Multicomponent mannich reactions with boron enolates derived from diazo esters and 9-BBN

Article abstract of DOI:10.1021/ol200766t

Chemical equations presented. Diazo esters, arylboranes, and carbamoyl imines undergo a 3-component Mannich condensation reaction. Catalyzed by Cu(II) salts, the reaction affords the corresponding isocyanate Mannich product: one that can be easily trapped in situ by other nucleophiles. The Mannich condensation corresponds to an α,α-disubstituted enolate addition to imines. The reaction was rendered asymmetric by using the (-)-phenylmenthol ester in good yield and selectivities.

Full text of DOI:10.1021/ol200766t

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2510–2513
Multicomponent Mannich Reactions with
Boron Enolates Derived from Diazo Esters
and 9-BBN
Yi Luan and Scott E. Schaus*
Department of Chemistry, Center for Chemical Methodology and Library Development
(CMLD-BU), Boston University, Boston, Massachusetts 02215, United States
seschaus@bu.edu
Received March 22, 2011
ABSTRACT
Diazo esters, arylboranes, and carbamoyl imines undergo a 3-component Mannich condensation reaction. Catalyzed by Cu(II) salts, the reaction
affords the corresponding isocyanate Mannich product: one that can be easily trapped in situ by other nucleophiles. The Mannich condensation
corresponds to an R,R-disubstituted enolate addition to imines. The reaction was rendered asymmetric by using the (À)-phenylmenthol ester in
good yield and selectivities.
Multicomponent condensation reactions are attractive
synthetic strategies for the rapid construction of com-
pounds.1 They are characteristically proficient due to
operational efficiency, reagent accessibility, and value of
the products generated.2 Boronates and boranes have
proven most effective as carbon donors in these reactions
most notably exemplified by the Petasis reaction.3 In 1968,
John Hooz initially described the reaction of trialkylbor-
aneswith stabilized diazocompounds toaffordR-alkylated
nitriles and carbonyl compounds.4 In expanding the exist-
ing repertoire of multicomponent condensation reactions,
we envisaged a 3-component Mannich condensation reac-
tion that exploited this reactivity utilizing a carbon donor
boraneor boronate, anR-diazoester, and animine. Similar
strategies are effective in a two-step process involving
heteroatom-hydrogen insertion of diazocompounds and
followed by carbonyl condensation reactions promoted by
rhodium.5 In contrast, we proposed that in situ formation
of an enolate equivalent using Hooz insertion chemistry6
would address the addition of R,R-disubstituted enolates
toimines. Herein we report the successful development ofa
3-component Mannich reaction employing this approach
and the unanticipated result of using carbamoyl imines in
the reaction, the isocyanate Mannich product.
We initiated our investigations by evaluating boronate
and borane carbon donors in the reaction utilizing R-diazo
esters to make enolates competent in the Mannich conden-
sation with acyl imines. Hooz demonstrated vinyloxybor-
anes were the intermediates generated from diazoacetate or
diazoacetone and trialkylboranes, then vinyloxyboranes
could be trapped by electrophiles, such as aldehydes, ke-
tones, or dimethyl(methylene)ammonium iodide.7 Similarly,
ꢀ
(1) (a) Petasis, N. A. Multicomponent Reactions; Zhu, J., Bienayme,
H., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (b) Tietze, L. F. Chem.
Rev. 1996, 96, 115. (c) Armstrong, R. M.; Combs, A. P.; Tempest, P. A.;
Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123. (d) Domling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(2) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Tietze, L. F., Brasche, G., Gericke, K. M., Eds.; Wiley-
VCH: Weinheim, Germany, 2006.
(3) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
(4) (a) Hooz, J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 5936. (b) Hooz,
J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 6891. (c) Hooz, J.; Gunn, D. M.
J. Am. Chem. Soc. 1969, 91, 6195.
(5) (a) Wang, Y.; Zhu, Y.; Chen, Z.; Mi, A.; Hu, W.; Doyle, M. P.
Org. Lett. 2003, 5, 3923. (b) Hu, W.; Xu, X.; Zhou, J.; Liu, W.; Huang,
H.; Hu, J.; Yang, L.; Gong, L. J. Am. Chem. Soc. 2008, 130, 7782.
(6) For selected reactions using the Hooz insertion chemistry, see: (a)
ꢀ
ꢀ
Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Nat. Chem.
2009, 1, 494. (b) Peng, C.; Zhang, W.; Yan, G.; Wang, J. Org. Lett. 2009,
11, 1667.
(7) (a) Hooz, J.; Bridson, J. N. J. Am. Chem. Soc. 1973, 95, 602. (b)
Hooz, J.; Oudenes, J.; Roberts, J. L.; Benderly, A. J. Org. Chem. 1987,
52, 1347.
r
10.1021/ol200766t
Published on Web 04/07/2011
2011 American Chemical Society

Mukaiyama employed this approach for the in situ forma-
tion of boron enolates in the aldol reaction of benzaldehyde.8
The reaction of boronates and boroxines (1aÀe) resulted in
low conversion to the desired Mannich product although
complete consumption of phenyl diazoester 2 and imine 3a
occurred. The relatively low production of 4 was attributed
to competing reaction pathways that result in decomposition
of the imine or incomplete consumption of the diazoester
(Table 1). The relative rate of boron enolate formation
appeared to be slow with use of boronate carbon donors,
with electron deficient boronate donors showing only mar-
ginal improvement in yield (Table 1, entries 2 and 4).
of the literature illustrates that chlorocatecholborane is
capable of converting carbamates to the corresponding
isocyanate under basic conditions.9 The same pathway
appeared to be occurring under the Cu(I)-promoted reaction
conditions. Further experimentation revealed Cu(OTf)2 to
be the best catalyst, affording the isocyanate 5 in 76%
isolated yield (Table 1, entry 9) with CH2Cl2 being the ideal
solvent. The optimized reaction conditions utilized 5 mol %
Cu(OTf)2, 1.1 equiv of phenyl diazo ester, and 1.2 equiv of
imine relative to phenyl-9-BBN in CH2Cl2.
In situ formation of the isocyanate afforded the oppor-
tunity to yield any carbamate from the Mannich reaction.
Benzyl alcohol, allyl alcohol, and 9-fluorenemethanol were
effectively employed to generate the Cbz, Alloc, or Fmoc
protected amines 6a, 6b, and 6c, respectively, in good yields
(Table 2, entries 1À3). The scope of the reaction proved to
Table 1. Boron Enolate Mannich Reactionsa
Table 2. Four Component Boron Enolate Mannich Reactionsa
entry
R1
R2
Bn
product
yield [%]b
1
2
3c
Ph
Ph
Ph
6a
6b
6c
6d
6e
6f
75
72
70
71
71
75
71
80
62
79
61
Allyl
Fm
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
4
(E)-PhCHdCH
4-BrC6H4
5d
6
yield of yield of
entry boron
catalyst
solvent
4 [%]b
5 [%]b
3-FC6H4
7d
8e
3-BrC6H4
6g
6h
6i
1
2
1a
1b
1c
1d
1e
1f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
10
<5
0
3-CH3OC6H4
3,4-(OCH2O)C6H3
4-CH3C6H4
2-naphthyl
9e
3
10d
11c,d
6j
4
6k
5
5
a Reactions were run with 1.0 mmol of B-Ph-9-BBN 1f, 1.1 mmol of
phenyl diazo ester 2, 1.2 mmol of imine 3, 5 mol % Cu(OTf)2, in CH2Cl2
for 12 h under Ar, quenched with 5 equiv of alcohol and Et3N; mixed for
an additional 5 h, followed by flash chromatography on silica gel.
b Isolated yield of 6. c 2 equiv of benzyl alcohol and reflux for 1 h after
Et3N treatment. d 5 mol % more Cu(OTf)2 added with imine and 10%
DMF as the cosolvent. e 5 mol % more Cu(OTf)2 added with imine.
6
22
12
13
<5
13
6
<5
37
55
76
44
20
7
1f
Cu(NCCH3)4PF6 CH2Cl2
8
1f
CuOTf
CH2Cl2
CH2Cl2
PhCH3
THF
9
1f
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
10
11
1f
1f
a Reactions were run with 1.0 mmol of boronate 1, 1.0 mmol of diazo
ester 2, 1.0 mmol of acyl imine 3a, in CH2Cl2 (0.2 M) for 12 h under Ar,
followed by flash chromatography on silica gel. b Isolated yield.
be general for both electron-rich and electron-deficient
acyliminesutilizingbenzyl alcoholtoyield the correspond-
ing Cbz carbamate (Table 2, entries 4À11). The cinnamal-
dehyde-derived imine afforded the 1,2-addition product
selectively in 71% isolated yield (Table 2, entry 4). Electron-
deficient aromatic imines gave good yields, at room tem-
perature (Table 2, entries 5À7). However, electron-rich
aromatic imines underwent the condensation reaction in
moderate to good yields, requiring 10 mol % Cu(II) to
facilitate the reaction (Table 2, entries 8À10), as did the
2-naphthyl imine (entry 11).
However, the use of Ph-9-BBN 1f (B-phenyl-9-borabicyclo-
[3.3.1]nonane) gave the most appreciable yield of the Man-
nich adduct. We postulated that the use of a Cu catalyst may
promote the decomposition of the diazoester and the sub-
sequent Mannich reaction. Indeed, the use of 5 mol %
Cu(NCCH3)4PF6 afforded the Mannich product 4 but also
gave rise to an unanticipated product, isocyanate 5. A survey
(8) Mukaiyama, T.; Inomata, K.; Muraki, M. J. Am. Chem. Soc.
1973, 95, 967.
(9) (a) Valli, V. L. K.; Alper, H. J. Org. Chem. 1995, 60, 257. (b)
Butler, D. C. D.; Alper, H. Chem. Commun. 1998, 2575.
The nature of the borabicyclononane carbon donor was
also evaluated in the reaction. Both electron-donating and
electron-withdrawing B-aryl-9-BBNs were suitably reactive
Org. Lett., Vol. 13, No. 9, 2011
2511

and provided diastereoselectivies of 1:3 and 1:1.3, respec-
tively (Table 3, entries 1 and 2). Both electron-donating and
We next sought to develop an asymmetric Mannich
reaction using chiral phenyldiazoacetate esters (Table 4).
The commercially available (À)-phenylmenthol proved
to be the most effective chiral auxiliary among those
investigated including (À)-trans-2-phenyl-1-cyclohexanol,
Table 3. Diastereoselective Boron Enolate Mannich Reactionsa
Table 4. Chiral Boron Enolate Mannich Reactionsa
entry
Ar
R1
product yield [%]b
dr
1
4-CH3OC6H4 Ph
9a
9b
71
76
75
81
<5
1:3
2
4-FC6H4
Ph
Ph
1:1.3
1:1
3c
4
4-CH3OC6H4 9c
Ph
4-FC6H4
H
9d
9e
1:1
5
Ph
a Reactions were run with 1.0 mmol of B-Ar-9-BBN 7, 1.1 mmol of
phenyl diazo ester 8, 1.2 mmol of imine 3a, 5 mol % of Cu(OTf)2, in
CH2Cl2 for 12 h under Ar, quenched with 5 equiv of alcohol and Et3N
and stirring for another 5 h, followed by flash chromatography on silica
gel. b Isolated yield. c 0.25 mol % of Cu(OTf)2 was used in the reaction.
electron-withdrawing aryl diazoacetates provided similar
yield, but lower diastereoselectivity (entries 3 and 4). Ethyl
diazoacetate failed to provide the desired product under the
current reaction conditions due to the undesired migration
of the borabicyclononane ring (Table 3, entry 5).10 How-
ever, the Mannich condensation reaction could be run
with 2-alkyl-diazo esters. Ethyl 2-diazopropanoate 10, with
Ph-9-BBN 1f and acyl imine 3a, provided the syn β-amino
ester product 11 in 73% yield and 3:1 diastereoselectivity.
The use of ethyl 2-diazopropanoate allowed us to isolate
the corresponding silyl ketene acetal using N-trimethyl-
silylimidazole11 13 (Scheme 1). Upon isolation, a single
a Reactions were run with 1.0 mmol of B-Ph-9-BBN 1f, 1.0 mmol of
phenyl diazo ester 14, 1.0 mmol of imine 3a, 5 mol % Cu(OTf)2, in
CH2Cl2 for 12 h under Ar, quenched with 5 equiv of methanol and Et3N
and stirring for another 5 h, followed by flash chromatography on silica
gel. b Isolated yield. c 1.0 mmol of 1f, 1.1 mmol of 14, and 1.2 mmol of 3a
were used, reaction was run for 24 h under À20 °C.
(À)-menthol, and (À)-borneol: affording the S-configura-
tion at the new chiral center in 6:1 dr and 85% yield
(Table 4, entries 1À5). Running this reaction at less than
À20 °C for 24 h yielded the β-amino ester in 10:1 dr and
89% yield. The isocyanate precursor 16 can be isolated in
crystalline form directly from the reaction in similar dr and
yield (10:1 dr and 87% yield). The diastereomer purity
could be further improved by recrystallization (up to 30:1
dr and 76% overall yield from the reaction). The absolute
configuration was determined by X-ray crystallographic
analysis of 16 (Figure 1).
Scheme 1. Boron Enolate Mannich Reaction of Ethyl 2-Dia-
zopropanoate and Enolate Geomtery of Insertion
We propose a mechanism for the borane insertion
similar to one originally proposed by Hooz13 and
(10) For examples of undesired migration of B-phenyl-9-BBN ring,
see: (a) Hooz, J.; Gunn, D. M. Tetrahedron Lett. 1969, 40, 3455. (b)
Fang, G. Y.; Wallner, O. A.; Di Blasio, N.; Ginesta, X.; Harvey, J. N.;
Aggarwal, V. K. J. Am. Chem. Soc. 2007, 129, 14632.
(11) Hooz, J.; Oudenes, J. Tetrahedron Lett. 1983, 24, 5695.
(12) (a) Suginome, M.; Uehlin, L.; Yamamoto, A.; Murakami, M.
Org. Lett. 2004, 6, 1167. (b) Hagiwara, H.; Iijima, D.; Awen, B. Z. S.;
Hoshi, T.; Suzukic, T. Synlett 2008, 10, 1520.
(13) Hooz, J.; Oudenes, J.; Roberts, J. L.; Benderly, A. J. Org. Chem.
1987, 52, 1347.
(14) Canales, E.; Prasad, K. G.; Soderquist, J. A. J. Am. Chem. Soc.
2005, 127, 11572.
enolate geometry was observed and determined to be the
E-silyl ketene acetal. Despite the high selectivity in the
formation of the enolate, the moderate selectivity in the
ensuing Mannich reaction indicates multiple pathways in
the imine addition reaction may be possible under Lewis
acid-promoted conditions.12
2512
Org. Lett., Vol. 13, No. 9, 2011

Scheme 2. Proposed Mechanism for One-Pot Isocyanate For-
mation
Figure 1. (S)-(À)-Phenylmenthyl 3-isocyanato-2,2,3-triphenyl
propanoate 16.
an R,R-disubstituted enolate addition to imines. The reac-
tion was rendered asymmetric by using the (À)-phenyl-
menthol ester in good yield and selectivities. Ongoing
studies include expansion of the scope and utility of the
reaction.
Soderquist14 (Scheme 2). Enolate carbon attack of the diazo
ester on the boron p-orbital followed by Ar-group migra-
tion with concomitant N2 displacement affords the boron
enolate. The ensuing Mannich condensation with the imine
yields the borated carbamate. Subsequent elimination of
B-CH3O-9-BBN results in isocyante formation.
Acknowledgment. This research was supported by the
NIH (R01 GM078240).
In summary, we have developed a 3-component con-
densation reaction using diazo esters, arylboranes, and
carbamoyl imines. The reaction is catalyzed by Cu(II) salts
and affords the corresponding isocyanate Mannich pro-
duct: an intermediate that can be easily trapped in situ by
other nucleophiles. The overall Mannich condensation is
Supporting Information Available. Synthetic proce-
dures, CIF file of compound 16, together with character-
ization and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 9, 2011
2513