Asymmetric synthesis of aminochromanes via intramolecular indium-mediated allylation of chiral hydrazones

Article abstract of DOI:10.1021/jo901195g

(Chemical Equation Presented) The asymmetric intramolecular indium-mediated cyclization reaction delivers chromanes with excellent diastereoselectivity (68-91% yield, dr >99:1). The reaction was efficient for aryl substrates with both electron-withdrawing

Full text of DOI:10.1021/jo901195g

pubs.acs.org/joc
intermolecular C-C bond formation, the corresponding
Asymmetric Synthesis of Aminochromanes via
Intramolecular Indium-Mediated Allylation of Chiral
Hydrazones
intramolecular cyclizations are somewhat limited. Examples
include the cyclization of enynes,4 cyclization of tethered
propargyl bromides to carbonyl compounds,5 Pd/In-
mediated cyclization,6 atom-transfer cyclization,7 intramole-
cular allylindation of terminal alkynes,8 and cyclization via
hydrometalation of alkynes.9 As part of our continued effort
to expand the synthetic utility of organoindium reagents, we
disclose for the first time an efficient asymmetric indium-
mediated intramolecular cyclization of chiral hydrazone
derivatives and its application toward the synthesis of
chromane antibiotics.
Hydrazones are relatively stable imine equivalents and are
significantly less reactive than imines. Consequently, there
are fewer reports of organometallic addition to hydrazones
than to imines.10 Due to their greater reactivity, imines are
also prone to hydrolytic degradation and tend to be unstable
during purification or prolonged storage. This is particularly
problematic for aliphatic imines.11 This limits their utility as
precursors for chiral amine compounds. Therefore, addition
of carbon fragments to CdNX bonds (where X=stabilizing
group) and related compounds are increasingly being used
for the synthesis of chiral amines.12 Practical catalytic,
enantioselective addition to CdN bonds is highly desir-
able.13 Chiral auxiliaries offer a useful approach for chiral
amine synthesis. The use of a stabilizing group allows a chiral
auxiliary to be incorporated and cleaved without affecting
the efficiency of the process.14,15
Debasis Samanta, Robert B. Kargbo, and Gregory
R. Cook*
Department of Chemistry and Molecular Biology, North
Dakota State University, Department 2735, P.O. Box 6050,
Fargo, North Dakota 58108-6050
gregory.cook@ndsu.edu
Received June 5, 2009
The asymmetric intramolecular indium-mediated cycliza-
tion reaction delivers chromanes with excellent diaster-
eoselectivity (68-91% yield, dr >99:1). The reaction was
efficient for aryl substrates with both electron-withdraw-
ing and -donating groups. Carboxylic acid additives were
found to be necessary for optimal reaction.
We have reported several examples of highly efficient stereo-
selective intermolecular allylations of chiral hydrazones.16
(4) Lee, P. H.; Kim, S.; Lee, K.; Seomoon, D.; Kim, H.; Lee, S.; Kim, M.;
Han, M.; Noh, K.; Livinghouse, T. Org. Lett. 2004, 6, 4825.
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Y. Synlett 2004, 45.
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4376. (b) Nguyen, V. C.; Kim, Y.-T.; Yu, Y.-K.; Kang, H.-Y. Bull. Korean
Chem. Soc. 2005, 26, 711.
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Y. Tetrahedron Lett. 2002, 43, 4585. (b) Cook, G. R.; Hayashi, R. Org. Lett.
2006, 8, 1045.
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124, 5640. (b) Friestad, G. K.; Ding, H. Angew. Chem., Int. Ed. 2001, 40,
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42, 5061. (b) Friestad, G. K.; Qin, G. K, J. J. Am. Chem. Soc. 2001, 123, 9922.
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Chem., Int. Ed. 2000, 112, 4280. (b) Saaby, S.; Bayo, P.; Aburel, P. S.;
Jørgensen, K. A. J. Org. Chem. 2002, 67, 4352. (c) Johannsen, M. Chem.
Commun. 1999, 2233.
Chiral amine compounds display unique biological prop-
erties, and this has inspired a great deal of effort in the
development of asymmetric methods for their synthesis.1
Furthermore, the increased need for enantiopure medicinal
compounds and the rapid advancement for the field of
asymmetric synthesis encourages the development of syn-
thetic methods that utilize reagents and promoters of low
relative toxicity.2 Indium has emerged as a metal of high
potential in organic synthesis because of its unique proper-
ties. For example, indium metal is relatively unaffected by air
or oxygen at ambient temperatures and can be handled safely
without apparent toxicity. Allyl indium reagents are also
tolerant of many functional groups and display low basicity
and selective nucleophilicity, which permits excellent che-
moselective transformations.3 Despite its extensive utility in
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Maryanoff, C. A. Chem. Rev. 2004, 104, 1431. (b) Weinreb, S. M. Top. Curr.
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(15) (a) Friestad, G. K. Eur. J. Org. Chem. 2005, 3157. (b) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895. (c) Davis, F. A.; Zhou,
P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27, 13. (d) Bloch, R. Chem. Rev. 1998,
98, 1407. (e) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984. (f) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253. (g) Zhou, P.; Chen, B.; Davis, F. A. Tetrahedron
2004, 60, 8003. (h) Friestad, G. K. Eur. J. Org. Chem. 2005, 3157. (i) Ogawa,
C.; Sugiura, M.; Kobayashi, S. J. Org. Chem. 2002, 67, 5359.
(16) Cook, G. R.; Maity, B. C.; Kargbo, R. Org. Lett. 2004, 6, 1741.
(1) (a) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–2569.
(b) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069. (c) Bloch, R. Chem.
Rev. 1998, 98, 1407. (d) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry
1997, 8, 1895. (e) Denmark, S. E.; Nicaise, O. J.-C. Chem. Commun. 1996,
999.
(2) (a) Li, C.-J. Chem. Rev. 1993, 93, 2023. (b) Noyori, R. Green Chem.
2003, 5, G37. (c) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751. (d) Yanada,
R.; Obika, S.; Nishimori, N.; Yamauchi, M.; Takemoto, Y. Tetrahedron
Lett. 2004, 45, 2331. (e) Li, C.-J. Acc. Chem. Res. 2002, 35, 533.
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(b) Ranu, B. C.; Dutta, J.; Guchhait, S. K. J. Org. Chem. 2001, 66, 5624.
DOI: 10.1021/jo901195g
r
Published on Web 08/24/2009
J. Org. Chem. 2009, 74, 7183–7186 7183
2009 American Chemical Society

Samanta et al.
JOCNote
Considering the excellent success obtained in diastereoselec-
tive allylation, we sought to develop an intramolecular
variation of the reaction. Chromanes and related com-
pounds have attracted interest due to their occurrence in
many biological compounds. Vitamin E components,17 cro-
makalim,18 and chromane antibiotics,19 to name a few, are
examples of chromanes with desirable biological properties.
We envisioned that an allylic bromide tethered hydrazone
would provide the framework for entry into the core
chromane structure.
TABLE 1. Effect of Additives on the Cyclization of 1aa
entry
additive (equiv)
none
aq HCl (6)
H3PO4 (6)
CH3SO3H (6)
In(OTf)3 (1.3)
InBr3 (1.3)
TFA (6)
BOC-L-Pro-OH (1.3)
BOC-L-Phe-OH (1.3)
BOC-Gly-OH (1.0)
BOC-Gly-OH (1.5)
BOC-Gly-OH (2)
BOC-Gly-OH (6)
time (h)
yieldb (%)
drc
Many indium-mediated allylation reactions are found to
be optimal with at least 50% excess allyl halide (halide/In
3:2). Thus the extension of this reaction to an intramolecular
cyclization is not necessarily straightforward as it is inher-
ently restricted to 1 equiv of the allyl halide. Protic acid
additives have been shown to improve such reactions.20
Thus, our initial studies scrutinized the influence of different
Lewis acid and protic acid additives on the outcome of the
cyclization. To investigate the intramolecular indium-
mediated allylation reaction, we first examined the cycliza-
tion of 1a which was easily prepared from the condensation
of the corresponding aldehyde with chiral hydrazine fol-
lowed by reaction with 1,4-dibromo-2-butene.21 The results
of our initial screen are summarized in Table 1. Treating 1a
with 2 equiv of indium metal in THF at room temperature
was completely ineffective, and the starting material was
recovered intact (entry 1). Similarly, in the presence of protic
acids HCl, H3PO4, and methanesulfonic acid no reaction
ensued (entries 2-4). As we have previously shown,16
indium(III) Lewis acids are effective in promoting the inter-
molecular allylation of hydrazones, and the addition of
In(OTf)3 and InBr3 was tested as well (entries 5 and 6). To
our disappointment, these reactions also failed affording
only trace amounts of 2a. Furthermore, a mixture of at least
three stereoisomers was produced with poor selectivity.
However, when 6 equiv of trifluoroacetic acid was added
the reaction proceeded with good efficiency to produce 2a as
a single isomer. The stereochemistry of the product was
confirmed by the X-ray crystal structure of the N-trifluor-
acetate derivative 3 (see the Supporting Information). The
cis-stereochemistry was also observed in an analogous
racemic cyclization.20
1
2
3
4
5
6
7
8
9
10
11
12
13
10
10
10
10
48
48
10
12
12
12
12
12
12
0
0
0
0
<5
<5
68
10
20
60
65
72
65
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
aSee the Experimental Section for details. bIsolated yield.
cDiastereomer ratio of the major isomer 2a shown vs three
other possible isomers. Determined by 1H NMR.
selectivity of the reaction was observed. We were pleased to
discover that the simple glycine derivative was more effective
and provided the highest observed yields (entires 10-13).
Optimal reaction was obtained with 2 equiv each of BOC-
Gly-OH and indium metal affording a 72% isolated yield of
2a (entry 12). We have determined that both proton and
carboxylate are required for the best reaction results as both
simple protic acids (vide supra) as well as carboxylate salts
(not shown) were ineffective. This may suggest that the
carboxylate bridges between the hydrazone and the allylic
indium species that would be formed upon reduction of the
allyl bromide. However, this is only supposition, and no
further evidence has yet been obtained to conclude the role of
acid. No reaction was observed in the absence of reducing
In(0) metal.
Under the established optimal reaction conditions, a
variety of chiral hydrazones were efficiently converted into
the corresponding cyclized products (Table 2). Substitution
on the ring was well tolerated. Substrate 1d, having an
electron-donating group para to the allyl ether moiety and
meta to the hydrazone, resulted in the highest yield (91%,
entry 3). On the other hand, placing an electron-donating
group meta to the allyl ether moiety and para to the
hydrazone resulted in lower yield (68%, entry 4). In general,
all reactions proceeded with good to excellent yield and
complete stereocontrol to give the cis products. Although
the cyclization of aliphatic hydrazones was not attempted on
the basis of analogous intermolecular allylation reactions it
should be feasible.16
The observation that carboxylic acid had a pronounced
effect on the cyclization of 1a led us to investigate other
carboxylic acids as additives. As shown in Table 1, the
addition of BOC-protected amino acids demonstrated a
similar enhancement of reactivity and selectivity shown by
TFA. The chiral amino acid derivatives of L-proline and
L-phenylalanine provided complete control of the stereo-
selectivity; however, the yields were low (entries 8 and 9). No
influence of the stereochemistry of the amino acid on the
(17) (a) Couladouros, E. A.; Moutsos, V. I.; Lampropoulou, M.; Little,
J. L.; Hyatt, J. A. J. Org. Chem. 2007, 72, 6735. (b) Trost, B. M.; Shen, H. C.;
Surivet, J. P. Angew. Chem., Int. Ed. 2003, 42, 3943. (c) Tietze, L. F.; Sommer,
K. M.; Zinngrebe, J.; Stecker, F. Angew. Chem., Int. Ed. 2004, 43, 2.
(18) Rovnyak, G. C.; Ahmed, S. Z.; Ding, C. Z.; Dzwonczyk, S.; Ferrara,
F. N.; Humphreys, W. G.; Grover, G. J.; Santafianos, D.; Atwal, K. S.;
Baird, A. J.; McLaughlin, L. G.; Normandin, D. E.; Sleph, P. G.; Traeger, S.
C. J. Med. Chem. 1997, 40, 24.
(19) (a) Zhao, Q.; Han, F.; Romero, D. L. J. Org. Chem. 2002, 67, 3317.
(b) Broggini, G.; Folcio, F.; Sardone, N.; Sonzogni, M.; Zeechi, G. Tetra-
hedron: Asymmetry 1996, 7, 797.
(20) Kang, H.-Y.; Yu, Y.-K. Bull. Korean Chem. Soc. 2004, 25, 1627.
(21) See the Supporting Information.
The role of TFA in both promoting the reaction and
controlling the stereochemical outcome is unknown but
may involve multiple roles in templating and activating the
transition state. Group 13 metal halides are well-known to
form bridged dimers which would likely be unable to cyclize
in the intramolecular allylation. The carboxylic acid may help
in breaking up aggregated organometallic intermediates.
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Samanta et al.
JOCNote
TABLE 2. Indium/Carboxylic Acid-Mediated Cyclization of Chiral
Hydrazonesa
FIGURE 1. Possible transition state for the carboxylic acid pro-
moted In-mediated allylation.
SCHEME 1. Synthetic Route to Intermediate 5
of the trifluoracetate provided amino alcohol 5 with good
efficiency. Compound 5 was previously prepared by a ni-
trone cycladdition approach with poor stereoselectivity.
Spectroscopic data was identical to that reported in the
literature.
In conclusion, we have developed the first asymmetric
indium-mediated intramolecular cyclization of hydrazones.
This method proceeded with good chemical yield and ex-
cellent stereocontrol in the presence of simple carboxylic
acids. The stereochemistry of the product was established by
X-ray crystallography analysis. We have applied this method
to the synthesis of the key intermediate of a chromane
antibiotic via core structure 4. It should be pointed out that
4 possesses latent functionality in the olefin that could be
utilized for further manipulation. Thus, a variety of
subsequent modifications could be envisioned to generate a
diverse library of compounds with potential biological ap-
plications.
aSee the Experimental Section for details. bIsolated yield.
As illustrated in Figure 1, a chair transition state involving the
allylic indium and imine moieties would afford the cis-amino-
chromane product. The acid may aid in activating the reaction
through hydrogen bonding to the oxazolidinone carbonyl
while simultaneously enhancing the nucleophilicity of the
allylindium by donation from the acid carbonyl to the indium
metal.
To demonstrate the synthetic utility of this stereoselective
intramolecular cyclization methodology, 2b was elaborated
into a key intermediate (5, Scheme 1) for the synthesis of a
chromane antibiotic (6) discovered by Pharmacia to have
shown modest activity against S. aureus. Reductive cleavage
of the hydrazine was accomplished by acylating with tri-
fluoroacetic anhydride followed by treatment with SmI2 to
give 4 in good yield. Ozonolysis of the olefin and hydrolysis
Experimental Section
Cyclization of Hydrazone 1a To Afford 2a. To an oven-dried
Schlenk flask under argon were added indium powder (133.2
mg, 1.16 mmol), hydrazone 1a (250 mg, 0.58 mmol), and dry
THF (10.0 mL). BOC-Gly-OH (235.7 mg, 1.16 mmol) was
added, and the reaction mixture was stirred for 12 h at room
temperature. The mixture was concentrated and purified by
flash chromatography eluting initially with 20% ethyl acetate in
hexanes and then 80% dichloromethane in hexanes. Compound
2a was obtained in 72% yield: 147.2 mg (0.42 mmol); mp
108-110 °C; [R]20D=-97.6 (c=0.3 in THF); IR (film) 1747,
2962 cm-1; 1H NMR (CDCl3, 400 MHz) δ=8.03 (d, J=8.4 Hz,
1H), 7.72-7.68 (m, 2H), 7.49-7.45 (m, 1H), 7.31-7.27 (m, 1H),
7.05 (d, J=8.8 Hz, 1H), 6.05-5.96 (m, 1H), 5.41-5.35 (m, 2H),
5.21 (d, J=2.8 Hz, 1H), 4.70 (d, J=10.0 Hz, 1H), 4.67 (d, J=10.0 Hz,
J. Org. Chem. Vol. 74, No. 18, 2009 7185

Samanta et al.
JOCNote
1H), 4.31-4.27 (m, 1H), 3.60-3.57 (m, 1H), 3.11-3.07 (m, 1H),
2.93-2.87 (m, 1H), 2.15-2.11 (m, 1H), 1.87-1.81 (m, 1H), 0.65
(d, J = 6.8 Hz, 3H), 0.56 (d, J=7.2, 3H); 13C NMR (100 MHz,
CDCl3) δ=158.5, 152.6, 134.0, 133.9, 130.0, 128.7, 128.5, 126.9,
123.4, 121.7, 119.0, 118.8, 113.0, 63.8, 63.2, 61.2, 49.1, 38.7, 27.8,
17.4, 15.8; HRMS calcd for C21H24N2O3 (M þ Na)þ 375.1685,
found 375.1684.
(m, 1H), 5.79 (dd, J = 8, 4 Hz, 1H), 5.30 (d, J = 4 Hz, 1H), 5.21
(d, J = 15 Hz, 1H), 4.41 (ddd, J = 15, 4, 1.6 Hz, 1H), 4.01 (t, J =
12 Hz, 1H), 3.10-3.04 (m, 1H); 13C NMR (100 MHz) δ = 156.9
(d, JCF = 40 Hz), 152.9, 132.7, 132.0, 131.0, 129.0, 128.5, 127.8,
120.1 (d, JCF = 144 Hz), 120.1, 110.8, 76.6, 64.0, 43.7, 40.4;
HRMS calcd for C17H14F3NO2 (M þ Na)þ 344.0874, found
344.0876.
Preparation of 2,2,2-Trifluoro-N-(2,3-dihydro-2-vinyl-1H-
benzo[ f ]chromen-1-yl)acetamide (4). To a solution of ent-3 (100
mg, 0.22 mmol) in MeOH under argon was added a solution of
SmI2 (20 mL, 0.1 M in THF), and the reaction mixture was
stirred for 45 min. The solution was opened to air and stirred for
an additional 5 min. Concentration followed by flash chroma-
tography (10:1 hexanes/ethyl acetate) gave 4 (63 mg, 90%) as a
white solid: mp 166-168 °C; [R]20D=-222.8 (c=0.35 in THF);
Acknowledgment. We are grateful to the National Science
Foundation (NSF-CHM-0616485) and the NDSU NIH
Center for Protease Research (NCRR-P20-RR15566) for
financial support of this project.
Supporting Information Available: Experimental proce-
dures, characterization data, and 1H and 13C NMR spectra
for all new compounds. Crystallographic data for 3a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
IR (film) 1693 cm-1; H NMR (400 MHz) δ=7.77-7.72 (m,
2H), 7.65 (dd, J=8, 0.8 Hz, 1H), 7.52-7.48 (m, 1H), 7.39-7.35
(m, 1H), 7.05 (d, J=8 Hz, 1H), 6.33 (d, J=4 Hz, 1H), 5.93-5.85
7186 J. Org. Chem. Vol. 74, No. 18, 2009