Selective functionalization of sp3 C - H bonds adjacent to nitrogen using (diacetoxyiodo)benzene (DIB)

Article abstract of DOI:10.1021/jo901583r

(Chemical Equation Presented) A PhI(OAc)₂ mediated selective functionalization of sp³C - H bonds adjacent to a nitrogen atom has been reported. When piperidine derivates were used, direct diacetoxylation of α and β sp³ C - H adjacent to a nitrogen atom were observed to afford various cis-2,3-diacetoxylated piperidines. On the other hand, tetrahydroisoquinoline derivatives gave various α-C - H functionalized products in the presence of PhI(OAc)₂. Nitroalkanes, dialkyl malonates, and β-keto ester are active participants in this coupling reaction. Meanwhile, α-amino nitriles can also be obtained by oxidative coupling of amineswithmalononitrile. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901583r

pubs.acs.org/joc
Selective Functionalization of sp3 C-H Bonds Adjacent to Nitrogen Using
(Diacetoxyiodo)benzene (DIB)
Xing-Zhong Shu, Xiao-Feng Xia, Yan-Fang Yang, Ke-Gong Ji, Xue-Yuan Liu, and
Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P.R. China
liangym@lzu.edu.cn
Received July 22, 2009
A PhI(OAc)2 mediated selective functionalization of sp3 C-H bonds adjacent to a nitrogen atom has been
reported. When piperidine derivates were used, direct diacetoxylation of R and β sp3 C-H adjacent to a
nitrogen atom were observed to afford various cis-2,3-diacetoxylated piperidines. On the other hand,
tetrahydroisoquinoline derivatives gave various R-C-H functionalized products in the presence of
PhI(OAc)2. Nitroalkanes, dialkyl malonates, and β-keto ester are active participants in this coupling reac-
tion. Meanwhile, R-amino nitriles can also be obtained by oxidative coupling of amines with malononitrile.
Introduction
(DIB), which is found to be useful for the oxidative functio-
nalization of various functional groups.3 We envision that
iminium ions II could be formed in the presence of DIB.
β-Hydrogen elimination of II and further transformation
should afford the difunctionalized products (Scheme 1a).
On the other hand, direct capture of iminium ions II with
nucleophiles should lead to the monofunctionalized pro-
ducts (Scheme 1b). Herein we report our research on the
selective functionalization of sp3 C-H bonds adjacent to a
nitrogen atom using DIB as the oxidant.
Direct formation of C-C, C-O, and C-N bonds from
unactivated carbon-hydrogen bonds is one of the most
challenging projects in organic synthesis.1 In this content,
selective functionalization of C-H bonds adjacent to a
nitrogen atom is of great importance due to the fact that
important building blocks can be formed in a single step
using this approach.2 Various methods such as lithiation,
radical method, and transition metal catalysis have been
developed to achieve this functionalization.2 Our effort is to
achieve this transformation by oxidative method using hy-
pervalent iodine(III) reagents. Hypervalent iodine(III) re-
agents have recently received much attention due to their low
toxicity, easy handling, and high reactivity.3 The most well-
known representative of this class is (diacetoxyiodo)benzene
Results and Discussion
Selective cis-Diacetoxylation of Tertiary Amines Using
(Diacetoxyiodo)benzene (DIB). Recently, direct formation
of C-O bonds based on R-C-H activation of amines
has received great attention. One of the earliest strategies
was disclosed by Brown and further developed by Shono. It
utilizes electrochemical, anodic oxidation of tertiary amines
to deliver the corresponding R-aminals (Scheme 2a).4
Weinreb developed an alternative to the electrochemical
(1) For recent reviews on C-H activation and functionalization, see:
(a) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077. (b) Ritleng,
V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
(2) For recent reviews on activation of sp3 C-H bonds adjacent to a
nitrogen atom, see: (a) Li, C. J. Acc. Chem. Res. 2009, 42, 335. (b) Campos,
K. R. Chem. Soc. Rev. 2007, 36, 1069. (c) Doye, S. Angew. Chem., Int. Ed.
2001, 40, 3351. (d) Murahashi, S.-I. Angew. Chem., Int. Ed. 1995, 34, 2443.
(3) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523. (c) Togo, H.;
Katohgi, M. Synlett 2001, 565. (d) Stang, P. J.; Zhdankin, V. V. Chem. Rev.
1996, 96, 1123.
(4) (a) Shono, T.; Matsumura, Y.; Onomura, O.; Ogaki, M.; Kanazawa,
T. J. Org. Chem. 1987, 52, 536. (b) Shono, T.; Matsumura, Y.; Tsubata, K.
Org. Synth. 1985, 206. (c) Shono, T. Tetrahedron 1984, 811. (d) Shono, T.;
Hamaguchi, H.; Matsumura, Y. J. Am. Chem. Soc. 1975, 97, 4264.
(e) Weinberg, N. L.; Brown, E. A. J. Org. Chem. 1966, 31, 4058.
7464 J. Org. Chem. 2009, 74, 7464–7469
Published on Web 09/04/2009
DOI: 10.1021/jo901583r
r
2009 American Chemical Society

Shu et al.
JOCArticle
SCHEME 1. Selective Functionalization of Tertiary Amine
SCHEME 3. cis-Diacetoxylation of 1-Phenylpiperidine 1a
SCHEME 4. Proposed Mechanism
SCHEME 2. General Strategies for C-O Formation Adjacent
to Nitrogen
co-workers reported the OsO4-catalyzed cis-dihydroxylation
of alkenes and its asymmetric version.9 Because of the high
cost and toxicity of OsO4, various alternative metal catalysts
for alkene cis-dihydroxylations have been developed in the
past years.10 Currently, Celik reported that hypervalent
iodine compound can also mediate this transformation in
the absence of metal.11 However, an efficient method for the
direct dioxygenation of less reactive methylene group is not
disclosed so far. Herein, we report a direct 2,3-diacetoxyla-
tion of R,β-C-H of piperidine derivates promoted by hy-
pervalent iodine(III).
We focused our studies on the acetoxylation of piperidine
derivates using DIB. To a mixture of 1-phenylpiperidine
˚
1a (0.2 mmol) and 5 A molecular sieves (50 mg) in i-PrOH
oxidation, which take advantage of the 1,5-hydrogen atom
transfer, to achieve R-methoxylation of N-heterocycles
(Scheme 2b).5 Murahashi mimicked cytochrome P-450 type
reactivity using Ru(II) and Os(III) catalysts to afford various
R-oxygenated compounds (Scheme 2c).6 Very recently, Yu
and Corey reported a similar pathway, in the presence of
directing groups, to achieve the selective acetoxylation of
R-CH3 and β-CH2, respectively (Scheme 2d).7 Despite these
significant progress on the C-O bond formation via C-H
bond functionalization adjacent to nitrogen atom, direct
functionalization of β-C-H still remains a great challenge.
To the best of our knowledge, there are no generally effective
methods for dioxygenation of the both positions.8
(2 mL), DIB (4 equiv) was added in one portion. After
stirring at room temperature for 6 h, cis-2,3-diacetoxylated
product 2a was isolated in a 42% yield (Scheme 3).12 The
proposed mechanism of the formation of 2a is shown in
Scheme 4. Similar to strategies of the oxidation of tertiary
amines by either electrochemical pathway (Scheme 2a) or
metal-catalyzed pathway (Scheme 2c), intermediate iminium
(10) For Fe-catalyzed dihydroxylations: (a) Fujita, M.; Costas, M.; Que,
L., Jr. J. Am. Chem. Soc. 2003, 125, 9912. (b) Chen, K.; Costas, M.; Kim, J.;
Tipton, A. K.; Que, L., Jr. J. Am. Chem. Soc. 2002, 124, 3026. (c) Chen, K.;
Que, L. Angew. Chem., Int. Ed. 1999, 38, 2227. For Mn-catalyzed dihydroxyla-
tions: (d) Brinksma, J.; Schmieder, L.; Van Vliet, G.; Boaron, R.; Hage, R.; De
Vos, D. E.; Alsters, P. L.; Feringa, B. L. Tetrahedron Lett. 2002, 43, 2619. (e) De
Vos, D. E.; De Wildeman, S.; Sels, B. F.; Grobet, P. J.; Jacobs, P. A. Angew.
Chem., Int. Ed. 1999, 38, 980. For Ru-catalyzed dihydroxylations: (f) Yip, W.-P.;
Yu, W.-Y.; Zhu, N.; Che, C.-M. J. Am. Chem. Soc. 2005, 127, 14239. (g) Ho,
C.-M.; Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2004, 43, 3303.
(h) Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353. (i) Shing, T. K. M.;
Tai, V. W. F.; Tam, E. K. W. Angew. Chem., Int. Ed. 1994, 33, 2312. For Pd-
catalyzed dihydroxylations: (j) Wang, A.; Jiang, H.; Chen, H. J. Am. Chem. Soc.
2009, 131, 3846. (k) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179.
On the other hand, dioxygenation continues to be a
fascinating and useful area of research since Sharpless and
(5) (a) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002, 67, 4337.
(b) Han, G.; LaPorte, M.; McIntosh, M. C.; Weinreb, S. M. J. Org. Chem.
1996, 61, 9483.
€
(6) (a) Murahashi, S.-I.; Naota, T.; Miyaguchi, N.; Nakato, T. Tetra-
hedron Lett. 1992, 33, 6991. (b) Murahashi, S.-I.; Saito, T.; Naota, T.;
Kumobakashi, H.; Akutogaua, S. Tetrahedron Lett. 1991, 32, 5991.
(c) Murahashi, S.-I.; Saito, T.; Naota, T.; Kumobayashi, H.; Akutapxwa,
S. Tetrahedron Lett. 1991, 32, 2145. (d) Murahashi, S.-I.; Naota, T.;
Kuwzbara, T.; Saito, T.; Kumobayashi, H.; Akutagawa, S. J. Am. Chem.
Soc. 1990, 1l2, 7820. (e) Murahashi, S.-I.; Naota, T.; Yonemura, K. J. Am.
Chem. Soc. 1988, 110, 8256.
(7) (a) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391.
(b) Wang, D.-H.; Hao, X.-S.; Wu, D.-F.; Yu, J.-Q. Org. Lett. 2006, 8, 3387.
(8) The only example was achieved by electrochemical oxidation, see
ref 3a.
(11) Celik, M.; Alp, C.; Coskun, B.; Gultekina, M. S.; Balci, M. Tetra-
hedron Lett. 2006, 47, 3659.
(12) The cis-geometry was confirmed by the 1H NMR spectrum. The
observed coupling constants, J2,3 = 4.8 Hz for products 2a-2c, 2g, and
J
2,3 = 4.4 Hz for product 2d, are within the coupling constant of the two cis-
hydrogen of cyclohexane [JHH (ax-ex, cis): 0-5 Hz, JHH (ax-ax, trans):
6-14 Hz]. The coupling constants of similar structure, such as (cis and trans)-
2,3-dihydroxypyrans and substituted tetrahydroquinoline, can also be used
for reference. For detail, see: (a) Levecque, P.; Gammon, D.; Kinfe, H. H.;
Jacobs, P.; De Vos, D.; Sels, B. Org. Biomol. Chem. 2007, 5, 1800. (b) Sugai,
T.; lkeda, H.; Ohta, H. Tetrahedron 1996, 52, 8123. (c) Sridharan, V.;
Avendano, C.; Menendez, J. C. Tetrahedron 2007, 63, 673. Furthermore,
hypervalent iodine(III) reagents promoted dioxygenation of alkenes always
afford the cis-products. The mechanism of the formation of the cis-products
have been proposed before. For detail, see (d) Rebrovic, L.; Koser, G. F.
J. Org. Chem. 1984, 49, 2462. Also see ref 11.
~
ꢀ
ꢀ
€
(9) (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. (b) Johnson, R. A.;
Sharpless, K. B. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
VCH: New York, 2000.
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TABLE 1. DIB Promoted 2,3-Diacetoxylation of Aminesa
a
b
Unless noted, reaction was carried out with 1(0.2mmol),PhI(OAc)2 (2.2 equiv), and 5 A molecular sieves (50 mg) in 2 mL of solvent. PhI(OAc)2 (4equiv) used.
˚
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SCHEME 5. DIB Promoted 1,2-Diacetoxylation
SCHEME 6. DIB Mediated Cross Coupling Reaction and
Proposed Mechanism
ion A was formed in the presence of PhI(OAc)2. β-Hydrogen
elimination afforded R,β-unsaturated compound B, which
underwent electrophilic addition of PhI(OAc)2 to the double
bond to afford trans-compound D. Subsequent elimination
of iodobenzene via SN2 type nucleophilic substitution gave
cis-2,3-diacetoxylated product 2a.11,12d
TABLE 2. DIB Mediated Cross Coupling of Tertiary Amines with
Nitroalkanesa
Piperidine with various aryl substituents at the nitrogen
were investigated, as shown in Table 1. Substituent effect on
aryl groups was evident for both para- and meta-substituted
1-arylpiperidines and the desired products were obtained
with moderate yields, whereas ortho-substituents always led
to the decomposition of substrates. Tertiary amines with
electron-rich substituents were relatively more reactive and
afforded the product with increased yields and in the mean-
time, the reaction could be carried out at lower temperature
(entries 4, 5, 9, and 10). On the contrary, substrates with
electron-withdrawing substituents were less reactive (entries
2, 3, 7, and 8). A more electron-withdrawing group such as
acetyl did not give any diacetoxylated product, contrarily,
piperidine 1j with two donating groups afforded 2j in a
46% yield (entries 6 and 10). 1-(Naphthalen-1-yl)piperidine
1m was also oxidized to desired product 2m in a low yield
(entry 13).
Although 1-phenylpiperidines, containing chlorine and
methyl substituents at the ortho position led to decomposi-
tion in the oxidative system, a benzyl group was tolerated.
Amines 1n and 1o were oxidized to diacetoxylated products
in 45% and 32% yields, respectively (Scheme 5).
aThe reaction was run with 1p-1t (0.2 mmol), PhI(OAc)2 (1.2 equiv),
and 5 A molecular sieves (50 mg) in 1 mL of RCH2NO2 at rt.
˚
DIB Mediated Cross-Dehydrogenative Coupling (CDC)
Reaction. CDC reaction involving R-C-H bonds in amines
has attracted great attention recently due to its atom- and
step-economy, high efficiency, and low cost.13-17 Murahashi,13
Doyle,14 Li,15 and others16 have developed this oxidative
coupling reaction via transition metal catalysis in the pre-
sence of oxidants. Very recently, Todd developed a metal-
free CDC reaction using DDQ as oxidant with limited
reaction scope.17 Herein, we report our study in this area
by using hypervalent iodine(III) reagents.
When tetrahydroisoquinoline 1p was used to investigate
the oxidative functionalization in CH3NO2, a cross-dehy-
drogenative coupling (CDC) product 3a was isolated in a
91% yield after 2 h. The formation of 3a can be explained by
the mechanism that oxidation of tertiary amine 1p affords
the intermediate iminium ion F, subsequently, it is captured
by a nucleophile to generate the coupling product 3a
(Scheme 6).
Various β-nitroamine derivatives were generated in good
to high yields under the above conditions, as shown in
Table 2. The steric effect of nucleophiles was obvious.
CH3NO2 always gave better results than CH3CH2NO2
(3 vs 4). The electronic nature of aryl substituents of tetra-
hydroisoquinolines also affected the reactivities too. Elec-
tron-rich aryl groups gave slightly lower yields of desired
products, whereas electron-poor substituent afforded the
best yield (up to 94%) among all results (3b and 3c vs 3d).
(13) (a) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem.
Soc. 2008, 130, 11005. (b) Murahashi, S.; Komiya, N.; Terai, H. Angew.
Chem., Int. Ed. 2005, 44, 6931. (c) Murahashi, S.; Komiya, N.; Terai, H.;
Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312.
(14) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am.
Chem. Soc. 2006, 128, 5648.
(15) For select examples, see: (a) Zhao, L.; Li, C.-J. Angew. Chem., Int.
Ed. 2008, 47, 7075. (b) Basle, O.; Li, C.-J. Org. Lett. 2008, 10, 3661. (c) Basle,
O.; Li, C.-J. Green Chem. 2007, 9, 1047. (d) Li, Z.; Bohle, D. S.; Li, C.-J. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 8928. (e) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2005, 127, 3672. (f) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (g) Li,
Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 15, 3173. (h) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2004, 126, 11810. (i) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997.
(16) (a) Sud, A.; Sureshkumarz, D.; Klussmann, M. Chem. Commun.
2009, 3169. (b) Chu, L. L.; Zhang, X. G.; Qing, F.-L. Org. Lett. 2009, 11,
2197. (c) Volla, C. M. R.; Vogel, P. Org. Lett. 2009, 11, 1701. (d) Xu, X.-L.;
Li, X.-N. Org. Lett. 2009, 11, 1027. (e) Shen, Y.-M.; Li, M.; Wang, S.-Z.;
Zhan, T.-G.; Tan, Z.; Guo, C.-C. Chem. Commun. 2009, 8, 953. (f) Zhang, Y.;
Fu, H.; Jiang, Y.; Zhao, Y.-F. Org. Lett. 2007, 19, 3813.
(17) Tsang, A. S.-K.; Todd, M. H. Tetrahedron Lett. 2009, 50, 1199.
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TABLE 3. Coupling Reaction of Tertiary Amines with Activated
Methylene Compoundsa
ism of this transformation was still unclear. A probably
pathway is that a certain oxidative degradation of malono-
nitrile with the cleavage of the C-CN bond by PhI(OAc)2
takes place and gives the corresponding products 6.15g
According to this way, 2 equiv of PhI(OAc)2 are needed at
least to complete this transformation. However, 1.2 equiv of
PhI(OAc)2 was enough in this reaction.
Conclusions
In conclusion, we have reported a PhI(OAc)2 mediated
selective functionalization of sp3 C-H bonds adjacent to a
nitrogen atom. For piperidine derivates, various cis-2,3-
diacetoxylated piperidines were synthesized via direct diace-
toxylation of R and β sp3 C-H adjacent to a nitrogen atom.
On the other hand, for tetrahydroisoquinoline in the pre-
sence of nucleophiles, such as nitroalkanes, dialkyl malo-
nates, and β-keto ester, R-C-H functionalized products
were obtained. Furthermore, R-amino nitriles can also be
obtained from the oxidative coupling of amines with malo-
nonitrile.
aThe reaction was run with 1p (0.2 mmol), activated methylene
˚
compounds (2 equiv), PhI(OAc)2 (1.2 equiv), and 5 A molecular sieves
(50 mg) in 2 mL of 1,2-dimethoxyethane (DME) at rt.
TABLE 4. Oxidative Synthesis of a-Amino Nitrilesa
Experimental Section
General Procedure for the Preparation of 1-Arylpiperidine-2,3-
diyl Diacetate. To a stirred solution of 1-(4-chlorophenyl)-
˚
piperidine 1b (0.2 mmol) and 5 A molecular sieve (50 mg) in
CH3CN (2 mL), PhI(OAc)2 (0.44 mmol, 2.2 equiv) was added.
After completion of the addition, the solution was stirred at
room temperature. When the reaction was considered complete
as determined by TLC analysis, sodium thiosulfate was added
and the mixture was stirred for several minutes. After removal of
the solvent under reduced pressure, the residue was flash
chromatographed on silica gel to give desired product 2b in a
35% yield.
aThe reaction was run with 1 (0.2 mmol), malononitrile (2 equiv),
˚
PhI(OAc)2 (1.2 equiv), and 5 A molecular sieves (50 mg) in 2 mL of
1,2-dimethoxyethane (DME) at rt.
cis-1-(4-Chlorophenyl)piperidine-2,3-diyl Diacetate (2b), so-
lid; mp 102-104 °C. 1H NMR (400 MHz, CDCl3): δ
7.16-7.19 (m, 2 H), 6.84-6.85 (d, J = 4.8 Hz, 1 H), 6.70-
6.73 (m, 2 H), 3.98-4.01 (m, 1 H), 3.45-3.49 (m, 1 H),
3.09-3.16 (m, 1 H), 1.90-2.24 (m, 10 H). 13C NMR (100
MHz, CDCl3): δ 168.9, 168.8, 146.0, 128.8, 121.6, 113.6, 89.2,
59.7, 49.2, 26.6, 23.8, 20.9, 20.7. IR (neat, cm-1) 3263, 3045,
2957, 2926, 2853, 1763, 1674, 1596, 1497, 1372, 1238, 1205, 1094,
1010, 813, 717, 667, 602, 507. HRMS (EI) m/z: calcd for
C15H18ClNO4 M þ H = 312.0997; found 312.1004.
In addition to nitroalkanes, this metal-free CDC reaction
was also applicable to activated methylene compounds
(Table 3). Dialkyl malonate derivatives and β-keto esters
reacted smoothly with tertiary amine under very mild con-
ditions, affording the desired products in good to high yields.
Oxidative Synthesis of a-Amino Nitriles. When malononi-
trile was used as the pronucleophile to investigate the
coupling reaction with tertiary amine, instead of β-dicya-
no-substituted tetrahydroisoquinoline derivate, R-amino ni-
trile 6a was obtained as the sole product.
R-Amino nitriles are extremely useful synthetic intermedi-
ates. The nitrile functionality can be hydrolyzed easily to
produce R-amino acids, and nucleophilic additions to the
nitrile group provide access to R-amino aldehydes, R-amino
ketones, R-amino alcohols, and 1,2-diamines. An attractive
way to R-amino nitriles is achieved by oxidative cross
coupling reactions. However, toxic cyanides were always
needed.13,18 As a result, an alternative nitrile-saving
source, malononitrile, should be encouraged in this efficient
route.
cis-1-(2-Benzyl-phenyl)piperidine-2,3-diyl Diacetate (2n) was
obtained according to the above method using 2.2 equiv of
PhI(OAc)2 and 4 equiv of H2O in CH3CN/AcOH (20:1) at room
temperature. The reaction mixture was chromatographed using
10:1 hexanes/EtOAc to afford 28 mg (45%) of the indicated
1
compound as a solid after 12 h; mp 76-78 °C. H NMR (400
MHz, CD3COCD3): δ 7.26-7.31 (m, 3 H), 7.15-7.20 (m, 4 H),
6.95-6.97 (m, 2 H), 6.69-6.70 (d, J = 4.8 Hz, 1 H), 4.01-4.09
(m, 3 H), 3.27-3.32 (m, 1 H), 2.71-2.76 (m, 1 H), 2.11-2.19 (m,
1 H), 1.81-2.06 (m, 6 H), 1.74 (s, 3 H). 13C NMR (100 MHz,
CD3COCD3): δ 169.7, 169.6, 150.3, 143.1, 138.9, 131.8, 130.6,
129.6, 128.3, 127.1, 124.8, 123.2, 91.4, 63.1, 57.2, 38.4, 27.7, 25.7,
21.3, 21.0. IR (neat, cm-1) 3486, 3060, 3026, 2960, 2925, 2871,
1763, 1597, 1490, 1451, 1371, 1241, 1205, 1009, 987, 762, 734,
700, 607, 561, 532. HRMS (EI) m/z: calcd for C22H25NO4 M þ
H = 368.1856; found 368.1851.
Then we investigated various tetrahydroisoquinolines in
the synthesis of R-amino nitriles. The results were shown in
table 4. R-Amino nitriles 6 were always obtained in moderate
to good yields. Tetrahydroisoquinolines with an electron-
rich group gave slightly better results. The detailed mechan-
General Procedure for the Preparation of β-Nitroamine Deri-
vatives 3a-3e, 4a-4d. To a stirred solution of tetrahydroiso-
quinolines (0.2 mmol) and 5 A molecular sieves (50 mg) in 1 mL
˚
of RCH2NO2, PhI(OAc)2 (1.2 equiv) was added in one portion.
Then the mixture was allowed to stir at room temperature.
(18) North, M. Angew. Chem., Int. Ed. 2004, 43, 4126.
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2-(1,2,3,4-Tetrahydro-2-phenylisoquinolin-1-yl)-
When the reaction was considered complete as determined by
TLC analysis, the reaction mixture was then filtered and eva-
porated under reduced pressure. The residue was purified by
flash chromatography on alkalescence silica gel to afford corre-
sponding products.
Dimethyl
malonate (5a). The reaction mixture was chromatographed
using 10:1 hexanes/EtOAc to afford 38.6 mg (57%) of the
indicated compound as an oil after 5.5 h. 1H NMR (400 MHz,
CD3COCD3): δ 7.23-7.09 (m, 6 H), 7.02-7.00 (d, J = 8.4 Hz,
2 H), 6.74-6.70 (t, J = 7.2 Hz, 1 H), 5.68-5.66 (d, J = 9.6 Hz,
1 H), 4.01-3.98 (d, J = 9.6 Hz, 1 H), 3.74-3.68 (m, 2 H), 3.63 (s,
1,2,3,4-Tetrahydro-1-(nitromethyl)-2-phenylisoquinoline (3a).
The reaction mixture was chromatographed using 20:1 hexanes/
EtOAc to afford 48.9 mg (91%) of the indicated compound as a
solid after 2 h; mp 84-86 °C. 1H NMR (400 MHz, CDCl3): δ
7.28-7.16 (m, 6 H), 7.12-7.10 (d, J = 7.2 Hz, 1 H), 6.97-6.95
(d, J = 8.4 Hz, 2 H), 6.85-6.81 (t, J = 7.2 Hz, 1 H)), 5.55-5.51
(t, J = 7.2, 1 H), 4.86-4.81 (m, 1 H), 4.56-4.51 (m, 1 H),
3 H), 3.53 (s, 3 H), 3.10-3.02 (m, 1 H), 2.92-2.85 (m, 1 H). 13
C
NMR (100 MHz, CD3COCD3): δ 169.4, 168.5, 150.6, 137.1,
136.6, 130.5, 130.4, 129.0, 128.4, 127.3, 119.9, 116.7, 60.2, 59.6,
53.4, 53.3, 53.2, 43.3, 26.9. HRMS (EI) m/z: calcd for
C20H21NO4 M þ H = 340.1550; found 340.1554.
3.66-3.55 (m, 2 H), 3.10-3.02 (m, 1 H), 2.80-2.73 (m, 1 H). 13
C
General Procedure for the Synthesis of r-Amino Nitriles
6a-6c. To a stirred solution of tetrahydroisoquinoline 1p (0.2
mmol), malononitrile (2 equiv), and 5 A molecular sieves
NMR (100 MHz, CDCl3): δ 148.4, 135.2, 132.9, 129.5, 129.1,
128.1, 126.9, 126.6, 119.4, 115.1, 78.7, 58.1, 42.0, 26.4. HRMS
(EI) m/z: calcd for C16H16N2O2 M þ H = 269.1285; found
269.1281.
˚
(50 mg) in 2 mL of 1,2-dimethoxyethane (DME), PhI(OAc)2
(1.2 equiv) was added in one portion. Then the mixture was
allowed to stir at room temperature. When the reaction was
considered complete as determined by TLC analysis, the reac-
tion mixture was then filtered and evaporated under reduced
pressure. The residue was purified by flash chromatography on
alkalescence silica gel to afford corresponding products 6.
1,2,3,4-Tetrahydro-2-phenylisoquinoline-1-carbonitrile (6a).
The reaction mixture was chromatographed using 20:1 hex-
anes/EtOAc to afford 28.1 mg (60%) of the indicated compound
as a solid after 5 h; mp 99-101 °C. 1H NMR (400 MHz, CDCl3):
δ 7.36-7.22 (m, 6 H), 7.09-7.07 (m, 2 H), 7.03-6.99 (t, J = 7.6
Hz, 1 H), 5.51 (s, 1 H), 3.80-3.75 (m, 1 H), 3.52-3.46 (m, 1 H),
3.20-3.12 (m, 1 H), 3.00-2.94 (m, 1 H). 13C NMR (100 MHz,
CDCl3): δ 148.4, 134.6, 129.6, 129.6, 129.4, 128.8, 127.1, 126.9,
121.9, 117.6, 53.2, 44.2, 28.5. IR (KBr, cm-1) 3627, 3461, 2983,
2925, 2853, 1888, 1739, 1598, 1374, 1242. Anal. Calcd for
C16H14N2: C, 82.02; H, 6.02; N, 11.96. Found: C, 82.11; H,
6.23; N, 11.89.
1,2,3,4-Tetrahydro-1-(1-nitroethyl)-2-phenylisoquinoline (4a).
The reaction mixture was chromatographed using 20:1 hexanes/
EtOAc to afford 39.6 mg (70%) of the indicated diastereoi-
somers (2:1) as an oil after 1.5 h. 1H NMR (400 MHz,
CD3COCD3, 2:1 mixture of diastereoisomers): δ 7.36-7.00
(m, 8 H), 6.78-6.70 (m, 1 H), 5.33-5.09 (m, 2 H), 3.93-3.55
(m, 2 H), 3.10-2.88 (m, 2 H), [1.67-1.65 (d, J = 6.8 Hz),
1.60-1.58 (d, J = 6.4 Hz), 3 H]. 13C NMR (100 MHz,
CD3COCD3, 2:1 mixture of diastereoisomers): δ 150.8, 150.6,
137.3, 136.8, 135.5, 133.9, 130.7, 130.6, 130.4, 130.2, 129.4,
128.7, 127.5, 127.1, 120.2, 119.8, 116.8, 115.8, 89.9, 87.0, 63.6,
62.4, 44.4, 43.2, 27.5, 26.8, 18.2, 17.9. HRMS (EI) m/z: calcd for
C17H18N2O2 M þ H = 283.1441; found 283.1437.
General Procedure for the Coupling Reaction of Tertiary
Amines with Activated Methylene Compounds. To a stirred
solution of tetrahydroisoquinoline 1p (0.2 mmol), activated
˚
methylene compounds (2 equiv) and 5 A molecular sieves
(50 mg) in 2 mL of 1,2-dimethoxyethane (DME), PhI(OAc)2
(1.2 equiv) was added in one portion. Then the mixture was
allowed to stir at room temperature. When the reaction
was considered complete as determined by TLC analysis,
the reaction mixture was then filtered and evaporated under
reduced pressure. The residue was purified by flash chro-
matography on alkalescence silica gel to afford corresponding
products.
Acknowledgment. We thank the NSF (NSF-20732002,
NSF-20872052) for financial support.
Supporting Information Available: Detailed experimental
procedure and 1H NMR and 13C NMR spectra of all com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 19, 2009 7469