Exploration of Aberrant Behaviour of Grignard Reagents with Indole-3-carboxaldehyde: Application to the Synthesis of Turbomycin B and Vibrindole A Derivatives

Article abstract of DOI:10.1055/s-0036-1588885

An aberrant reaction of Grignard reagents with N-alkylated indole-3-carboxaldehyde has been observed. Contrary to the usual formation of an alcohol, it afforded an unusual bis(indolyl)methane product. A systematic study on this new mode of reactivity and its application to a synthesis of the potent antibiotic turbomycin B and vibrindole A derivatives is reported.

Full text of DOI:10.1055/s-0036-1588885

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
A. Bahuguna et al.
Letter
Synlett
Exploration of Aberrant Behaviour of Grignard Reagents with
Indole-3-carboxaldehyde: Application to the Synthesis of Turbo-
mycin B and Vibrindole A Derivatives
A. Bahugunaa
MgBr
R. Sharmaa
P. S. Sagaraa
O
H
P. C. Ravikumar*a,b
Et2O–THF (2:1)
0 °C, 50 min
N
a School of Basic Sciences, Indian Institute of Technology Mandi,
Kamand Campus, HP,175005, India
b School of Chemical Sciences, National Institute of Science
Education and Research (NISER) Bhubaneshwar, Jatni Campus,
Odisha 752050, India
H
HN
NH
N
2 atmosphere
92%
turbomycin B reductant
a potent antibiotic
pcr@niser.ac.in
Received: 02.07.2016
Accepted after revision: 27.08.2016
Published online: 14.09.2016
DOI: 10.1055/s-0036-1588885; Art ID: st-2016-d0427-l
Abstract An aberrant reaction of Grignard reagents with N-alkylated
indole-3-carboxaldehyde has been observed. Contrary to the usual for-
mation of an alcohol, it afforded an unusual bis(indolyl)methane prod-
uct. A systematic study on this new mode of reactivity and its applica-
tion to a synthesis of the potent antibiotic turbomycin B and vibrindole
A derivatives is reported.
Key words Grignard, vibrindole, turbomycin
Figure 1 Crystal structures of 2aa and 2ca. ORTEP diagrams for the
crystals showing 20% thermal ellipsoids.
The reaction of Grignard reagents1 with carbonyl com-
pounds is frequently used in organic syntheses. Inserting
magnesium metal between a carbon–halogen bond makes
the carbon center nucleophilic and such reagents have spe-
cial emphasis due to their umpolung reactivity.2 Due to this,
Grignard reagents have been applied in diverse organic
transformations from carbonyl addition to cross-coupling
reactions.3a Sometimes side products of this reaction can
lead to unexplored chemistry. Formation of abnormal prod-
ucts such as pinacols,3b,c alkanes,3d and the Bartoli reaction
with nitroarenes3e,f have been well documented with Gri-
gnard reagents. Moreover, it has been also observed that
Grignard reagents can also bring about nucleophilic aro-
matic substitution3g and opening of strained ring systems.3h
During the synthesis of some aromatic alcohols, we per-
formed a Grignard addition (PhMgBr) to N-methyl indole-
3-carboxaldehyde. Surprisingly, we observed a series of
nonpolar reaction components instead of the expected po-
lar alcohol on TLC analysis. After purification of the com-
plex crude mixture, NMR spectroscopic and mass spectro-
metric analysis of the purified product confirmed the for-
mation of an unusual phenyl bis(indolyl)methane (Table,
entry 1).4
The structure of the bis(indolyl)methane product was
also confirmed by single-crystal X-ray analysis (Figure 1,
2aa). This abnormal behavior of the phenyl Grignard re-
agent with N-methyl indole-3-carboxaldehyde can be part-
ly attributed to the fact that the carbonyl group is rendered
less electrophilic due to the electron-donating ability of the
indole nitrogen,5 therefore it is less reactive towards usual
Grignard addition. As the yield of the bis(indolyl)methane
product was low, we attempted to optimize the yield. On
changing the solvent from THF to diethyl ether (Table 1, en-
try 2) the yield dropped to 10%, but this occurred partly be-
cause of the low solubility of N-methyl indole-3-carboxal-
dehyde. Therefore we tried this reaction in various combi-
nations of THF and diethyl ether (Table 1, entries 3–13). The
best yield (76%) was obtained with a 2:1 combination of di-
ethyl ether and THF (Table 1, entry 5). As we presumed that
the electron-donating ability of nitrogen is the key for this
unusual transformation, we tested these conditions on the
more electron-rich, unprotected indole-3-carboxaldehyde,
and we observed a 92% yield (Table 1, entry 14). When the
solvent concentration was changed from 0.5 M to 0.25 M,
the yield was reduced to 84% (Table 1, entry 15) under simi-
lar conditions.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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A. Bahuguna et al.
Letter
Synlett
Table 1 Optimization of Reaction Conditions
MgBr
O
H
solvent
temp, time
N
N
N
N2 atmosphere
R
R
R
1a R = Me
1b R = H
2a R = Me
2b R = H
Entry
Aldehyde
PhMgBr (equiv)
Solvent
Solvent conc. [M]
Temp (°C)
Time (min)
Yield (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
2.25
2.25
THF
0.5
0.5
0.5
0.5
0.5
0.5
0.25
0.1
0.05
0.5
0.5
0.5
0.5
0.5
0.25
0
0
60
60
50
50
50
50
75
90
120
50
50
50
50
50
60
15
10
42
64
76
64
70
60
51
68
60
40
43
92
84
Et2O
3
Et2O–THF (4:1)
Et2O–THF (3:1)
Et2O–THF (2:1)
Et2O–THF (1:1)
Et2O–THF (2:1)
Et2O–THF (2:1)
Et2O–THF (2:1)
Et2O–THF (2:1)
Et2O–THF (2:1)
Et2O–THF (2:1)
Et2O–THF (2:1)
Et2O–THF (2:1)
Et2O–THF (2:1)
0
4
0
5
0
6
0
7
0
8
0
9
0
10
11
12
13
14
15
–5
–10
–15
r.t.
0
0
a All the reactions were carried out at a 0.5 mmol scale under N2 atmosphere.
Intrigued by this abnormal bis(indolyl)methane forma-
tion, we explored the transformation with different N-al-
kylated indole-3-carboxaldehydes (Scheme 1). We protect-
ed the nitogen atom6 of indole-3-carboxaldehyde with eth-
yl, allyl, n-propyl, butyl, hexyl, benzyl, and cyclopentyl
groups, which all gave good to moderate yields (Scheme 1,
2aa–ha) except N-benzyl (2ha) and N-cyclopentyl (2ia)
substrates. The poor reactivity of the N-benzyl substrate
could be caused by the presence of the relatively acidic ben-
zylic protons, which could lead to side reactions. Further-
more, we explored this protocol with aryl Grignard re-
agents possessing electron-withdrawing and -donating
groups. All gave the bis(indolyl)methane moiety (2bb–cc)
in good yields. We also tested the reaction with electron-
donating substituents on the indole ring system, which
gave bis(indolyl)methane products in moderate yields
(2abx,cbx). As the electron-withdrawing nitro and cyano
substituents interfere with Grignard reagents, we tried the
reaction of the phenyl Grignard with N-alkylated 7-azain-
dole 3-carboxaldehyde but no bis(indolyl)methane product
was detected. Therefore we presume that the electron-rich
indole system is the driving force for the reaction. To exam-
ine the reactivity of the phenyl Grignard with other nitrog-
enous heterocyclic aldehydes, we performed reactions with
pyrrole-2-carboxaldehyde and imidazole-2-carboxaldehyde
(Scheme 1, 2eea and 2ffa) but we could not detect any
product. We also explored this protocol without protecting
the nitrogen atom of indole-3-carboxaldehyde. When phe-
nyl magnesium bromide was used as the reagent, the reac-
tion proceeded cleanly in more than 90% yield7 (Scheme 1,
2ba). The product is the potent antibiotic natural product
turbomycin B.8,11 Although there are many methods9
known for the synthesis of this natural product, this is the
first report using a Grignard reagent in a single step. N-
Methyl and N-ethyl indole-3-carboxaldehyde with methyl
magnesium bromide gave the N-methyl and ethyl deriva-
tives of the natural product vibrindole A in modest yields
(Scheme 1, 2ad,cd). For the synthesis of vibrindole A itself,
we utilized the N-allyl precursor (Scheme 1, 2dd). Unfortu-
nately, deprotection of the allyl group using standard pro-
cedures10 was not successful, due to the instability of the
bis(indolyl)methane at high temperatures. Single-crystal X-
ray analysis of compounds 2aa and 2ca (Figure 1) unambig-
uously confirmed the structure of the bis(indolyl)methane
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
A. Bahuguna et al.
Letter
Synlett
X
H
X
O
R
H
Y
R
X
RMgBr (1.25–2.5 equiv), Et2O–THF (2:1)
or
Y
Y
or
O
N
–20 to 0 °C or r.t.
50–120 min or 8–10 h
N
R1
H
N
R1
N
R1
NH HN
1
Y = CH or N
2
N
N
N
N
N
N
N
N
N
N
N
N
n-Bu
Me
n-Pr
n-Bu
Et
Allyl
Me
n-Hex
n-Pr
Et
Allyl
n-Hex
2aa, 76%
2ca, 71%
2da, 68%
2ea, 58%
2fa, 53%
2ga, 41%
F
F
OMe
OMe
OMe
N
N
HN
NH
N
N
N
N
N
N
Bn
Bn
HN
NH
Me
Me
Me
Me
Et
Et
2ha, 20%*
2bb, 68%
2ab, 65%
2cb, 62%
2bc, 58%
2ac, 62%
F
OMe
OMe
MeO
OMe
MeO
OMe
N
N
N
N
Et
HN
NH
N
N
Me
N
N
Me
Me
Et
Me
Et
Et
2cc, 60%
2abx, 54%
2cbx, 51%
2ba, 92%
2ad, 40%
turbomycin B
N
N
N
N
N
N
N
N
Et
Et
NH HN
NH HN
2cd, 26%
2dd, 38%
2ia, 0%
2eea, 0%
2ffa, 0%
Scheme 1 Substrate scope with various Grignard reagents. a All the reactions were carried out at –20 °C to 0 °C or at r.t. by using 1.25 equiv of
Grignard reagents with 0.5 M concentration of Et2O–THF(2:1). b In the case of 2bb, 2bc, and 2ba, 2.5 equiv of Grignard reagents were used. *NMR
yield.
skeleton.11 Finally, we extended our study to explore the re-
activity of N-methyl indole-3-carboxaldehyde with various
other Grignard reagents (Table 2, entries 1–6). Reactions of
ethnyl, isopropyl, isopropenyl, and allyl magnesium halides
(Table 2, entries 2 and 4–6) gave exclusively carbonyl addi-
tion products; on the other hand, benzyl and vinyl Grignard
reagents gave the desired products in low yields along with
alcohols (Table 2, entries 1 and 3). Substrates with N-phenyl
and N-tosyl groups gave exclusively alcohols (Table 2, en-
tries 11 and 12). Thus, we came to the conclusion that only
aryl and methyl Grignard reagents give acceptable results
(Scheme 1).
We also isolated small amounts of benzaldehyde as a
side product when one equivalent of phenyl Grignard re-
agent was used. To investigate the mechanism, we per-
formed the reaction with 4-methoxy- and 4-fluorophenyl
Grignard reagents and, as expected, we isolated the corre-
sponding 4-methoxybenzaldehyde and 4-fluorobenzalde-
hyde. From this observation, we suggest a plausible mecha-
nism as described in Scheme 2. We propose that the initial
Grignard addition product undergoes fragmentation by ex-
pulsion of XMgO– to form a conjugated iminium species 3
(due to the electron-rich nature of the indole ring at C-3)
and further fragmentation leads to the formation of tran-
sient indole magnesium reagent 4 and the corresponding
aldehyde. Reaction between the two intermediates 3 and 4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
A. Bahuguna et al.
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Table 2 Reaction of Various Grignard Reagents with Differently Substi-
tuted Indole 3-Carboxaldehyde under Optimized Temperature
XMgO
O
R
H
RMgX
X
X
R2
N
R1
N
R1
– MgO
MgX
N
R1
N
R1
R
A
H
O
RCHO
R1 = Alkyl, allyl, Bn, Ph, Ts
–
R2MgBr (1.25 equiv)
X
OMgX
N
R1
+
N
+
Et2O/THF (2:1)
temp
N
4
3
R1
HO
R2
R1
X
R
N
R1
N
R1
B
N
R1
X = H, OMe
balanced equation
Entry
R1
R2
Temp
(°C)
Product A ProductB
O
H
(%)
(%)
R
1
2
Me
Me
Me
Me
Me
Me
Et
Bn
–20
20
70
+
+
2
2 RMgX
RCHO
N
R1
ethynyl
vinyl
isopropyl
isopropenyl
allyl
0
–10
–10
–10
–10
–10
–20
–10
–20
0
0
16
0
99
60
80
99
90
70
30
80
50
99
99
N
R1
N
R1
3
4
Scheme 2 Proposed mechanism
5
0
6
0
7
Et
0
Acknowledgment
8
Et
allyl
15
0
9
Bn
Bn
Ph
Ts
Me
Financial assistance from Science and Engineering Research Board
(CS-185/2011) New Delhi under Fast Track Scheme and SEED grant by
IIT Mandi is gratefully acknowledged. A.B., P.S.S., R.S. are grateful to
CSIR, UGC, and DST, respectively, for fellowships. We acknowledge D.
Rambabu for his help in solving crystal structures. AMRC, IIT Mandi is
acknowledged for providing instrumentation facilities. We are also
thankful to Prof. N. G. Ramesh, IIT Delhi for helpful discussions.
10
11
12
allyl
10
0
Ph
Ph
0
0
a All the reaction were carried out at 0.5 mmol scale under N2 atmosphere.
leads to the formation of the bis(indolyl)methane. This
mechanism also explains the reason why indole 3-carboxal-
dehydes possessing electron-withdrawing substituents do
not lead to bis(indolyl)methane products. To support the
mechanism and observation of aldehyde we added an ex-
cess of phenyl Grignard to the above reaction and con-
firmed the formation of diphenylmethanol.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588885.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References and Notes
(1) (a) Shintani, R.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 1057.
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In conclusion we have developed a new nucleophilic ad-
dition reaction of methyl and aryl Grignard reagents with
indole-3-carboxaldehyde. Although literature reports12,13
have disclosed how to synthesize bis(indolyl)methanes, to
the best of our knowledge this strategy is the first report14
using indole-3-carboxaldehyde and a Grignard reagent.15
(2) Orchin, M. J. Chem. Educ. 1989, 66, 586.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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Letter
Synlett
(3) (a) Yamamoto, H. Organo Magnesium Compounds, In Science of
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(11) CCDC No. for 2aa and 2ca are 1038915 and 1038916, respec-
tively.
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(14) Based on Scifinder search till 14 April 2016.
(15) Procedure for the Synthesis of Representative Substrate Tur-
bomycin
B Reductant {3-[(1H-indol-3-yl)(phenyl)methyl]-
1H-indole}
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101.
Indole-3-carboxaldehyde was dissolved in a Et2O–THF (2:1)
mixture and the solution cooled to 0 °C. The Grignard reagent
(PhMgBr, 2.5 equiv) was added dropwise to the solution. After
addition, the reaction mixture was stirred at the same tempera-
ture for 50 min. After completion of the reaction (monitored by
TLC), sat. aq NH4Cl was added to quench the reaction, and the
reaction mixture was allowed to warm to r.t. The resultant
mixture was then extracted with EtOAc or CH2Cl2 (3×) and dried
over anhydrous Na2SO4. The resultant solution was filtered and
concentrated under vacuum to obtain the crude product, which
was then purified by column chromatography using a hexane–
EtOAc solvent system to give turbomycin B.
Note: If the above-mentioned reaction was performed in just
THF, exclusively the alcohol product was formed in the given
time. It was observed that the crude mixture must be purified
within 1 h of completion of the reaction, and the concentration
of the reaction mixture must be carried out at moderate tem-
peratures (30–35 °C) under vacuum. CH2Cl2 (a low boiling sol-
vent) was preferred over EtOAc for extraction purposes.
White solid; mp 125–127 °C. 1H NMR (500 MHz, CDCl3): δ =
7.76 (s, 2 H) 7.30 (d, 2 H, J = 8.2 Hz), 7.27–7.24 (m, 4 H), 7.20–
7.16 (m, 2 H), 7.14–7.06 (m, 3 H), 6.92 (t, 2 H, J = 6.9 Hz), 6.54 (d,
2 H, J = 2.1 Hz), 5.80 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ =
143.9, 136.6, 128.7, 128.2, 127.0, 126.1, 123.6, 121.9, 120.0,
119.7, 119.2, 111.0, 40.1.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E