Alkaloid Photochemistry

Baran Lab

ALKALOID PHOTOCHEMISTRY
(for a nice review of photochemistry of alkaloids prior to 1980 see Singh, A.
P.; Stenberg, V. I.; Parmar, S. S. Chem. Rev. 1980, 80, 269-282)

K. J. Eastman

The following scheme represents a likely pathway for the observed products
(see Santamaria, J. Pure & Appl. Chem., 1995, 67, 141-147).

I. Introduction:

[O]

-H

The photochemistry of alkaloids represents a field rich in diversity including

oxidation, reduction, dimerization, addition, hydrogen abstraction,
dealkylation, epimerization, isomerization and degradation. Yet 60 years after
Weil's1 observation of the photochemical oxidation of nicotine, much remains
to be discovered in this field.
Alkaloid photochemistry includes a wide variety of chromophoric substrates
including: pyrrolidine, piperdine, pyridine, quinoline, isoquinoline, and indole,
and come from a various alkaloid classes, colchicine, isocolchicine, tropane,
opium, ergot, strychnose, steriod and others.

Py

Py

H2O 2

H2O 2

Py

KCN

CN

O2H
Py

N
H

Py

Py

The survey to follow will primarily features nitrogen as the key participant for
both sensitized and direct photochemically induced reactions.

H2O2

CONH2

O
Py

Py

Py

II. Pyrrolidine, Piperdine, and Pyridine Alkaloids:

Upon irradiation of a methanolic solution of nicotine in the presence of O 2 and
methylene blue, Hubert-Brierre and co-workers observed the formation of
nicotyrine, cotinine, and nicotine N-oxide (Hubert-Brierre, Y.; Herlem, D.;
Khuong-Huu, F. Tetrahedron 1975, 31, 3049-3054).
sens/h
/O2
H

H
N

N+

H
O

sens/h
/O2/KCN

CN
N

CONH2

H2O 2

H
N

Py

N
H

Py

N
CH2 CN

Py

N
CH2CONH2

The observation of the N-demethy lated compound, an aminonitrile and

a carboxamide lead to the conclusion that the oxidation with the six
membered ring is exocyclic vs. the five membered ring which was endocyclic.

H
N

sens/h /O2/KCN
Py

Hubert-Brierre and co-workers also investigated the irradiation of N-methylanabasine under a similar set of conditions.

CONH2

Alkaloid Photochemistry

Baran Lab

Photohydration of Pyridinium ions first observed by Kaplan and Wilzbach

(Kaplan, L.; Pavlik, J. W.; Wilzbach, K. E. J. Am. Chem. Soc. 1972, 94, 32833284) went nearly unnoticed for 10 years before Mariano and co-workers
described their observations of the divergent photochemical behavior of
N-allylpyridinium perchlorates (Yoon, U. C.; Quillen, S. L.; Mariano, P. S.;
Swanson, R.; Stavinoha, J. L.; Bay, E. J. Am. Chem. Soc. 1983, 105, 12041218).
Kaplan (1972):
Cl - N+

H 2O-KOH

K. J. Eastman

Thirteen years after thier first observations with the pyridinium salt
photocyclization process, Mariano and co-workers returned to this area and have
subsequently reported on several occasions their investigations into the potential
synthetic power of a tandem sequences involving:
(1) photoinduced cyclization of pyridinium cations
(2) stereocontrolled nucleophile addition to produce bicyclic aziridines, and
(3) stereocontrolled nucleophilic cleavage of the bicyclic aziridine to produce
highly functionalized aminocyclopentenes.
(Ling, R.; Yoshida, M.; Mariano, P. S. J. Org. Chem. 1996, 61, 4439-4449, Song, L.;
Duesler, E. D.; Mariano, P. S. J. Org. Chem. 2004, 69, 7284-7293).
X-

R1

1. h

HNu 1

N+

OH

R1
H

2. base
R2

Nu1

R2

NHR1

1. h
HNu1

Nu2

2. base
R2

Mariano (1983):
OCH3

CH2CH=C(CH3 )2

ClO4- N+

CH2CH=CH2

IIa. -aziridinylacrylonitriles and acrylates:

It has been well established that heating or irradiating aziridines, usually
bearing an adjacent electron-withdrawing group, results in the formation of
azomethane ylides. The 1,3-dipolar cycloaddition of azomethane ylides with
alkenes plays an important role in the synthesis of nitrogen containing fivemembered rings (see Ishii, K. et. al. Tetrahedron 2004, 60, 10887-10898 and
references within for some examples).

CH3OH

ClO4- N+

Nu1

CH2CH=CH2

CH3OH

OCH3

HClO4
CH3OH

Bn

Bn

h or

CN
CN

NHCH2 CH=CH2
H3CO

EWG

EWG

head-to-head adducts

OCH3

Alkaloid Photochemistry

Baran Lab

III. Isoquinoline Alkaloids:

Direct photooxidation of glaucin gave O-methylatheroline (85 %) and corunnine

(10 %) (Castedo, L.; Suau, R.; Mourino, A. An. Quim. 1977, 73, 290).

Noyori and co-workers observed that Irradiation of equimolar quantities of

isoquinoline and the appropriate carboxylic acids in benzene resulted in the
formation of the corresponding 1-alkylisoquinolines in poor yield (Noyori, R.;
Lato, M.; Kawanisi, M.; Nozaki, H. Tetrahedron 1969, 25, 1125-1169).

+ RCOOH

H3CO

H3 CO
N

H3CO

h
-CO2

K. J. Eastman

H3CO
N

H3 CO

h /O 2

10-20 %
R

H3CO

Bick and co-workers reported the photo-oxidative cleavage of some benzylisoquinoline-based alkaloids (Bick, I. R. C.; Bremner, J. B.; Wiriyachitra, P.
Tet. Lett. 1971, 50, 4795-4797).
laudanosine:
H3CO

H3CO
N

H3CO

h /O2

H3CO

HO -

H3CO

CHO

NaBH4

H3 CO

H3 CO

H3 CO
H3 CO

N+

I-

h
/ROH

H3 CO
H3 CO

OCH3

Photoinduced elimination products were obtained in moderate to high yield

upon irradiation of a methanolic solution of the quaternary salt of glaucine
(Bremner, J. B.; Winzenberg, K. N.; Aust. J. Chem. 1978, 31, 313).
H3CO

XN+

H3 CO

h
/ROH

H3CO

H3CO

H3 CO

OCH3

OCH3

Photosolvolysis of laudanosine methyliodide (Bremner, J. B.; Thuc, L. V.

Chem. Ind. (London) 1976, 453).
H3 CO

10 %

H3CO

H3 CO

H3CO
H3CO

OCH3

O
H3CO

OCH3

H3CO

85 %

H3 CO

H3 CO

H3CO

N+

H3CO

N
OR

Stermitz and co-workers made the following observation of the irradiation of

alcoholic solutions of papaverine (Stermitz, F. R.; Seiber, R. P.; Nicodem, D. E.;
J. Org. Chem. 1968, 33, 1136-1140).
H3 CO
H3 CO
H3 CO

h
/ROH

H3 CO
N

H3 CO
R

H3 CO

H3 CO

H3 CO

Alkaloid Photochemistry

Baran Lab

Many have observed the biogenetic conversion protoberberine-type alkaloids

into phthalideisoquinoline alkaloids (see Kondo, Y.; Imai, J.; Nozoe, S. J. Chem.
Soc. Perkin Trans. I 1980, 919-923).
H3 CO

Noyori and co-workers observed that Irradiation of equimolar quantities of

quinoline and equimolar quantities of the appropriate carboxylic acids in benzene
resulted in the formation of the corresponding 2-alkylquinolines in low yield
(Noyori, R.; Lato, M.; Kawanisi, M.; Nozaki, H. Tetrahedron 1969, 25, 1125-1169).

H3CO
N

H3 CO

h
/O2

H3CO
O
O

RCOOH

OCH3
OCH3

The irradiation of a methanolic solution of tropanol in the presence of a sensitizer

gave formamido, demethylated and N-oxytropanol products (Herlem, D.; HubertBrierre, Y.; Khuong-Huu, F.; Goutarel, R. Tetrahedron 1973, 29, 2195-2202).

H3 CO

OHC

N
O

NaBH4

H3 CO

V. Tropane alkaloids:

OCH3

H3CO

OCH3

H3CO

K. J. Eastman

sens/h
/O2

HO
O
OCH3

H3CO

OH

OH

OCH3

OH

VI. Amaryllidaceae Alkaloids:

The photolysis of crinamine in MeOH under N2 gave the following result (Tsuda, Y.;
Kanede, M.; Takagi, S.; Yamaki, M.; Iitaka, Y. Tet. Lett. 1978,19, 1199-1200).

IV. Quinoline Alkaloids:

Quinoline suffers dimerization upon irradiation in alcoholic solution (Pfordte,
K.; Leuschner, G. Justus Liebigs Ann. Chem. 1061, 30, 646).

OCH3
OH
O
H

h
O
N

OH

OCH3

h
/MeOH/no O2

O
O

OCH3

OH
H

Alkaloid Photochemistry

Baran Lab

K. J. Eastman

VII. Opium Alkaloids:

Lotfy and co-workers have recently disclosed thier observations of the

irradiation of variably substituted codeinones and morphinones (Lotfy, H. R.;
Theuns and co-workers reported the biomimetic synthesis of neodihydrothebaine Schultz, A. G.; Metwally, M. A.; Russ. J. Org. Chem. 2003, 39, 1261-1263).
and bractazonine via simple irradiation of thebaine and subsequent reduction
(Theuns, H. B.; Vos, G. F.; ten Noever de Braw, M. C.; Salemink, C. A.; Tet. Lett.
1984, 25, 4161-4162).
OCH3

H3 CO

OCH3

h, 366 nm

H3 CO

OCH3

OCH3

OH
R
O

H3CO
-

OH

OH

R
-

85 %

O
N

H3CO

OH

N+
H3CO

R
O

CH2R

OH

H3 CO

H3 CO

N
H3CO

H3CO+

VIII. Indole Alkaloids:

Nakagawa and co-workers reported the results of irradiation of indoloquinolizide

chloride and its 1-methyl derivative in the presence of a sensitizer (Nakagawa,
M.; Okajima, Y.; Kobayashi, K.; Asaka, T.; Hino, T. Heterocycles 1975, 3, 799-803).

H3CO+

reduction
H3CO

Cl-

H3CO

HO

HO

N
H

sens/h /O 2

N
N

H3CO
OCH3

Alkaloid Photochemistry

Baran Lab

Enamide photochemistry is well known and its useful application has been
thoroughly investigated. Simple enamides generally undergo a [1,3]-acyl radical
shift to afford vinylogous amides. Below are examples of the photorearrangement
of 1-acylindoles to 3 acylindolenines (Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am.
Chem. Soc. 1981, 103, 6990-6992).

O
ClN+

sens/h /O2

Cl-

N+
N

K. J. Eastman

H3COC

COCH3

H3COC
O

Cl-

N
N

N
H

COCH3

An interesting observation was made by Guise, Ritchie and Taylor regarding

the difference in irradiation products of voacangine and ibogaine (Giuse, G. B.;
Ritchie, E.; Taylor, W. C.; Aust. J. Chem. Soc. 1965, 18, 279-286).

O
alkyl

20 %

H3 CO
O
N

N
H

sens/h

H3 CO
N
H

CO2CH3

H3 CO

alkyl

O
N

unstable!

CO2 CH3
N

HO

NH2
N
H

CO2CH3

NH
O

80 %
N

O
O

sens/h

H3CO

H3 CO
N

N
H

N
H

H
N

OH

Alkaloid Photochemistry

Baran Lab

Sinibaldi and co-workers have demonstrated the the feasibility for a photochemical approach to 3,3-spiro indolines (Ibrahim-Ouali, M.; Sinibaldi, M. E.;
Troin, Y., Cuer, A.; Dauphin, G.; Gramain, J-C. Heterocycles 1995, 41, 1939-1950).
O

h
N

CH2OBn
Ph

X. Misc. Examples of Photochemical Alkaloid Chemistry:

Electron-transfer photochemistry of allylsilane-iminium salt systems have been
shown to serve as a viable carbon-carbon forming methodology (Chiu, F-T.;
Ullrich,
J. T.; Mariano, P. S. J. - Org. Chem. 1984, 49, 228-236).
ClO4

N
Ph

O
O

CH2OBn

25 %

N+

NH

RO

RO

a) h
b) SET
ClO4 -

ClO4N

HN

TMS

-TMS

I2
67 %

H
N

RO

RO

Coyle and co-workers have shown the irradiaton of Mannich bases obtained from
phthalimides, formaldehyde and 1,2,3,4-tetrahydroisoquinolines carrying methoxy
substituents gives pentacyclic photoproducts (Coyle, J. D.; Bryant, L. R. B.; Cragg,
J. E. J. Chem. Soc. Perkin Tans. I 1985, 1177-1180).

IX. Steroidal Alkaloids:

Irradiation of the steroidal alkaloid nitrone in acetonitrile gave the following

result (Parello, J.; Beugelmans, R.; Millient et Xavier Lusinchi, P. Tet. Lett.
1968, 10, 5087-5092).
-

38 %

Ph

HN

TMS

CH2 OBn

Cryptosanguinolentine was prepared by Mohan and co-workers as part of their

program of syntheis of heteroannelated acridines, below is the formation of the
tetracyclic system of cryptosanguinolentine (Nandha Kumar, R.; Suresh,
T.; Mohan, P. S. Tet. Lett. 2002, 43, 3327-2228).

K. J. Eastman

N
N

O
H
N

6%

18 %

OCH3

HCl
28 %

OH

OCH3
OCH3

H3 CO
H3 CO

N
N

25 %

HO

N+

H3CO

7%

Alkaloid Photochemistry

Baran Lab

In their investigation of elusive intramolecular hydrogen transfer reactions, Kessar

and co-workers investigated the intramolecular photoreactions of 2-formyl
benzamides and 2-formylbanzylamines (Kessar, S. V.; Singh Mankotia, A. K.;
Agnihotri, K. R. J. Chem. Soc. Chem. Commun. 1993, 598-599).

A similar transformation described by Kanaoka (Sato, Y.; Nakai, H.; Misogucho,

T.; Hatanaka, Y.; Kanaoka, Y. J. Am. Chem. Soc. 1976, 98, 2349-2350) has been
employed by Mazzocchi in the synthesis of the functionalized ring system of
Chilinene, a berberine alkaloid (Mazzocchi, P. H.; King, C. R.; Ammon, H. L.; Tet.
Lett. 1987, 28, 2473-2476).

H3CO

N
H3CO

H3 CO

StBu

tBuS

H3CO
H3CO

OH

* H C

OH

OH

StBu

OTMS

h
N
O

N H
RO2 C

H3 CO

HO

OH

CHO

CO2R
H
H
CO2R

CO2R
HO H

Tsuda and co-workers have employed a simple [2+2] cycloaddition of an activated

butadiene to a dioxopyrroloisoquinoline followed by a 1,3-anionic rearrangement
to fashion the core of erythrin alkaloids (Tsuda, Y.; Oshima, T.; Hosoi, S.; Kaneuchi,
S.; Kiuchi, F.; Toda, J.; Sano, T. Chem. Pharm. Bull 1996, 44, 500-508, for a review
of light induced [2+2] cycloadditions see Crimmins, M. T. Chem. Rev. 1988, 88,
1453-1473).

O
H

MeOOC

H3 CO

StBu

H3 CO

K. J. Eastman

H
C

C
H

OH

N
TMSO
MeOOC

OHC

HO

O
COOMe
O

N
OTMS

HO

O
O