Regioselective allene synthesis and propargylations with propargyl diethanolamine boronates

Article abstract of DOI:10.1021/ol9022529

"Chemical Equation Presented" The utility of propargyl diethanolamine boronates as reagents for the preparation of allenes and homopropargylic alcohols is presented. Protonolysis with TFA and electrophilic substitution with N-halosuccinimides proceeded wi

Full text of DOI:10.1021/ol9022529

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5458-5461
Regioselective Allene Synthesis and
Propargylations with Propargyl
Diethanolamine Boronates
Daniel R. Fandrick,* Jonathan T. Reeves, Zhulin Tan, Heewon Lee, Jinhua
J. Song, Nathan K. Yee, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc.,
900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368
daniel.fandrick@boehringer-ingelheim.com
Received September 29, 2009
ABSTRACT
The utility of propargyl diethanolamine boronates as reagents for the preparation of allenes and homopropargylic alcohols is presented.
Protonolysis with TFA and electrophilic substitution with N-halosuccinimides proceeded with inversion to provide the corresponding allene
in high yield and regioselectivity. Alternatively, the propargylation of aldehydes was achieved with use of the in situ generated lithiated
complex.
Organoboronic acids and their derivatives are valuable
synthetic building blocks.1 Typically, the utility of these
reagents is achieved through a Lewis base interaction with
a Lewis acidic boron atom. Such reactivity is exemplified
through boron-based transmetalations,2 Petasis reactions,3
Matteson homologation,4 and the closed six-membered
transition states proposed for allenylations, allylations, and
propargylations.5 However, organoboronic acids pose dif-
ficulties in characterization due mainly to the ease with which
they dehydrate and oligomerize.2b While boronic esters are
more stable toward oligomerization, they are still susceptible
to hydrolysis and oxidation upon prolonged exposure to air.
Derivatization of organo-boronic acids or esters to the
crystalline trifluoroborate salts,2b,6 diethanolamine based7,8
or N-methyl-iminodiacetic acid (MIDA)8 complexes dramati-
cally facilitates the isolation of the organoboron compounds
(1) Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, Germany, 2005.
(2) For examples see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457–2483. (b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40,
275–286. (c) Jimeno, C.; Sayalero, S.; Fjermestad, T.; Colet, G.; Maseras,
F.; Pericas, M. A. Angew. Chem., Int. Ed. 2008, 47, 1098–1101. (d) Saito,
B.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 9602–9603. (e) Guan, B.-T.;
Wang, Y.; Li, B.-J.; Yu, D.-G.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130,
14468–14470. (f) Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.; Kurihara, H.;
Dreher, S. D.; Weissman, S. A.; Stauffer, S. R.; Burgey, C. S. Org. Lett.
2009, 11, 345–347.
(5) For examples see: (a) Wang, K. K.; Liu, C. J. Org. Chem. 1985, 50,
2578–2580. (b) Ikeda, N.; Arai, I.; Yamamoto, H. J. Am. Chem. Soc. 1986,
108, 483–486. (c) Li, Y.; Houk, K. N. J. Am. Chem. Soc. 1989, 111, 1236–
1240. (d) Hernandez, E.; Burgos, C. H.; Alicea, E.; Soderquist, J. A. Org.
Lett. 2006, 8, 4089–4091. (e) Paton, R. S.; Goodman, J. M.; Pellegrinet,
S. C. Org. Lett. 2009, 11, 37–40.
(3) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583–
586. (b) Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922–6923.
(4) For examples see: (a) Matteson, D. S.; Majumdar, D. J. Am. Chem.
Soc. 1980, 102, 7588–7590. (b) Matteson, D. S.; Ray, R. J. Am. Chem.
Soc. 1980, 102, 7590–7591. (c) Brown, H. C.; Jayaraman, S. J. Org. Chem.
1993, 58, 6791–6794. (d) Brown, H. C.; Roy, C. D.; Soundararajan, R.
Tetrahedron Lett. 1997, 38, 765–768. (e) Fang, G. Y.; Wallner, O. A.;
Blasio, N. D.; Ginesta, X.; Harvey, J. N.; Aggarwal, V. K. J. Am. Chem.
Soc. 2007, 129, 14632–14639. (f) Vedrenne, E.; Wallner, O. A.; Vitale,
M.; Schmidt, F.; Aggarwal, V. K. Org. Lett. 2009, 11, 165–168. (g) Berree,
F.; Gernigon, N.; Hercouet, A.; Lin, C. H.; Carboni, B. Eur. J. Org. Chem.
2009, 329–333.
(6) For a review see: Darses, S.; Genet, J.-P. Chem. ReV. 2008, 108,
288–325
.
(7) Brown, H. C.; Prasad, J. V. N. V. J. Org. Chem. 1986, 51, 4526–
4530, and references cited therein
.
(8) (a) Mancilla, T.; Carrillo, L.; Reducindo, M. de la P. Polyhedron
1996, 15, 3777–3785, and references cited therein. (b) Gillis, E. P.; Burke,
M. D. J. Am. Chem. Soc. 2007, 129, 6716–6717. (c) Lee, S. J.; Gray, K. C.;
Paek, J. S.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466–468. (d) Gillis,
E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084–14085. (e)
Contreras, R.; Garcia, C.; Mancilla, T. J. Organomet. Chem. 1983, 246,
213–217
.
10.1021/ol9022529 CCC: $40.75
Published on Web 10/30/2009
 2009 American Chemical Society

Scheme 1
.
Precedent Regioselective Alkylation with Propargyl
Boronates (ref 10)
Scheme 2. Preparation of DEA Boronate 4
in chloroform afforded only partial conversion to the
trimethylsilyl allene and propyne in low yield (entries 1-3).
Alternatively, protonolysis of DEA propargyl boronate 5 with
a strong anhydrous acid such as TFA afforded the allenyl
product 15 in 90% yield and >40:1 regioselectivity (entry
9). The protonolysis with a strong aqueous acid afforded a
lower yield and poor regioselectivity (entry 6). This contrast
can be rationalized by a competitive hydrolysis under
aqueous conditions and subsequent nonselective protonolysis
of the resulting boronic acid.
and increases the stability of these reagents to air, moisture,
and numerous reaction conditions. X-ray analysis of the
N-methyldiethanolamine and MIDA organo-boronates dem-
onstrated bonding between the boron and nitrogen atoms.8
According to Gutmann’s rules,9 the boron “ate” character
of the diethanolamine derivatives should enhance the nu-
cleophilicity of the organic component. For example, pro-
pargyl boron “ate” complexes are reasonably nucleophilic,
and the regioselective alkylation with allyl bromides and
addition to carbonyl species for the generation of allenes have
been demonstrated (Scheme 1).10 Although the diethanola-
mine-type derivatives have shown utility for Suzuki-Miyaura
couplings,11 hydrolysis, and transesterifications,12 limited
extension to directly reacting the activated organic function-
ality with electrophiles has been reported.13 Herein we report
the regioselective electrophilic substitution of propargyl
diethanolamine (DEA) boronates for the preparation of
allenes and propargylation of aldehydes with use of the
lithiated reagent.
Table 1. Conditions Examined for the Protodeborolation of
Propargyl Boronates
regioselectivity
c
entry substrate
conditionsa
6:7b
yield,
%
1
2e
3
4
5
6
7
8
9
4
EtOH (1 equiv) 18 h
EtOH (3 equiv) 18 h
TFA (1 equiv) 18 h
EtOH (1 equiv) 18 h
H2Og 18 h
1.0:1.1
1:1.3
<1:40
1.0:1.0
1:7.9
1:1.5
1:3.5
>40:1
>40:1
>40:1
6d
30
23f
5
83
69
69
73
90
65
Reaction of propargyl borolane 414 with diethanolamine
in MTBE afforded the DEA boronate 5, which directly
crystallized from the reaction mixture (Scheme 2). The DEA
propargyl boronate 5 can be stored at ambient temperature
for months without detectable degradation. Our initial interest
in the DEA derivative was as an intermediate to facilitate
transesterification.12 However, under numerous acidic condi-
tions, the major product identified was trimethylsilylallene
in surprisingly high regioselectivity.
5
HClh (1 equiv) 18 h
AcOH (1 equiv) 6 h
TFA (1 equiv) 1 h
TFA (2 equiv) 0.25 h
MsOH (1 equiv) 1 h
10
a Time until complete conversion or until 18 h. b Ratio determined
by GC and 1H NMR analysis. c Assay yield determined by GC or 1H NMR
d
with dimethyl fumarate as an internal standard. ∼80 mol % starting
material remaining. e Reaction conducted at 60 °C. f <10 mol % starting
borolane remaining. g 30 vol % H2O to CDCl3. h 3 M HCl (aq). TFA )
trifluoroacetic acid. MsOH ) methanesulfonic acid.
Conditions to effect protonolysis of both the pinacolyl and
DEA propargyl boronates were further investigated (Table
1). Treatment of propargyl borolane 4 with ethanol or TFA
After optimizing the protonolysis, examination of other
DEA propargyl boronates was initiated (Table 2). The
silylated DEA propargyl boronates underwent rapid proto-
nolysis in good to high regioselectivity with excellent yields
(entries 1-5). In general, the regioselectivity for the proto-
deborolation was sensitive to steric effects wherein the
highest selectivities were observed with the smaller alkynyl-
trialkylsilyl substituent (TMS, TES, PhMe2Si > TBS > TIPS).
The alkyl-substituted DEA propargyl boronate 12 also
reacted with TFA but required 18 h and proceeded with no
selectivity.
The propargyl DEA boronates are also reactive for halo-
deborolation. Typically, electrophilic substitution of aryl
boronic acids15 or DEA boronates13a,b with halides provides
the corresponding ipso-substituted product. Treatment of
propargyl borolane 4 with NBS at 55 °C for 15 h afforded
(9) Jenson, W. B. The Lewis Acid-Base Concepts; John Wiley & Sons:
New York, 1980; Chapter 4.
(10) Pearson, N. R.; Hahn, G.; Zweifel, G. J. Org. Chem. 1982, 47,
3364–3366.
(11) For examples see: (a) Bouillon, A.; Lancelot, J.-C.; Sopkova-de
Oliveira Santos, J.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2003,
59, 10043–10049. (b) Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett.
2004, 45, 685–687. (c) Gros, P.; Doudouh, A.; Fort, Y. Tetrahedron Lett.
2004, 45, 6239–6241. (d) Billingsley, K. L.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 4695–4698.
(12) For examples see: (a) Roush, W. R.; Ando, K.; Powers, D. B.;
Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339–
6348. (b) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem.
Soc. 1998, 120, 11943–11952. (c) Jung, M. E.; Lazarova, T. I. J. Org. Chem.
1999, 64, 2976–2977.
(13) For examples of flourinations see: (a) Diorazio, L. J.; Widdowson,
D. A.; Clough, J. M. Tetrahedron 1992, 48, 8073–8088. (b) Clough, J. M.;
Diorazio, L. J.; Widdowson, D. A. Synlett 1990, 761–762. For an example
of a cycloaddition see: (c) Davies, C. D.; Marsden, S. P.; Stokes, E. S. E.
Tetrahedron Lett. 2000, 41, 4229–4233.
(14) Hoffmann, R. W.; Brinkmann, H.; Frenking, G. Chem. Ber. 1990,
123, 2387–2394.
Org. Lett., Vol. 11, No. 23, 2009
5459

Table 2. Regioselective Protonolysis of Propargyl DEA
Boronates
Table 3. Regioselective Halogenation of Propargyl DEA
Boronates
a Major regioisomer product. b Regioselectivity determined by 1H NMR.
c Isolated yields. d The volatile oil was isolated as a solution in CDCl3 and
yield was determined by 1H NMR assay with internal standard. e Reaction
conducted for 18 h. TMS ) trimethylsilyl, TBS ) tert-butyldimethylsilyl,
TES ) triethylsilyl, TIPS ) triisopropylsilyl.
a Major regioisomer product. b Regioselectivity determined by 1H NMR.
c Isolated yields. d Reaction preformed at 55 °C for 15 h in CHCl3. NCS )
N-chlorosuccinimide, NBS ) N-bromosuccinimide. NIS ) N-iodosuccinimide.
the allenyl bromide in moderate selectivity and poor conver-
sion (Table 3). DEA boronates 5 and 11 were more reactive
toward NBS than the borolane species and furnished the
allene product in good yield. Electrophilic substitution of
DEA boronate 5 with NCS is also effective but requires 15 h
at 55 °C for complete conversion. The halo-deborolation with
NCS and NBS afforded high regioselectivities (>20:1) with
the examined DEA boronates. Interestingly, iodo-deborola-
tion of the alkyl DEA boronate 12 also proceeded in high
yield and regioselectivity under the standard conditions
contrary to the corresponding proto-deborolation. The regi-
oselectivity for the reactions with NIS proved sensitive to
steric effects with a similar trend for higher selectivities with
the smaller alkynyl substituent (RCH2 > TMS > PhMe2Si).
ceeded with nearly complete selectivity for the homoprop-
argylic product. The use of NaHMDS as a base afforded an
8:1 regioselectivity and only 20% yield. The propargylation
is general for a variety of substituted aryl aldehydes and
proceeded with moderate yields (Table 4).
Scheme 3.
Regioselective Propargylation with DEA Boronatesa
Reactions of propargyl boron species with carbonyl
compounds, in general, provide the allene product due to an
inversion mechanism through either an addition with a boron
“ate” complex10 or a Zimmerman-Traxler-type transition
state with trivalent boron reagents.5 The nucleophilic addition
of propargyl DEA boronate 5 to p-anisaldehyde proceeded
with essentially no regioselectivity (Scheme 3). The reactivity
of the DEA boronate toward aldehydes should be perturbed
by deprotonation of the heteroatom proton. N-Deprotonation
and N-alkylation of iminodiacetic acid boronates has been
demonstrated.8a After treatment of the DEA boronate 5 with
LiHMDS, the nucleophilic addition to p-anisaldehyde pro-
a Regioselectivity was determined by HPLC.
A reasonable rationalization for the regioselectivity ob-
served for the reaction of propargyl DEA boronates toward
electrophiles relates to the reactions proceeding through either
an open or closed transition state (Scheme 4). The selectivity
observed for electrophilic substitution of DEA boronates
indicates an open transition state with preference for reaction
at the alkyne functionality. Silicon substituents are known
(15) (a) Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 567–
570. (b) Thiebes, C.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett
1998, 141–142.
5460
Org. Lett., Vol. 11, No. 23, 2009

Table 4. Propargylations with DEA Boronate 5
Scheme 4. Regioselectivity Rationalization
regioselectivity for both proto- and halo-deborolation was
observed with the smaller alkynyl substituent. Interestingly,
reaction of propargyl DEA boronates toward aldehydes was
not regioselective. After deprotonation with LiHMDS, the
reaction strongly favored the homopropargylic product. A
six-membered closed transition state with a chelated lithium
cation can explain this reversal in regioselectivity. Accord-
ingly, a lower reactivity and regioselectivity was observed
with the sodium cation. The deprotonation can also lead to
a stronger B-N bond thereby perturbing the conformational
dynamics of the DEA complex8 and influencing the regi-
oselectivity by making the boron p-orbital relatively inac-
cessible. Precedented alkylations of lithiated iminodiacetic
acid boronates demonstrated preference for nucleophilic
addition at the nitrogen atom.8a However, this addition with
aldehydes is reversible, and the reaction ultimately proceeded
with C-C bond formation.
In conclusion, we demonstrated the utility of propargyl
DEA boronates as reagents for the preparation of allenes and
homopropargylic alcohols. In addition to improving the
reactivity of the propargyl functionality toward electrophiles,
the DEA boronates afforded higher regioselectivities than
the corresponding borolane species. Furthermore, the crystal-
line nature of the DEA boronates provides ease of handling
and ability for purification by recrystallization.
a Isolated yields. LiHMDS ) lithium bis(trimethylsilyl)amide.
to facilitate electrophilic substitution of alkenes and favor
reaction at the R-position.16 This effect appears to operate
for protonolysis of propargyl DEA boronates wherein reac-
tions with alkynyl-silyl substituents are both more reactive
and regioselective than that with alkyl substituents. The effect
is minimized for reactions with N-halo-succinimides, and no
difference between these substituents was observed. The
steric effect of the alkynyl substituent can hinder the
electrophilic attack at the alkynyl position and enable the
reaction at the sp3 position to compete. Therefore, higher
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
for boronates 5, 8-12 and all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) (a) Wierschke, S. G.; Chandrasekhar, J.; Jorgensen, W. L. J. Am.
Chem. Soc. 1985, 107, 1496–1500. (b) Lambert, J. B.; Wang, G. T.; Finzel,
R. B.; Teramura, D. H. J. Am. Chem. Soc. 1987, 109, 7838–7845. (c)
Fleming, I.; Dunogues, J.; Smithers, R. Org. React. (N.Y.) 1989, 37, 57–
575. (d) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599–7662.
OL9022529
Org. Lett., Vol. 11, No. 23, 2009
5461