Synthesis of β-carbolines from aldehydes and ketones via the α-siloxy α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tetlet.2010.06.053

We report an efficient method for the synthesis of β-carbolines from α-siloxy α,β-unsaturated esters, which are accessible from a variety of aldehydes and ketones.

Full text of DOI:10.1016/j.tetlet.2010.06.053

Tetrahedron Letters 51 (2010) 4361–4364
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Tetrahedron Letters
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Synthesis of b-carbolines from aldehydes and ketones via the a-siloxy
a,b-unsaturated esters
*
Shuwen He , Zhong Lai, David X. Yang, Qingmei Hong, Mikhail Reibarkh, Ravi P. Nargund,
William K. Hagmann
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report an efficient method for the synthesis of b-carbolines from
which are accessible from a variety of aldehydes and ketones.
a-siloxy a,b-unsaturated esters,
Received 28 April 2010
Revised 6 June 2010
Accepted 11 June 2010
Available online 16 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
b-Carboline
Pictet–Spengler reaction
a-Siloxy
a,b-unsaturated ester
Tryptamine
a-Ketoester
Since its original description in the literature, the Pictet–Spen-
oxy
a
,b-unsaturated ester, which was prepared from the reaction
gler reaction has become one of the most powerful reactions for
the preparation of tetrahydro-b-carbolines and tetrahydro-iso-
quinolines.1 Through this reaction, structures of a high degree of
molecular complexity can be constructed from relatively simple
starting materials. Tetrahydro-b-carboline, in particular, has been
featured as an important pharmacophore in many biologically ac-
tive natural products and drugs (e.g., yohimbine and tadalafil)
(Fig. 1). The method development and the total synthesis of natural
products based on the Pictet–Spengler reaction remain an active
area of research.2
of an aldehyde with a Horner–Emmons reagent (Scheme 2).6
We became interested in the last method listed above. We con-
sidered the possibility of using the intermediate
unsaturated ester directly in Pictet–Spengler reaction bypassing
the isolation of -ketoesters (Scheme 3). Since the Pictet–Spengler
reaction is typically facilitated by a strong acid, we envisioned that
a strong acid would deprotect the silyl enol ether, generating the
a-siloxy a,b-
a
required
a-ketoester in situ for the Pictet–Spengler reaction. Fur-
thermore, we were surprised to find that although the preparation
In a medicinal chemistry research program, we were particu-
larly interested in the tetrahydro-b-carbolines prepared from the
O
N
reaction of a substituted tryptamine with
a-ketoesters (Scheme
1). To facilitate our SAR studies, we needed to synthesize a series
of compounds with different R groups. Therefore, we were seeking
N
N
N
a convenient method for the preparation of
-Ketoesters have been prepared by many methods,3 including
the reaction of organometallic reagents with oxalic ester deriva-
tives, the Friedel–Crafts acylation of arenes, oxidation of -hydroxy
a-ketoesters.
H
H
H
N
O
a
H
H
O
O
a
O
OH
esters prepared from the hydrolysis of the Strecker reaction prod-
O
ucts followed by the esterification, ozonolysis of cyano keto phos-
a
-keto vinyl ethers,4 the oxidation of hydroxyl alkynyl
Yohimbine
Tadalafil
phoranes or
ethers by potassium permanganate,5 and desilylation of the
a
-sil-
Figure 1. Structures of yohimbine and tadalafil (CialisÒ).
* Corresponding author. Tel.: +1 732 594 0881; fax: +1 732 594 3007.
E-mail address: shuwen_he@merck.com (S. He).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.053

4362
S. He et al. / Tetrahedron Letters 51 (2010) 4361–4364
O
O
P
O
P
CO2Et
OH
CO2Et
OTBS
a
b
EtO
EtO
EtO
EtO
R
CO2Et
R'
NH
CO2Et
R'
NH2
O
3
R1
R2
1
2
N
N
H
H
R
Scheme 1. Pictet–Spengler reaction of tryptamine with
a
-ketoester.
R'
NH
R1
R2
CO2Et
OTBS
c
1
N
H
CO2Et
R1
R2
O
MeO
4
5
P
CO2Me
OTBS
MeO
OTBS
CO2Me
Scheme 4. Reagents and conditions: (a) TBSCl, imidazole, DMF, 52%; (b) LiHMDS,
THF, À78 °C 30 min; then ketone or aldehyde, À78 °C to rt overnight; (c) method A:
tryptamine HCl salt (1 equiv), p-TsOH monohydrate (1 equiv), 80 °C, EtOH,
overnight; method B: p-TsOH monohydrate (2 equiv), 80 °C, EtOH, 5 h, then:
tryptamine HCl salt added (1 equiv), 80 °C, overnight.
O
CsF, AcOH, MeCN
RCHO
CO2Me
DBU, LiCl
R
R
Scheme 2. Preparation of the
,b-unsaturated esters.
a-ketoester from an aldehyde via a-siloxy
a
tion conditions, both isomers will be desilylated to converge to
the same
the most accessible starting materials in organic synthesis, a vari-
ety of -siloxy ,b-unsaturated esters should be accessible as the
surrogates for the -ketoester.
We carried out the Pictet–Spengler reaction of these
,b-unsaturated esters with tryptamine HCl salt to prepare the cor-
responding b-carbolines (Table 1). As an example, simply heating a
mixture of 4a with tryptamine HCl salt and 1 equiv of p-TsOH
monohydrate each in ethanol overnight at 80 °C gave the b-carbo-
line product 5a in good yield (Method A).11 Compound 5c with an
interesting difluoro substitution on the cyclohexyl ring was pre-
pared accordingly. Compound 4d gave b-carboline 5d as a 1.6:1
cis/trans mixture in respect to the cyclohexyl ring. Compounds
5e and 5f with a piperidine ring were prepared conveniently from
the piperidone starting materials 3e and 3f, respectively. Com-
pound 4g prepared from 2-indanone gave b-carboline 5g contain-
a-ketoester. Since aldehydes and ketones are among
of
a-siloxy a,b-unsaturated esters from ketones was known in the
literature,7 there has been no report on the desilylation to generate
a
a
the corresponding
od using -siloxy
and ketones as surrogates to
a-ketoesters. Herein, we describe a novel meth-
a
a
a
,b-unsaturated esters derived from aldehydes
a
-siloxy
a-ketoesters in the Pictet–Spengler
a
reaction with tryptamine.
The
a-siloxy a,b-unsaturated esters 3 were prepared conve-
niently from the phosphonate reagent 2 and the aldehyde or ke-
tone by the Horner–Emmons reaction6,7 (Scheme 4). The
phosphonate 2 was prepared from commercially available 1 fol-
lowing a known procedure.8,9 A variety of ketones and aldehydes
participated in this Horner–Emmons reaction efficiently to give
the corresponding
demonstrate the utility of the current method, we chose to prepare
-siloxy ,b-unsaturated esters whose corresponding -ketoesters
a-siloxy a
,b-unsaturated esters (Table 1).10 To
a
a
a
are not commercially available and not easily accessible by other
methods. We were gratified to find that even 4g can be prepared
efficiently from 2-indanone 3g, which is well known to be prone
ing indane in good yield. More interestingly, when L-tryptophan
ester was used instead of tryptamine, the product 5h was also pro-
duced as a diastereomeric mixture (1.4:1) in good yield (entry 8).
to enolization. The a-siloxy a,b-unsaturated esters 4 are generally
Method A worked well with
rived from aliphatic aldehydes and ketones. However, when the
exact method was applied to the -siloxy ,b-unsaturated esters
a-siloxy a,b-unsaturated esters de-
a mixture of two geometric isomers when R1 and R2 are different
groups. However, it is interesting to note that aldehyde 3a gives
exclusively one isomer 4a due to the steric bulk of both the OTBS
group and the tetrahydropyran ring. The product 4a most likely
has E configuration.6b Since the cyclopropyl ring in aldehyde 3b
is sterically less demanding, the product 4b is a mixture of two iso-
mers in a ratio of 17:1. The mixture of geometric isomers is of little
significance because under the subsequent Pictet–Spengler reac-
a
a
prepared from aromatic carbonyl compounds, the yield of the Pic-
tet–Spengler products was low. Method B, a slight modification of
Method A, whereby the a-siloxy a,b-unsaturated ester was heated
with 2 equiv of p-TsOH in ethanol for 6 h to achieve complete desi-
lylation before tryptamine HCl salt was added, circumvented this
problem.12 In this way, b-carbolines 5i–k were prepared in good
yields. As demonstrated by the examples, the current method for
the synthesis of carbolines is quite general. However, this method
is limited to the structure of 5 (Scheme 4) with a methyne carbon
attached to the C1 carbon of the b-carboline.
aldehyde/ketone
OTBS
In summary, we describe a novel efficient method for the prep-
aration of b-carbolines from a variety of aldehydes and ketones via
a-siloxy a,b-unsaturated esters. Since ketones and aldehydes are
widely available starting materials, we believe that this novel
method will complement known methods in the synthesis of b-
carbolines.
R1
CO2Et
R'
NH
CO2Et
R'
NH2
R2
acid
N
N
R1
H
H
Supplementary data
R2
Supplementary data (the supplementary material contains the
1H NMR spectra for all new compounds) associated with this
Scheme 3. Pictet–Spengler reaction of tryptamine with
esters.
a-siloxy a,b-unsaturated

S. He et al. / Tetrahedron Letters 51 (2010) 4361–4364
4363
Table 1
Synthesis of tetrahydro-b-carbolines 5 from aldehydes/ketones 3 via
a-siloxy a,b-unsaturated esters 4
Entry Aldehyde/ketone 3
a
-Siloxy
a
,b-unsaturated
Yield (%) of 4a Pictet–Spengler product 5
Method for Pictet–Spengler
reactionc
Yield (%)
esters 4
of 5b
OTBS
CHO3a
91 (Single
isomer)
O
NH
1
A
A
A
A
A
A
78
88
84
N
CO2Et
H
O5a
EtO2C
O
4a
OTBS
CHO3b
NH
NH
NH
NH
NH
NH
2
81 (17:1)
N
CO Et4b
2
H
EtO2C
5b
OTBS
F
O
F
F
F
3
88
78
93
81
3c
N
F
F
CO Et 4c
2
H
EtO2C
5c
OTBS
O
O
BnO
Cbz
BnO
4
5
6
74 (1.6:1)
N
CO Et4d
2
3d
H
OBn5d
EtO2C
OTBS
N
Cbz
F3C
N
67
81
N
CO2Et
4e
H
3e
N
N
Cbz5e
EtO2C
OTBS
CO2Et
O
N
N
F3C
3f
CF3
N
4f
H
EtO2C
5f
OTBS
CO2Et
O3g
N
H
7
8
83
A
A
78
4g
EtO2C
5g
OTBS
CO2Et
COOEt
CHO
O
NH
NH
NH
NH
91 (Single
isomer)
3a
N
80 (1.4:1)
H
O
O
4a
EtO2C
5h
OTBS
CO2Et
CHO3i
I
N
9
78 (3.6:1)
99 (3.9:1)
62 (11:1)
B
B
B
84
H
I5i
EtO2C
I
4i
CHO
OTBS
N
CO2Et
N
N
N
10
11
78
H
N
N
EtO2C
N
5j
3j
4j
O
OTBS
CO2Et
F
3k
N
77 (1:1)
H
F
EtO2C
5k
F
4k
a
b
c
The ratio of the geometric isomers is noted in the parentheses.
The diastereomeric ratio is noted in the parentheses.
Method A: tryptamine HCl salt (1 equiv), p-TsOH monohydrate (1 equiv), 80 °C, EtOH, overnight; method B: p-TsOH monohydrate (2 equiv), 80 °C, EtOH, 5 h, then:
tryptamine HCl salt added (1 equiv), 80 °C, overnight.
2. For the most recent reports on the synthesis of b-carboline by the Pictet–
Spengler reaction, see: (a) Vinu, A.; Kalita, P.; Samie, L.; Chari, M. A.; Pal, R.;
Reddy, B. V. S. Tetrahedron Lett. 2010, 51, 702; (b) Bandini, M.; Eichholzer, A.
Angew. Chem., Int. Ed. 2009, 48, 9608; (c) Edwankar, C. R.; Edwankar, R. V.;
Namjoshi, O. A.; Rallapalli, S. K.; Yang, J.; Cook, J. M. Curr. Opin. Drug Dis. Dev.
2009, 12, 752; (d) Liu, H.; Dömling, A. J. Org. Chem. 2009, 74, 6895; (e) Ito, T.;
Kitajima, M.; Takayama, H. Tetrahedron Lett. 2009, 50, 4506; (f) Wanner, M. J.;
Boots, R. N. A.; Eradus, B.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. Org.
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.06.053.
References and notes
1. (a) Pictet, A.; Spengler, T. Berichte 1911, 44, 2030; (b) Cox, E. D.; Cook, J. M.
Chem. Rev. 1995, 95, 1797.

4364
S. He et al. / Tetrahedron Letters 51 (2010) 4361–4364
Lett. 2009, 11, 2579; (g) Bailey, P. D.; Beard, M. A.; Phillips, T. R. Tetrahedron Lett.
2009, 50, 3645; (h) Bou-Hamdan, F. R.; Leighton, J. L. Angew. Chem., Int. Ed.
2009, 48, 2403.
chromatography eluted by a gradient of hexanes to 30% ethyl acetate to
afford 4a (2.5 g, 91%) as an oil. 1H NMR (CDCl3, 500 MHz) d = 0.15 (6H, s), 0.97
(9H, s), 1.35 (3H, t, J = 7 Hz), 1.46 (2H, qd, J = 12 Hz, 4.5 Hz), 1.67 (2H, d,
J = 12 Hz), 3.25 (1H, m), 3.48 (2H, t, J = 12 Hz), 3.96 (2H, d, J = 12 Hz), 4.25 (2H,
q, J = 7 Hz), 5.33 (1H, d, J = 10 Hz).
3. de las Heras, M. A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J. J. Org.
Chem. 1996, 61, 9009. references cited therein.
4. Angelastro, M. R.; Peet, N. P.; Bey, P. J. Org. Chem. 1989, 54, 3913.
5. Tatlock, J. H. J. Org. Chem. 1995, 60, 6221–6223.
11. Pictet–Spengler reactions with
a
-siloxy
a
,b-unsaturated ester 4, Method
A
exemplified by the synthesis of b-carboline 5a:
A
mixture of tryptamine
6. (a) Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Am. Chem. Soc.
1997, 119, 7159; (b) Nakamura, E. Tetrahedron Lett. 1981, 22, 663; (c) Horne, D.;
Gaudino, J.; Thompson, W. Tetrahedron Lett. 1984, 25, 3529.
7. Pujol, B.; Sabatier, R.; Driguez, P. A.; Doutheau, A. Tetrahedron Lett. 1992, 33,
1447–1450.
hydrochloride (125 mg, 0.636 mmol), p-TsOH monohydrate (121 mg,
0.636 mmol), and silyl enol ether 4a (200 mg, 0.636 mmol)in ethanol (8 mL)
was stirred at 80 °C under N2 overnight. The reaction mixture was cooled to rt
and treated with solid NaHCO3 (534 mg, 6.36 mmol). The solvent was removed
and the residue was dry-loaded on a silica gel column. Elution by a gradient to
CH2Cl2 to 50% acetone afforded the product 5a (170 mg, 78%) as a solid. LC–MS:
M+H = 343.21. 1H NMR (CD3OD, 500 MHz) d = 1.26 (3H, t, J = 7 Hz), 1.26 (1H,
m), 1.32 (1H, m), 1.39 (1H, d, J = 12.5 Hz), 1.65 (1H, d, J = 12.5 Hz), 1.84 (1H, m),
1.93 (1H, dd, J = 14 Hz, 5 Hz), 2.18 (1H, dd, J = 14 Hz, 6.5 Hz), 2.64 (1H, dt,
J = 15 Hz, 3.1 Hz), 2.76 (1H, m), 3.13 (1H, m), 3.21 (1H, dq, J = 12 Hz, 3.1 Hz),
3.33 (2H, m), 3.76 (1H, d, J = 12 Hz), 3.84 (1H, d, J = 12 Hz), 4.19 (2H, m), 6.96
(1H, t, J = 8 Hz), 7.06 (1H, d, J = 8 Hz), 7.32 (1H, d, J = 8 Hz), 7.38 (1H, d, J = 8 Hz).
8. Itoh, H.; Kaneko, T.; Tanami, K.; Yoda, K. Bull. Chem. Soc. Jpn. 1988, 61, 3356.
9. Preparation of phosphonate 2: To a solution of ethyl 2-(diethoxyphosphoryl)-2-
hydroxyacetate
1 (50 g, 208 mmol) (purchased from Toronto Research
Chemicals, Ontario, Canada) in DMF (170 mL) at 0 °C was added imidazole
(35.4 g, 520 mmol) followed by TBSCl (37.7 g, 250 mmol). The reaction mixture
was warmed to rt and stirred overnight under N2. The reaction mixture was
partitioned between water and ethyl acetate. The organic layer was separated,
dried (Na2SO4), and concentrated. The residue was purified by silica gel column
eluted by a gradient of hexanes to ethyl acetate to afford phosphonate 2
12. Pictet–Spengler reactions with
a
-siloxy
a
,b-unsaturated ester 4, Method
B
exemplified by the synthesis of b-carboline 5i:
A
mixture of p-TsOH
(38.43 g, 52%) as
a
colorless oil. LC–MS: M+H = 355.12. 1H NMR (CDCl3,
monohydrate (164 mg, 0.86 mmol) and silyl enol ether 4i (186 mg,
0.43 mmol) in ethanol (5 mL) was stirred at 80 °C under N2 for 6 h. LC–MS
indicated that 4 g was consumed. The mixture was treated with tryptamine
hydrochloride (85 mg, 0.43 mmol) and then stirred at 80 °C under N2
overnight. Further processing as described for Method A afforded product 5g
(166 mg, 84%) as a solid. LC–MS: M+H = 460.99. 1H NMR (CD3OD, 500 MHz)
d = 1.23 (3H, t, J = 7 Hz), 2.66 (1H, dt, J = 15 Hz, 3.9 Hz), 2.68 (1H, m), 3.04 (1H,
m,), 3.10 (1H, m,), 3.14 (1H, d, J = 13.5 Hz), 3.54 (1H, d, J = 13.5 Hz), 4.17 (2H,
dd, m), 6.93 (2H, d, J = 8 Hz), 6.98 (1H, d, J = 7.5 Hz), 7.10 (1H, t, J = 7.5 Hz), 7.38
(1H, d, J = 7.5 Hz), 7.41 (1H, d, J = 7.5 Hz), 7.58 (2H, d, J = 8 Hz).
500 MHz) d = 0.083 (3H, s), 0.091 (3H, s), 0.902 (9H, s), 1.30 (9H, m), 4.21 (6H,
m), 4.56 (1H, d, J = 18 Hz).
10. Preparation of a-siloxy a,b-unsaturated esters from phosphonate 2 exemplified by
4a: Phosphonate 2 (3.73 g, 10.51 mmol) was dissolved in THF (16 mL) and
cooled to À78 °C. LiHMDS (1 M solution in THF, 9.64 mL, 9.64 mmol) was
added. The reaction mixture was stirred at À78 °C for 30 min. Aldehyde 3a (1 g,
8.76 mmol) was added. The reaction mixture was allowed to warm to rt
overnight. The reaction was quenched by satd aqueous NH4Cl solution. The
mixture was extracted with CH2Cl2 and extracts were dried (Na2SO4). The
extracts were concentrated and the residue was purified by silica gel