FeCl3-Catalyzed oxidative allylation of sp2 and sp3 C-H bond adjacent to a nitrogen atom: Easy access to homoallyl tertiary amines

Article abstract of DOI:10.1021/jo1005813

Figure presented Oxidative allylation to sp²- and sp ³-carbon attached to the nitrogen atom was accomplished. The α-allylation of tertiary amines was catalyzed by easily available hydrated iron(III) chloride in combination with air or aqueous ^tBuOOH. Remarkably, N-allyl- and N-propagyl-tethered tertiary amines were also allylated through this protocol.

Full text of DOI:10.1021/jo1005813

pubs.acs.org/joc
FeCl3-Catalyzed Oxidative Allylation of sp2 and sp3
C-H Bond Adjacent to a Nitrogen Atom: Easy
Access to Homoallyl Tertiary Amines
SCHEME 1. FeCl3-Catalyzed Allylation of Electronically
Activated Tetrahydroisoquinoline
Gullapalli Kumaraswamy,*,† Akula Narayana Murthy,†,‡
and Arigala Pitchaiah†
†Organic Division-III, Indian Institute of Chemical
Technology, Hyderabad 500 007, India, and
‡An Associate Institution of University of Hyderabad,
Hyderabad 500 046, India
have also been explored for this transformation.4 Among
them, copper salts turned out to be the most efficient
catalysts5 for the R-functionlization to nitrogen. With our
continued interest in developing transition-metal-catalyzed
novel methodologies,6 we focused on oxidative coupling of
tertiary amines7 with allyl tributyltin using a catalytic
amount of FeCl3 in the presence of air or T-HYDRO
(70% tBuOOH in H2O) as terminal oxidant.
gkswamy_iict@yahoo.co.in
Received March 27, 2010
After considerable experimentation, N-phenyltetrahydro-
isoquinoline 1a (3 equiv) reacted with allyl tributyltin 2
(1 equiv) in acetonitrile at room temperature using 10 mol % of
FeCl3 6H2O. It was observed that the desired reaction
3
proceeded within 30 min under the atmosphere of air to give
3a in 85% yield (Scheme 1).
Oxidative allylation to sp2- and sp3-carbon attached to
the nitrogen atom was accomplished. The R-allylation of
tertiary amines was catalyzed by easily available hydrated
iron(III) chloride in combination with air or aqueous
tBuOOH. Remarkably, N-allyl- and N-propagyl-tethered
tertiary amines were also allylated through this protocol.
Further, under the same conditions, improvement of yield
was observed when the N-phenyl moiety was replaced with
electron-rich 4-methoxyphenyl 1b (3b, 90% yield) or
2-naphthyl moiety 1c (3c, 90%) (Scheme 1), while N-benzyl-
tetrahydroisoquinoline 1d failed to yield the required pro-
duct 3d under similar conditions. On the other hand, using
t
T-HYDRO (70% BuOOH in H2O) (2 equiv) as terminal
oxidant under otherwise identical conditions resulted in 3d in
85% yield (Table 1, entry 11). The reaction performed under
air balloon and oxygen balloon did not proceed. A longer
reaction time decreased the product yield.
In recent years, there has been a resurgence of interest in
the oxidative functionalization of sp3 C-H bonds adjacent
to a nitrogen atom.1 A plethora of methods have been
developed to achieve this functionalization with various
nucleophiles.2 The prominent route appears to be transi-
tion-metal catalysis together with either organic peroxides or
elemental oxygen to generate iminium cation, which in turn
reacts with various nucleophiles. Following the pioneering
work of Murahashi et al. on the Ru-catalyzed R-cyanation of
tertiary amines,3 many other alternative transition metals
(4) (a) Yamaguchi, R.; Ikeda, C.; Takahashi, Y.; Fujita, K. I. J. Am.
Chem. Soc. 2009, 131, 8410. (b) Nishinaga, A.; Yamazaki, S.; Matsuura, T.
Tetrahedron Lett. 1988, 29, 4115. (c) Wang, J. R.; Fu, Y.; Zhang, B. B.; Cui,
X.; Liu, L.; Guo, Q. X. Tetrahedron Lett. 2006, 47, 8293. (d) Grirrane, A.;
Corma, A.; Garcia, H. J. Catal. 2009, 264, 138. (e) Zhu, B.; Angelici, R. J.
Chem. Commun. 2007, 2157.
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Org. Lett. 2004, 6, 4997. (b) Shen, Y.; Tan, Z.; Chen, D.; Feng, X.; Li, M.;
C.-C. Guo, C. C.; Zhu, C. Tetrahedron. 2009, 65, 158. (c) Sureshkumar, D.;
Sud, A.; Klussmann, M. Synlett 2009, 1558. (d) Basle, O.; Li, C. J. Chem.
Commun. 2009, 4124. (e) Ying, B.-P.; Trogden, G. B.; Kohlman, D. T.;
Liang, S. X.; Xu, Y.-C. Org. Lett. 2004, 6, 1523. (f) Huang, L.; Zhang, X.;
Zhang, Y. Org. Lett. 2009, 11, 3730. (g) Chu, L.; Zhang, X.; Qing, F.-L. Org.
Lett. 2009, 11, 2197.
(6) (a) Kumaraswamy, G.; Sadaiah, K.; Ramakrishna, D. S.; Naresh, P.;
Sridhar, B.; Jagadeesh, B. Chem. Commun. 2008, 5324. (b) Kumaraswamy, G.;
Ankamma, K.; Pitchaiah, A. J. Org. Chem. 2007, 72, 9822. (c) Kumaraswamy,
G.; Rambabu, D.; Jayaprakash, N.; Venkata Rao, G.; Sridhar, B. Eur. J. Org.
Chem. 2009, 4158. (d) Kumaraswamy, G.; Venkata Rao, G.; Ramakrishna, G.
Synlett 2006, 1122. (e) Kumaraswamy, G.; Venkata Rao, G.; Narayana Murthy,
A.; Sridhar, B. Synlett 2009, 1180.
(7) (a) Liu, P.; Zhou, C.-Y.; Xiang, S.; Che, C.-M. Chem. Commun. 2010,
DOI: 10.1039/c001209b. (b) Han, W.; Ofial, A. R. Chem. Commun. 2009, 5024.
(c) Han, W.; Ofial, A. R. Chem. Commun. 2009, 6023. (d) Volla, C. M. R.; Vogel,
P. Org. Lett. 2009, 11, 1701. (e) Ohta, M.; Quick, M. P.; Yamaguchi, J.; Wunsch,
B.; Itami, K. Chem.;Asian J. 2009, 4, 1416. (f) Murata, S.; Teramoto, K.; Miura,
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(1) (a) Murahashi, S.-I.; Imada, Y. In Transition Metals for Organic Synth-
esis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, p
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Venkataramani, C. Angew. Chem., Int. Ed. 2002, 41, 2197. (d) Davies,
H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063.
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(2) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew.
Chem., Int. Ed. 2003, 42, 4077. (b) Shu, X. Z.; Xia, X. F.; Yang, Y. F.; Ji,
K. G.; Liu, X. Y.; Liang, Y. M. J. Org. Chem. 2009, 74, 7464. (c) Muller, P.;
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Brasse, C.; Backvall, J. E. Chem. Commun. 2002, 1144. (e) Jiang, G.; Chen, J.;
Huang, J. S.; Che, C. M. Org. Lett. 2009, 11, 4568. (f) Pandey, G.;
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3916 J. Org. Chem. 2010, 75, 3916–3919
Published on Web 05/06/2010
DOI: 10.1021/jo1005813
r
2010 American Chemical Society

Kumaraswamy et al.
JOCNote
TABLE 1. Screening of Catalysts, Oxidants, And Molar Ratios of
Substratea,b
TABLE 2. FeCl3 6H2O-Catalyzed Oxidative Allylation of Various
3
Tertiary Amines with Allyltributyltin 2a,b
entry
catalyst
RuCl3
Pd(OAc)2
CuCl2
CuCl
1d (equiv)
oxidant
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
T-HYDRO
TBHP(anhydrous)
T-HYDRO
T-HYDRO
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3
3
NR
NR
NR
30
50
42
NR
85
30
70
3
3
3
3
3
1
2
3
3
3
3
CuBr
CuI
FeCl2
FeCl3 6H2O
3
FeCl3 6H2O
FeCl3 6H2O
3
3
FeCl3 6H2O
FeCl3 6H2O
T-HYDRO
85
50
NR
NR
3
H2O2 (50% aqueous)
BzOOBz
urea peroxide
3
FeCl3 6H2O
FeCl3 6H2O
3
3
aAll reactions carried out in open air with 10 mol % of catalyst, 2
equiv of oxidant, and 1 equiv of 2. bYield based on 2 but not optimized.
NR = no reaction.
Interestingly, experiments were conducted with other
metal salts (RuCl3, CuCl2, FeCl2, and Pd(OAc)2) as catalyst
in combination with T-HYDRO for this transformation, but
none could catalyze the desired reaction (Table 1, entries
1-3), whereas CuCl, CuBr, and CuI initiated the reaction
and the corresponding product 3d was obtained albeit low
yields (Table 1, entries 4-6).
Molar ratios of reactants and solvents have shown influence
on product yields. The use of excess tertiary amine substrate
(1d/2 is 3:1 molar equiv) improved the desired product 3d yield
(Table 1, entries 9-11). In addition to T-HYDRO, other
oxidants, namely 50% aqueous H2O2, urea peroxide, and
benzoyl peroxide, were also investigated. Only H2O2 provided
the desired product but with low yields in comparison to
T-HYDRO (Table 1, entries 12-14). A brief survey of solvents
indicated that the acetonitrile is the only suitable solvent for
this reaction. Using anhydrous TBHP as oxidant did not
improve the product 3d yield (Table 1, entry 8). However, in
the absence of metal catalyst no reaction was observed. The
optimum catalyst loading was found to be 10 mol % (based on
2), while reducing it to 5 mol % led to a significant drop in the
yield of product 3d. Interestingly, replacing allyltributyltin with
allyltrimethylsilane8 or allyltrichlorosilane failed to generate
allyl-coupled product 3d. However, allyl dioxaborinane coup-
led with only sp3-carbon containing tertiary amine 6a under
the standard protocol furnished the expected product 7a in
70% yield (Table 2, entry 3).
aAll reactions carried out in open air with a molar ratio of 1:3:2 allyl-
tributyltin/tertiaryamine/T-HYDRO with 10 mol % of FeCl3 6H2O,
3
and reactions were quenched after 30 min. bYield based on 2 but not
optimized. All products gave satisfactory analytical data.
with 2 to lead to the products 3e and 3f in good yields (Table 2,
entry 1). Remarkably, the products 3e and 3f have an option of
being subjected to the RCM reaction followed by one-pot
oxidation, which would result in hydroxylated motifs as struc-
tural units.6a Similarly, N-(4-methoxyphenyl)tetrahydroquino-
line 4 and N-substituted N-methylbenzeneamine 6a-e with
various activating groups on the aromatic nucleus coupled with
2 efficiently furnished the corresponding products 5 and 7a-e9
with moderate to good yields (Table 2, entries 2 and 3). Cyclic
amines 8 and 10 were also coupled with allyl moiety to yield the
desired product 9 and 11 in moderate yield (Table 2, entries 4
and 5).
When N-benzyl-N-methyl-4-methoxybenzeneamine 6d was
reacted with 2 under standard protocols, allylation of the
methyl group was observed (Table 2, entry 3). This result
indicates that oxidation takes place at less hindered sp3
carbon rather than at the benzylic carbon. In a similar vein,
To check the generality of this protocol, the experiment was
extended to various tertiaryamine substrates under optimized
conditions, and the results are summarized in Table 2. Much to
our delight, N-allyl- and N-propagyl-tethered tetrahydroiso-
quinoline 1e and 1f underwent efficiently oxidative coupling
(8) Allylation of cyclic carbamate has been achieved with allyltrimethyl-
silane by electrochemical methods in moderate yields. See: Horii, D.;
Amemiya, F.; Fuchigami, T.; Atobe, M. Chem.;Eur. J. 2008, 14, 10382.
(9) The isolated product 7e was subjected to RCM and the resulting
product 3,4-dihydro N-(4-methoxyphenyl)piperidine isolated in 90% yield.
J. Org. Chem. Vol. 75, No. 11, 2010 3917

Kumaraswamy et al.
SCHEME 4. FeCl3/T-HYDRO-Induced Enantioselective
Allylation
JOCNote
SCHEME 2. FeCl3/T-HYDRO-Catalyzed ortho-Allylation of
Anisidine Derivative
SCHEME 5. Tentative Mechanism for Oxidation of Tertiary
Amines
SCHEME 3. FeCl3/T-HYDRO-Catalyzed Synthesis of 1,3-
Oxazolidines
unsymmetrical trans-2, 5-dialkylpyrrolidines which are ant
venom alkaloids.12
A tentative mechanism is proposed in analogy with Cu-
catalyzed oxidative reaction of tertiary amines.5 Initial acti-
vation by FeCl3-tBuOOH generates metal-coordinated imi-
nium intermediate A. Intermolecular nucleophilic addition
on iminium ion A could lead to the observed product
(Scheme 5).
In conclusion, we have demonstrated a rapid oxidative
coupling protocol with readily available benchtop chemical
hydrated FeCl3 in combination with T-HYDRO. To the best
of our knowledge, this is the first report wherein the allyl
functionality is introduced to the sp2- and sp3-carbon at-
tached to the nitrogen atom by FeCl3-mediated catalysis.
Remarkably, N-allyl- and N-propagyl-tethered tertiary
amines were also allylated, which can lead the RCM reaction
to generate cyclic nitrogen structural units.
12a, 12b, and 14 were subjected to oxidation using the above
conditions. To our surprise, allylation has occurred in both
cases at the ortho-position to amine of the aromatic ring, and
subsequent products 13a (70%), 13b (80%), and 15 (50%)10
were isolated in good yields (Scheme 2).
As a representative example, FeCl3/T-HYDRO induced
the oxidation of cyclic amines tethered with oxynucleophiles
16a, 16b, and 18, which were investigated in the absence of 2.
The expected products 1,3-oxazolidines 17a, 17b, and 19
were obtained with 55%, 65%, and 83% yields, respec-
tively.11 This result is significant, as alkyl tertiary amines
also undergo oxidation generating iminium ion which in turn
reacts with nucleophiles leading to the observed product
(Scheme 3).
Finally, we focused on diastereoselctive allylation of (S)-
2-(methoxymethyl)-N-(4-methoxyphenyl)pyrrolidine 20a
with 2 using similar conditions. We were pleased to see the
corresponding 5-allylated product 21a in moderate yield
(55%). By replacing methyl protection group with benzyl
in 20a, the substrate 20b led to trans-5-allylated product 21b
in good yield (77%) with er >99%. The er value was ana-
lyzed by HPLC on the chiral stationary phase. The relative
stereochemistry was confirmed by NOE studies (Scheme 4).
Routine synthetic manipulations on 21b could lead to
Experimental Section
1-Allyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline (3a). A 25
mLround-bottom flask was charged with FeCl3 6H2O (0.027 g,
3
10 mol %) and 1a (0.624 g, 3.0 mmol). To this were added
successively acetonitrile (5 mL) and allyltributyltin (0.33 g, 1.0
mmol) via syringe. The resulting reaction mixture was stirred at
room temperature for 30 min under open air. Thereafter, the
reaction mixture was filtered through a Celite pad and washed
with EtOAc (2 ꢀ 5 mL). The combined organic layers were
evaporated under reduced pressure. The crude residue was
purified by column chromatography (silica gel 100-200 mesh)
eluting with hexane-EtOAc (98: 2) to give 3a as a yellow oil
(0.211 g, 85%): 1H NMR (300 MHz, CDCl3) δ 7.21-7.06 (m,
6H), 6.83 (d, J = 7.9 Hz, 2H), 6.69-6.65 (m, 1H), 5.88-5.74
(m, 1H), 5.05-5.00 (m, 2H), 4.71 (t, J= 6.7 Hz, 1H), 3.66-3.52(m,
2H), 3.05-2.95 (m, 1H), 2.89-2.80 (m, 1H), 2.75-2.66 (m, 1H,),
(10) Further, the compound 15 was subjected to hydrogenation (10% Pd/C,
EtOH, 20 min, H2 balloon). The resulting product 2-propyl-4-methoxyaniline
was isolated and confirmed by 1H NMR and MS.
(11) (2-Pyrrolidine)ethanol did not cyclize under these conditions. Only
starting material was recovered.
(12) Shiosaki, K.; Rapoport, H. J. Org. Chem. 1985, 50, 1229.
3918 J. Org. Chem. Vol. 75, No. 11, 2010

Kumaraswamy et al.
JOCNote
2.50-2.40 (m, 1H); 13C NMR (75 MHz, CDCl3); δ 138.9,
135.6, 134.9, 129.2, 127.3, 126.4, 125.6, 117.1, 116.9, 113.8,
59.3, 41.8, 40.8, 27.3; IR (KBr, cm-1) 2917, 2837, 1638, 1597,
1503, 1474, 1391, 1222, 1154, 989, 914, 746, 691; HRMS (ESI)
calcd for C18H20N [M þ H]þ 250.1595, found 250.1588.
2,3,4,6,7,11b-Hexahydro[1,3]oxazino[2,3-a]isoquinoline (19).
4.20 (dd, J = 4.9, 11.0 Hz, 1H), 3.89-3.81 (m, 1H), 3.28-3.20
(m, 1H), 3.13-3.08 (m, 1H), 3.00-2.70 (m, 3H), 2.66 (p, J = 6.0
Hz, 1H), 2.23-2.07 (m, 1H), 1.34 (t, J = 13.4 Hz, 2H); 13C
NMR (75 MHz, CDCl3) 128.2, 127.7, 127.2, 125.9, 89.7, 68.3,
53.0, 46.0, 28.9, 22.8; IR (KBr, cm-1) 2924, 2850, 1636, 1463,
1267, 1084, 1058, 745, 666, 501; MS (ESIMS) m/z 190 (M þ H)þ;
HRMS (ESI) calcd for C12H16NO [M þ H]þ 190.1231, found
190.1241.
Tertiary aminopropanol 18 (0.191 g, 1.0 mmol) and FeCl3
3
6H2O (0.09 g, 10 mol %) were dissolved in acetonitile (5 mL).
To this stirred reaction mixture was added dropwise tert-
butyl hydroperoxide (0.257 mL, 70% tBuOOH in H2O,
2.0 mmol). The resulting reaction mixture was stirred at room
temperature for 30 min under open air. Thereafter, the reaction
mixture was filtered through a Celite pad and washed with
EtOAc (2 ꢀ 5 mL). The combined organic layers were evapo-
rated under reduced pressure. The crude residue was purified by
column chromatography on silica gel eluting with chloroform/
methanol (8:2) to give 19 as a yellow oil: yield yellow oil; yield
Acknowledgment. Financial support provided by the
DST, New Delhi, India (Grant No. SR/SI/OC-12/2007) and
UGC. CSIR (New Delhi) is also gratefully acknowledged for
awarding fellowships to A.N.M. and A.P.
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds along
with copies of 1H and 13C NMR spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
0.156 g (83%); H NMR (300 MHz, CDCl3) δ 7.28-7.24 (m,
1H), 7.15 (t, J = 3.5 Hz, 2H), 7.05-7.02 (m, 1H), 4.83 (s, 1H),
J. Org. Chem. Vol. 75, No. 11, 2010 3919