 mmol) in a mixture of MeOH and
H2O (1/1) (5.6 mL) at rt were successively added TFA (215 μL,
2.79 mmol), 97% KCN (187 mg, 2.79 mmol), and butyraldehyde
(254 μL, 2.79 mmol). The reaction mixture was stirred overnight,
diluted by CH2Cl2, and hydrolyzed by a solution of saturated
K2CO3 until becoming basic. The two phases were separated, and
the organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated to afford crude aminonitrile (841 mg, 90%). It was
dissolved in CH2Cl2 (1.2 mL), and Dess-Martin periodinane (15%
solution in CH2Cl2, 7.8 mL, 3.74 mmol) was added dropwise over a
period of 5 min. The reaction mixture was stirred for an additional
10 min and quenched by the addition of a saturated solution of
NaHCO3 (70 mL), a saturated solution of Na2S2O3 (70 mL), and
CH2Cl2 (110 mL). After the reaction mixture was stirred for 45 min,
the initially formed precipitate dissolved and the phases became
clear. The two phases were separated, and the organic layer was
1
Supporting Information Available: Copies of H and 13C
NMR spectra for compounds 4, 5, 9-15, 17-20, and 22-28.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 74, No. 24, 2009 9421